Online newspaper of professor Yasser Metwally

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

November 30, 2009 — Cryptococcus, aptly termed the “sugar-coated killer” [6] because of its thick polysaccaride capsule (Fig. 1A) and “once-sleeping giant” [7] because of its indolent nature, is a leading cause of fungal meningitis worldwide among those with HIV. [8] The organism is harbored in soil and bird excreta. Cryptococcosis primarily affects the immunosuppressed and infrequently invades immunocompetent patients. Infection remains difficult to diagnose and treat despite the enormous scientific advances made in understanding this encapsulated yeast. Only recently has the genome of C neoformans been sequenced, the cryptococcal taxonomy reorganized, and virulence factors genetically analyzed. [5, 9, 10] The current challenge is to develop pharmacologic interventions that target specific mediators of cryptococcal virulence and to systematize delivery of medical therapy to vulnerable populations.

Figure 1. Characteristic findings of cryptococcal CNS infection. (A) Brain biopsy (hematoxylin and eosin, ×400) shows multiple Cryptococci (black arrow) and inflammatory cells. The clear, mucoid appearance of the thick capsule (red arrow) results in a halo around the organism. (Courtesy of Dr Gretchen Johns, Mayo Clinic.) (B) MRI reveals dilated ventricles from communicating hydrocephalus in a patient with cryptococcal meningitis. (C) Multiple small gelatinous pseudocysts are evident in the basal ganglia. (Click to enlarge figure)

Cryptococcus as a human pathogen was first clearly described by physicians Otto Busse and Abraham Buschke in 1894 and recognized as a cause of meningitis in the early 1900s. [11] The upward spike in prevalence that occurred in the 1980s with the HIV pandemic has been diminished by combination antiretroviral therapy in developed countries. Lately, cryptococcal infection has re-emerged because of the immune reconstitution inflammatory syndrome in the HIV population and an increase in solid organ transplant recipients. [4] In contrast, cryptococcosis remains an infection of elevated disproportion in developing countries.

Current taxonomic schemes are medically relevant because they differentiate two disease-causing species, four serotypes, and hybrid serotypes. These are C neoformans (serotypes A, D, and AD) and C gattii (serotypes B and C). [12] Hybrids AD and BC and BD are human pathogens. Serotypes A and D and AD are responsible for 98% of all cryptococcal infections. [1] C gattii, pathogenic in immunocompetent hosts, was found mostly in tropical and subtropical regions before an epidemic on Vancouver Island, Canada, in 1999. A hybrid of C neoformans and C gattii has been proposed as a candidate for a worldwide “superpathogen” with potential to infect immunocompetent individuals. [13]

Before 1981, the total number of cases of C neoformans in the United States was between 500 and 1000 cases annually. [11] Recent data show a staggering estimation of 957,900 yearly cases of cryptococcal meningitis in HIV-affected patients worldwide and an associated 624,725 deaths. In 2006, sub-Saharan Africa had the highest number of estimated cases at 720,000 yearly with associated deaths estimated at 500,000. The comparable annual figures for North America are 7800 cases with 700 deaths. [8]

The lungs serve as the primary site of infection, but most symptomatic infections are in the CNS, chiefly as meningitis. CNS disease usually occurs in isolation and infrequently presents with pneumonia or focal skin lesions. [14] Chronic granulomas or cryptococcomas occur in the parenchyma and occasionally in the choroid plexus and ventricles. Deep cerebral infarcts affecting the basal ganglia and thalamus are caused by an arteritis of small penetrating arteries.[2]

Headache, often mild, is the most common symptom and progresses slowly over days, weeks, or months. [15] Other symptoms of subacute meningoencephalitis, such as lethargy, confusion, and personality changes, arise. Fever is less common. [1] Occasionally, psychiatric symptoms or a subacute dementia is the only clinical finding. Hydrocephalus caused by elevated intracranial pressure occurs in two thirds of patients and is an important complication to recognize (Fig. 1B). Fungal infection and inflammation obstructs CSF outflow in the arachnoid villi and subarachnoid spaces, and requires urgent relief. [16] Nuchal rigidity and cranial neuropathies are more common in Africa among those with meningoencephalitis. [42] Immunocompetent patients tend to have localized, slowly progressive disease compared with those who are immunosuppressed. [1, 2, 15]

Figure 2. AIDS patient with cryptococcal meningitis. A, Gadolinium-enhanced coronal Tl -weighted (500/14) MR image shows leptomeningeal enhancement along the cerebral sulci bilaterally. B, Gadolinium-enhanced axial Tl -weighted (500/20) MR image shows areas of enhancement along the perivascular (Virchow-Robin) spaces in the basal ganglia bilaterally, characteristic of this infection.

• Neuroimaging in CNS Cryptococcosis (Click for more details)

Radiologic findings include meningeal enhancement, abscesses, and cryptococcomas in intraparenchymal, intraventricular, or perivascular spaces. Clusters of pseudocysts in the basal ganglia and thalami strongly suggest cryptococcal infections (Fig. 1C). These cysts are composites of yeasts with little surrounding edema and are well-circumscribed, round-to-oval lesions of low density on CT and have CSF intensity on MRI. [2]

	Figure 3. Postcontrast MRI T1 images showing cerebellar abscess with ring enhancement and soap-bubble pseudocysts in the region of the basal ganglia due to infiltration of the Virchow-Rubin spaces by the organisms.

Meningitis is the most common form of CNS disease caused by C. neoformans, but the organism may also cause brain abscesses and granuloma, either alone or in association with meningitis. Most frequently, these present with focal weakness or hemiparesis, papilledema, or cranial nerve signs, The pathology ranges from mild congestion to meningeal thickening and distention of the subarachnoid spaces by abundant mucoid exudate. Fungi may enter the subarachnoid spaces and accompany the perforating arteries in the Virchow- Rubin spaces, These give rise to small soap-bubble or gelatinous pseudo-cysts in the adjacent parenchyma. The T2 images show bilateral small well-defined foci of high signal intensity in the region of basal ganglia.These lesions appear hypointense to isointense on the T1 images and may not enhance after contrast injection. Dilated perivascular spaces of Virchow- Rubin are characteristic of cryptococcal infection.

• The role of Lumbar puncture in CNS Cryptococcosis

Lumbar puncture with manometry is necessary to diagnose cryptococcal meningitis after a large cerebral mass has been excluded by neuroimaging. Spinal fluid examination often reveals a mononuclear pleocytosis with a range of 20 to 200 cells/mm3 in non-HIV patients and 0 to 50 cells/mm3 in HIV cases. Typically, the protein is elevated and the glucose is decreased. India ink preparations are very worthwhile, especially in spun down, concentrated CSF specimens. [1] The thick capsule does not stain, but rather highlights the organism with a halo. [3] The organism is found in more than 50% of HIV-negative cases and 90% of patients with AIDS. Cryptococcal antigen assays in CSF specimens are positive in more than 90% of patients. Serum antigen has a high specificity in those with meningitis and HIV and is less sensitive in patients without HIV.1, [8] Lastly, the diagnosis is conclusively established by culture of organisms from the CSF, especially if large volumes of fluid are submitted. [1]

• Management of CNS Cryptococcosis (Click for more details)

The goals of therapy are CSF sterilization; reduction of intracranial pressure; prevention of serious sequelae, such as blindness and cranial nerve abnormalities; and radiographic resolution of mass lesions. Current practice guidelines for treatment of cryptococcal CNS disease recommend combination therapy using an induction with AmB plus 5-FC followed by oral fluconazole. [4, 14, 17] Recommendations for reduction of elevated intracranial pressure include percutaneous lumbar or ventricular drainage or, if persistent, by VP shunt. Lipid formulations of AmB are given if renal impairment occurs. [17, 18]

• Cryptococcal Meningitis  in AIDS patients

Cryptococcus neoformans is an encapsulated yeast found throughout the world. C. neoformans is spread through inhalation of spores, which can be found in dust and bird droppings. The initial infection is usually a self-limited pneumonitis. In most individuals the immune system clears the disease, but some of the organism remains in a latent state within granulomas, from which it can disseminate to multiple organs, particularly in immunosuppressed patients. In AIDS, the most common presentation is a subacute meningoencephalitis, usually in a patient with less than 100 CD4+ cells/mm3. Cryptococcus has an affinity for the CNS, possibly related to its consumption of catecholamines.

Common presenting symptoms of cryptococcal meningitis (CM) include malaise, headache, and fever. As the disease progresses, patients may develop seizures and signs of increased intracranial pressure (nausea, vomiting, visual loss, diplopia, coma). A diagnosis of CM can be made by visualizing the yeast in CSF using India ink; or by detecting cryptococcal antigen in the CSF using the latex agglutination test. If lumbar puncture is contraindicated, a presumptive diagnosis can be made with a serum antigen test. AIDS patients may not have a CSF cellular pleocytosis, abnormal protein, or low CSF glucose. Neuroimaging may be normal, but abnormalities such as masses (cryptococcomas), dilated perivascular spaces, or pseudocysts are associated with higher blood and CSF antigen titers.

• Management of CNS Cryptococcosis in AIDS patients (Click for more details)

Immediate treatment is essential to prevent loss of brain and loss of life, as this is a lethal disease, and even with optimal treatment the mortality rate is still 15%. The recommended initial standard treatment is amphotericin B, at a dose of 0.7–1.0 mg daily, combined with flucytosine, at a dose of 100 mg/kg daily in 4 divided doses, for at least 2 weeks for those with normal renal function. Primary treatment with fluconazole has failed. In addition to antifungal therapy and cART, it is important to manage increased intracranial pressure, as this may lead to permanent neurologic deficits, blindness, and death. The CSF can be removed by repeated lumbar puncture, or a lumbar drain or shunt may be necessary. After at least a 2-week period of successful induction therapy, defined as significant clinical improvement and a negative repeat CSF culture, amphotericin B and flucytosine may be discontinued and follow-up therapy initiated with fluconazole 400 mg daily. This regimen should continue for at least 8 weeks. Discontinuation of secondary prophylaxis can be considered in patients with sterile CSF, clinical improvement, and an increase in CD4+ cell count to at least 200 cells/mm3.

With treatment, most HIV+ individuals will survive CM. Long-term outcomes in neurocognitive functioning have only recently been examined. In an exploratory study, Levine and colleagues [22] examined neurocognitive functioning in a cohort of 15 individuals with a history of AIDS and CM, compared with 61 individuals with AIDS but without history of CNS disease. Those with a history of CM continued to demonstrate deficits in verbal fluency and motor functioning relative to HIV-infected controls without CM.

References

1. Satishchandra P, Mathew T, Gadre G, et al. Cryptococcal meningitis: clinical, diagnostic and therapeutic overviews. Neurol India. 2007;55(3):226–232.
2. Jain KK, Mittal SK, Kumar S, et al. Imaging features of central nervous system fungal infections. Neurol India. 2007;55(3):241–250.
3. Davis JA, Costello DJ, Venna N. Laboratory investigation of fungal infections of the central nervous system. Neurol India. 2007;55(3):233–240.
4. Cannon RD, Lamping E, Holmes AR, et al. Efflux-mediated antifungal drug resistance. Clin Microbiol Rev. 2009;22(2):291–321.
5. Espinel-Ingroff A. History of medical mycology in the United States. Clin Microbiol Rev. 1996;9(2):235–272.
6. Perfect JR. Cryptococcus neoformans: a sugar-coated killer with designer genes. FEMS Immunol Med Microbiol. 2005;45(3):395–404.
7. Levitz SM, Boekhout T. Cryptococcus: the once-sleeping giant is fully awake. FEMS Yeast Res. 2006;6(4):461–462.
8. Park BJ, Wannemuehler KA, Marston BJ, et al. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS. 2009;23(4):525–530.
9. Loftus BJ, Fung E, Roncaglia P, et al. The genome of the basidiomycetous yeast and human pathogen Cryptococcus neoformans. Science. 2005;307(5713):1321–1324.
10. Liu OW, Chun CD, Chow ED, et al. Systematic genetic analysis of virulence in the human fungal pathogen Cryptococcus neoformans. Cell. 2008;135(1):174–188.
11. 38. Casadevall A, Perfect JR. In: Cryptococcus neoformans. Washington, DC: American Society for Microbiology; 1998;p. 1–27.
12. Kwon-Chung KJ, Varma A. Do major species concepts support one, two or more species with Cryptococcus neoformans?. FEMS Yeast Res. 2006;6(4):574–587.
13. Bovers M, Hagen F, Kuramae E, et al. Unique hybrids between the fungal pathogens Cryptococcus neoformans and Cryptococcus gatti. FEMS Yeast Res. 2006;6(4):599–607.
14. Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Clin Infect Dis. 2000;30(4):710–718.
15. Casadevall A, Perfect JR. In: Cryptococcus neoformans. Washington, DC: American Society for Microbiology; 1998;p. 407–456.
16. Denning DW, Armstrong RW, Lewis BH, et al. Elevated cerebrospinal fluid pressures in patients with cryptococcal meningitis and acquired immunodeficiency syndrome. Am J Med. 1991;91(3):267–272..
17. Redmond A, Dancer C, Woods ML. Fungal infections of the central nervous system: a review of fungal pathogens and treatment. Neurol India. 2007;55(3):251–259.
18. Pukkila-Worley R, Mylonakis E. Epidemiology and management of cryptococcal meningitis: developments and challenges. Expert Opin Pharmacother. 2008;9(4):551–560.
19. Neuroimaging of some fungal brain infection: An overview [Full text]
20. Management of fungal infections of the CNS [Full text]
21. Fungal infections of the CNS [Full text]
22. Levine AJ, Hinkin CH, Ando K, et al. An exploratory study of long-term neurocognitive outcomes following recovery from opportunistic brain infections in HIV+ adults. J Clin Exp Neuropsychol. 2008;30(7):836–843.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

November 29, 2009 — Hepatic encephalopathy (HE) is a poorly defined, complex neuropsychological disorder that often accompanies portal hypertension. Although the mechanisms underlining HE and the characterization of Hepatic encephalopathy are still under investigation, the information derived from functional neuroimaging of patients with Hepatic encephalopathy complemented by laboratory investigation and neuropsychological and neurophysiological studies have clarified much of the neuroanatomical defects. In this post, we have provided an outline of the understood mechanisms of HE and the associated findings on neuroimaging.

Neuroimaging may or may not contribute toward the diagnosis of Hepatic encephalopathy. Computed tomography of the brain may be normal or may reveal cerebral edema in acute stages and cerebral atrophy in chronic cases. Brain MR imaging is more sensitive for demonstrating cerebral edema and its response to treatment. MR imaging can exclude other neurologic pathology, and, in cirrhotic patients, MR imaging reveals typical bilateral pallidal hyperintensity on T1-weighted images, probably reflecting manganese deposition. [1,2] However, pallidal hyperintense signal does not correlate with the clinical stage of HE. The fast, fluid-attenuated inversion recovery (FLAIR) T2-weighted sequence is a novel MR technique that, in patients with HE, shows hyperintense signals along the hemispheric white matter in or around the corticospinal tract. 1H-MR spectroscopy reveals abnormalities of cerebral osmolytes, including myoinositol, glutamate/glutamine, and choline. A pattern of decreased myoinositol and elevated glutamate/glutamine is associated with Hepatic encephalopathy. [1,2]

• Detailed neuroimaging studies
  • Computed tomography and magnetic resonance imaging studies of the brain may be important in ruling out intracranial lesions when the diagnosis of hepatic encephalopathy is in question. MRI has the additional advantage of being able to demonstrate hyperintensity of the globus pallidus on T1-weighted images, a finding that commonly is described in hepatic encephalopathy.
  • Although the diagnosis of HE is usually made on the basis of clinical information, imaging studies are occasionally helpful. There is frequently a high signal abnormality present in the pallidum on T1-weighted magnetic resonance images (MR). This appears to be caused by manganese in the brain. This abnormality is seen in patients receiving long-term hyperalimentation and can be produced in experimental animals; it regresses after liver transplantation. Abnormalities are also present on T2-weighted MR images, however, without absolute quantitation of the images, these abnormalities are very difficult to detect visually.
  • Magnetic resonance spectroscopy offers the potential to examine the neurochemical profile of the brain noninvasively. Several studies of patients with liver disease have been reported. Typically, spectroscopy shows depletion of myoinositol, preservation of N-acetylaspartate, and elevations in glutamine. The typical MRI magnet field strength of 1.5 T is suboptimal for these studies. Higher field strengths are required to resolve the glutamine + glutamate peak into its components, with increases in glutamine identifying the encephalopathic patients. Technical improvements now make it possible to do single voxel spectroscopy with 1.5 T magnets in very short times (approximately 5 minutes added to a typical MRI session). This technique may become more useful in the future as this technology proliferates.
  • Positron emission tomography (PET) has been used to study patients with liver disease. This technique is too cumbersome and expensive to be used clinically; however, advances in the understanding of the pathophysiology of HE have been made using PET. With PET it is possible to measure ammonia uptake by the brain and examine the characteristics of the blood-brain barrier. Both are abnormal in patients with liver disease. PET has also been used to study cerebral glucose metabolism in patients with Hepatic encephalopathy. The metabolic rate for glucose was reduced in the anterior cingulate gyrus in a small group of patients with alcoholic cirrhosis. This neural center is a critical component of the anterior attention system, a part of the brain that mediates focused neural activity. More recent studies show bifrontal and biparietal reductions in metabolism that correlate well with performance on neuropsychological.

Figure 1. A, Coronal spin-echo T1-weighted image shows symmetrical and bilateral hyperintensity at the level of the globus pallidus and hypothalamus (arrows). B, No evidence of abnormal signal intensity is seen on the coronal spin-echo T2-weighted image. C, Axial spin-echo T1-weighted image shows symmetrical and bilateral hyperintensity at the level of the globus pallidus and hypothalamus (arrows). D, No evidence of abnormal signal intensity is seen on the axial spin echo T2-weighted image. (Click to enlarge figure)

Table 1. Differences between brain neuroimaging findings in wilson disease and non -Wilsonian chronic liver disease

Figure 2. A, MRI T2 image of a patient with wilson disease, B, Precontrast MRI T1 image of a patient with hepatic encephalopathy due to causes other than Wilson disease. Notice the T2 mixture of hyper and hypointensities (in the putamen and head of caudate nuclei) in Wilson disease (A) which is always symptomatic and correlates with pseudoparkinsonian signs, while in hepatic encephalopathy there is asymptomatic precontrast hyperintensity in the globus pallidus. (Click to enlarge figure)

Figure 3. Transverse T1-weighted MR images of a patient with chronic liver failure and parkinsonism. Note the bilateral and symmetric hyperintense signals involving globus pallidus and anterior brainstem. (Click to enlarge figure)

Figure 4. Axial T2-weighted fast FLAIR images of a patient with hepatic cirrhosis during an episode of HE. Note the symmetric hyperintense signals along the corticospinal tracts in both cerebral hemispheres (A). The abnormal hyperintense signals resolved almost completely during a follow-up study obtained few months later, when the patient showed no overt HE (B). (Click to enlarge figure)

References

1. Kulisevski J, Pujol J, Balanzo J, et al. Pallidal hyperintensity on magnetic resonance imaging in cirrhotic patients: clinical correlations. Hepatology. 1992;16(6):1382–1388.
2. Rovira A, Alonso J, Cordoba J. MR imaging findings in hepatic encephalopathy. AJNR Am J Neuroradiol. 2008;29(9):1612–1621.
3. Neuroimaging of Wilson disease [Full text]
4. Neurological videos…Hepatolenticular Degeneration (Wilson Disease) [Full text]
5. Management of Wilson disease [Full text]
6. Wilson disease [Full text]
7. Case of the week……Wilson disease [Click to download in PDF format]
8. Case of the week……Wilson disease [Click to download in PDF format]
9. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 10.4a October 2009 [Click to have a look at the home page]

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

November 28, 2009 — The hypothesis concerning the role of “GABAergic tone” in Hepatic encephalopathy (HE) was developed using animal models of ALF and implies that neuronal activity in hepatic coma is similar to that induced by GABAergic neural mechanisms. [1] Several mechanisms have been proposed to explain increased GABAergic tone: increased brain GABA, increased number of GABA-A receptors, increased concentration in brain of endogenous benzodiazepine-like compounds that would increase activation of GABA-A receptors, increased concentration in brain of neurosteroids that would increase activation of GABA-A receptors, and enhanced activation of GABA receptors by ammonia. [4] Although few studies have found evidence contradicting any of these mechanisms, [2,3] some support the concept that hyperammonemia is responsible for the apparent increase in GABAergic tone in HE by enhancing activation of GABA-A receptors through a direct effect or via increase in neurosteroids that positively modulate these receptors.[4,5,6,7,8]

Zinc, which is a negative modulator of GABA-A receptor mediated currents, may also play a role in the pathogenesis of HE, although its mechanism is not completely understood. [9] What is known is that ammonia, TNF-a, benzodiazepines, and osmotic astrocyte swelling activate an NO-dependent mobilization of zinc that may augment GABAergic neurotransmission. [16] A consequence of this action is a translocation of stimulatory protein 1 (SP1), which participates in the expression of the peripheral benzodiazepine receptor (PBR). [10,11,12] The peripheral-type benzodiazepine receptors (PBR) is upregulated in HE [13] and plays a role in mitochondrial permeability transition  (MPT) involving the oxidative stress response toward benzodiazepines and is involved in the production of neurosteroids [6] that have a positive GABA-A receptor modulatory activity. This process could also account for the increased GABAergic tone seen in patients with HE. [9,16] Another study also suggests that ammonia-induced astrocyte swelling, and the subsequent increase in mitochondrial permeability transition  (MPT), could involve the peripheral-type benzodiazepine receptors (PBR).[15]

References

1. Schafer DF, Jones EA. Hepatic encephalopathy and the gamma-aminobutyric acid neurotransmitter system. Lancet. 1982;1(8262):18–20.
2. Ahboucha S, Pomier-Layrargues G, Butterworth RF. Increased brain concentrations of endogenous (non-benzodiazepine) GABA-A receptor ligands in human HE. Metab Brain Dis. 2004;19(3–4):241–251. MEDLINE | CrossRef
3. Ahboucha S, Araqi F, Layrargues GP, et al. Differential effects of ammonia on the benzodiazepine modulatory site on the GABA-A receptor of human brain. Neurochem Int. 2005;47(1–2):58–63. MEDLINE | CrossRef
4. Llansola M, Rodrigo R, Monfort P, et al. NMDA receptors in hyperammonemia and hepatic encephalopathy. Metab Brain Dis. 2007;22(3–4):321–325.
5. Itzhak Y, Roig-Cantisano A, Dombro RS, et al. Acute liver failure and hyperammonemia increase peripheral-type benzodiazepine receptor binding and pregnenolone synthesis in mouse brain. Brain Res. 1995;705(1–2):345–348. .
6. Norenberg MD, Itzhak Y, Bender AS. The peripheral benzodiazepine receptor and neurosteroids in HE. Adv Exp Med Biol. 1997;420:95–111. 
7. Takahashi K, Kameda H, Kataoka M, et al. Ammonia potentiates GABAA response in dissociated rat cortical neurons. Neurosci Lett. 1993;151(1):51–54.
8. Ha JH, Basile AS. Modulation of ligand binding to components of the GABAA receptor complex by ammonia: implications for the pathogenesis of hyperammonemic syndromes. Brain Res. 1996;720(1–2):35–44. .
9. Celentano JJ, Gyenes M, Gibbs TT, et al. Negative modulation of the gamma-aminobutyric acid response by extracellular zinc. Mol Pharmacol. 1991;40(5):766–773.
10. Kruczek C, Görg B, Keitel V, et al. Hypoosmolarity and ammonia affect zinc homeostasis in cultured rat astrocytes. Glia. 2009;57(1):79–92. .
11. Giatzakis C, Papadopoulos V. Differential utilization of the promoter of peripheral-type benzodiazepine receptor by steroidogenic versus nonsteroidogenic cell lines and the role of Sp1 and Sp3 in the regulation of basal activity. Endocrinology. 2004;145(3):1113–1123. .
12. Giguere JF, Hamel E, Butterworth RF. Increased densities of binding sites for the ‘peripheral-type’ benzodiazepine receptor ligand [3H]PK 11195 in rat brain following portacaval anastomosis. Brain Res. 1992;585(1–2):295–298. .
13. Lavoie J, Layrargues GP, Butterworth RF. Increased densities of peripheral-type benzodiazepine receptors in brain autopsy samples from cirrhotic patients with hepatic encephalopathy. Hepatology. 1990;11(5):874–878.
14. Butterworth RF. The astrocytic (peripheral-type) benzodiazepine receptor: role in the pathogenesis of portal-systemic encephalopathy. Neurochem Int. 2000;36(4–5):411–416.
15. Panickar KS, Jayakumar AR, Rama Rao KV, et al. Downregulation of the 18-kDa translocator protein: effects on the ammonia-induced mitochondrial permeability transition and cell swelling in cultured astrocytes. Glia. 2007;55(16):1720–1727.
16. Häussinger D, Schliess F. Pathogenetic mechanisms of hepatic encephalopathy. Gut. 2008;57(8):1156–1165.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

November 23, 2009 — The current management for CVT is determined mostly on a case-by-case basis [23]. In general, anticoagulation using heparin has been used as a safe and clinically effective treatment method [2–4,5,6,7]. Recently, endovascular management, including direct thrombolysis with or without mechanical thrombus extraction, has been advocated and has shown favorable outcomes [8–19]. These reports were based on nonrandomized uncontrolled case series, however.

• Heparin

Heparin treatment for CVT has been considered a standard therapy [3,4]. Theories on the pathophysiology of CVT suggest a continuing process of disequilibrium between prothrombotic and thrombolytic mechanisms. Heparin treatment may act by shifting the equilibrium away from the prothrombotic action toward thrombolysis and inhibiting further thrombosis [20].

Two randomized trials and one meta-analysis of heparin treatment for CVT have been performed. The first trial, from Germany, was a randomized, blinded, placebo-controlled study in 20 patients with dural sinus thrombosis [2]. The trial was discontinued after 20 patients because of significant differences in the recovery rate and mortality between the heparin and control group. The authors concluded that anticoagulation with dose-adjusted intravenous (IV) heparin (unfractionated heparin, bolus dose of 3000 IU and continuous infusion of 25,000–65,000 IU/day) was an effective treatment and an associated intracranial hematoma was not a contraindication for its use. This trial was criticized, however, because its outcome assessment was not validated and there was a significant treatment delay after onset of symptoms. The trial failed to clarify the issue of duration of heparin treatment and the use of warfarin was questioned [21,28]. A randomized, placebo-controlled study from the Netherlands investigated the role of subcutaneous low-molecular-weight heparin (LMWH) in the management of CVT [5]. In this study, 20% of patients in the heparin treatment group and 24% in the placebo group had a poor outcome after 3 weeks, and 13% in the treatment group and 21% in the placebo group had a poor outcome after 12 weeks. The definition of poor outcome was death or a Barthel index score of less than 15. This study did not demonstrate statistically significant clinical outcome improvement differences between the heparin treatment group and the control group; however, it revealed that the group treated with LMWH followed by oral anticoagulation showed a favorable outcome compared with the control group. The safety of anticoagulation was supported even in the setting of cerebral hemorrhage. A meta-analysis of the previously described two trials did not reveal a statistically significant improvement in outcome but demonstrated a 14.3% mortality reduction rate with heparin treatment and 15.5% risk reduction for death and dependency [8].

Heparin treatment remains a first-line treatment option in CVT because of the demonstrated safety of heparin and the favorable trend of clinical outcomes as shown in previous trials [4].

• Endovascular treatment

Patients with a rapidly progressive thrombosis and diffuse brain swelling, with or without multiple hemorrhages, should be considered for endovascular thrombolytic therapy. It has been the authors’ practice to start with at least 24 hours of heparin treatment. If clinical worsening of the patient’s condition continues during that time period, endovascular thrombolytic therapy should be considered (Fig. 1).

Figure 1. Direct thrombolytic therapy in a 57-year-old woman who presented with headache that progressed to aphasia and a decreased level of consciousness. (A) Venous phase of the right internal carotid artery angiogram shows nonvisualization of the anterior aspect of superior sagittal sinus (solid arrow) and absence of the straight sinus (open arrow). (B) Anteroposterior view of the skull shows the microcatheter and micro-guide wire (arrows) in the left transverse sinus and superior sagittal sinus. (C) Lateral venogram in the superior sagittal sinus shows filling defects within the superior sagittal sinus. Direct thrombolysis using rtPA (total, 30 mg) resulted in partial restoration of antegrade flow in the superior sagittal sinus. (D) Postthrombolysis right internal carotid artery angiogram demonstrates near-total restoration of antegrade flow in superior sagittal sinus and straight sinus. Patient had an immediate clinical improvement. (Click to enlarge figure)

Since 1988, several reports have demonstrated the feasibility of direct infusion of thrombolytic agents into the thrombosed dural sinus by way of a percutaneous or retrograde transvenous approach [8,11,12,15,18]. With improved catheter technology, it became possible to access and infuse thrombolytic agents into the deep cerebral venous system [16,22,23]. The potential benefit of local administration of thrombolytic therapy is that it may avoid the systemic hemorrhagic effect caused by high-dose IV anticoagulation therapy. The technique of endovascular thrombolytic therapy has changed over the past decade, from a therapy of prolonged infusions of low-dose urokinase (2- to 24-hour infusion, 0.5–20 million units) to a relatively rapid pulse-spray technique using recombinant tissue plasminogen activator (rtPA; 2–4 hours to administer 50–300 mg) [8,9,16,18,24].

The rtPA has many pharmacologic advantages over urokinase, including a short half-life [25], low antigenecity, and clot selectivity. The rtPA produces the lowest level of fibrinogen degradation products [26], which might contribute to the lower likelihood of hemorrhagic complications. There are two case series of local rtPA treatment with concomitant IV heparin treatments. Kim and Suh [24] reported complete flow restoration in 18 hours and clinical improvement in all patients after rtPA treatment. They reported two nonneurologic rtPA-related complications (22.2%), including intrapelvic hematoma and puncture-site oozing but no intracranial hemorrhagic complication. Frey et al [7] showed flow restoration in 75% (complete in 50% and partial in 25%) of the patients within 29 hours of the rtPA treatment. They demonstrated that clinical recovery was closely related to the degree of flow restoration. In the group with complete flow restoration, 83% of patients had a complete clinical recovery. In the group with partial recanalization, 66% had a complete recovery. In the group that did not recanalize, only 33% demonstrated functional independence. The rtPA treatment resulted in neurologic deterioration in 16.7% of patients, who experienced enlargement of the parenchymal hematoma. These two series show that the local infusion of rtPA in CVT was technically feasible and flow restoration after rtPA treatment was important for future clinical outcome. There is, however, a risk of clinical deterioration, especially in patients with intracranial hemorrhage.

At present, there does not exist a scientifically proven regimen of endovascular therapy that includes inclusion or exclusion criteria, dosage of thrombolytic agent, duration of treatment, concomitant usage of heparin, and a radiologic endpoint of the interventional procedure. Endovascular treatment can be performed only in highly sophisticated centers where interventional neuroradiologic expertise is available [3]. In the authors’ institution, physicians perform endovascular treatment in patients who show clinical deterioration despite 24 hours of heparin therapy. The authors and other physicians in their institution use a rapid-pulsed direct-infusion technique of 30 to 50 mg of rtPA through a microcatheter over 15 to 20 minutes. The authors use concomitant IV heparin; their angiographic endpoint is antegrade flow within the dural sinus and not the total absence of thrombus within the dural sinus. In the authors’ experience, the reestablishment of antegrade flow with continued anticoagulation is sufficient to facilitate clinical improvement [3].

Various dural sinus revascularization techniques other than local thrombolytic treatment have been reported, such as mechanical disruption using guide wires, rheolytic thrombectomy catheters, balloon thrombectomy with fibrinolysis, transluminal balloon angioplasty, with or without stenting, and surgical thrombectomy [9,10,13,14,17]. The role of endovascular reopening of the dural sinuses using angioplasty and stent placement in the presence of severe intracranial venous hypertension is anecdotal and long-term results are not known [27,29].

In conclusion, heparin is a first-line treatment option for CVT, and endovascular therapy should be considered if rapid clinical worsening occurs, despite anticoagulation. Endovascular treatment for CVT is feasible and effective in selected cases. Because the technology continues to improve, the potential role of endovascular treatment for CVT is promising.

References

1. Benamer HT, Bone I. Cerebral venous thrombosis: anticoagulants or thrombolyic therapy. J Neurol Neurosurg Psychiatry. 2000;69:427-430
2. Einhaupl KM, Villringer A, Meister W, et al. Heparin treatment in sinus venous thrombosis. Lancet. 1991;338:597-600
3. Ameri A, Bousser MG. Cerebral venous thrombosis. Neurol Clin. 1992;10:87-111
4. Bousser MG. Cerebral venous thrombosis: nothing, heparin, or local thrombolysis?. Stroke. 1999;30:481-483
5. de Bruijn SF, Stam J. Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral sinus thrombosis. Stroke. 1999;30:484-488
6. Brucker AB, Vollert-Rogenhofer H, Wagner M, et al. Heparin treatment in acute cerebral sinus venous thrombosis: a retrospective clinical and MR analysis of 42 cases. Cerebrovasc Dis. 1998;8:331-337
7. Frey JL, Muro GJ, McDougall CG, et al. Cerebral venous thrombosis: combined intrathrombus rtPA and intravenous heparin. Stroke. 1999;30:489-494
8. Barnwell SL, Higashida RT, Halbach VV, et al. Direct endovascular thrombolytic therapy for dural sinus thrombosis. Neurosurgery. 1991;28:135-142
9. Chaloupka JC, Mangla S, Huddle DC. Use of mechanical thrombolysis via microballoon percutaneous transluminal angioplasty for the treatment of acute dural sinus thrombosis: case presentation and technical report. Neurosurgery. 1999;45:650-656
10. Ekseth K, Bostrom S, Vegfors M. Reversibility of severe sagittal sinus thrombosis with open surgical thrombectomy combined with local infusion of tissue plasminogen activator: technical case report. Neurosurgery. 1998;43:960-965
11. Higashida RT, Helmer E, Halbach VV, et al. Direct thrombolytic therapy for superior sagittal sinus thrombosis. AJNR Am J Neuroradiol. 1989;10(Suppl 5):S4-S6
12. Horowitz M, Purdy P, Unwin H, et al. Treatment of dural sinus thrombosis using selective catheterization and urokinase. Ann Neurol. 1995;38:58-67
13. Malek AM, Higashida RT, Balousek PA, et al. Endovascular recanalization with balloon angioplasty and stenting of an occluded occipital sinus for treatment of intracranial venous hypertension: technical case report. Neurosurgery. 1999;44:896-901
14. Scarrow AM, Williams RL, Jungreis CA, et al. Removal of a thrombus from the sigmoid and transverse sinuses with a rheolytic thrombectomy catheter. AJNR Am J Neuroradiol. 1999;20:1467-1469
15. Scott JA, Pascuzzi RM, Hall PV, et al. Treatment of dural sinus thrombosis with local urokinase infusion. Case report. J Neurosurg. 1988;68:284-287
16. Smith TP, Higashida RT, Barnwell SL, et al. Treatment of dural sinus thrombosis by urokinase infusion. AJNR Am J Neuroradiol. 1994;15:801-807
17. S?derman M, Johnsson H, Ericson K, et al. Acute-sinus thrombosis in a child with antibodies against cardiolipins. Intervent Neuroradiol. 1996;2:143-148
18. Tsai FY, Higashida RT, Matovich V, et al. Acute thrombosis of the intracranial dural sinus: direct thrombolytic treatment. AJNR Am J Neuroradiol. 1992;13:1137-1141
19. Vines FS, Davis DO. Clinical-radiological correlation in cerebral venous occlusive disease. Radiology. 1971;98:9-22
20. Villringer A, Mehraein S, Einhaupl KM. Pathophysiological aspects of cerebral sinus venous thrombosis (SVT). J Neuroradiol. 1994;21:72-80
21. Stam J, Lensing AW, Vermeulen M, et al. Heparin treatment for cerebral venous and sinus thrombosis. Lancet. 1991;338:597-600
22. Holder CA, Bell DA, Lundell AL, et al. Isolated straight sinus and deep cerebral venous thrombosis: successful treatment with local infusion of urokinase. Case report. J Neurosurg. 1997;86:704-707
23. Spearman MP, Jungreis CA, Wehner JJ, et al. Endovascular thrombolysis in deep cerebral venous thrombosis. AJNR Am J Neuroradiol. 1997;18:502-506
24. Kim SY, Suh JH. Direct endovascular thrombolytic therapy for dural sinus thrombosis: infusion of alteplase. AJNR Am J Neuroradiol. 1997;18:639-645
25. Eisenberg PR, Sherman LA, Tiefenbrunn AJ, et al. Sustained fibrinolysis after administration of t-PA despite its short half-life in the circulation. Thromb Haemost. 1987;57:35-40
26. Sobel BE, Gross RW, Robison AK. Thrombolysis, clot selectivity, and kinetics. Circulation. 1984;70:160-164
27. Vilela P, Willinsky R, Terbrugge K. Treatment of intracranial venous occlusive disease with sigmoid sinus angioplasty and stent placement in a case of infantile multifocal dural arteriovenous shunts. Intervent Neuroradiol. 2001;7:51-60
28. Benamer HT, Bone I. Cerebral venous thrombosis: anticoagulants or thrombolyic therapy. J Neurol Neurosurg Psychiatry. 2000;69:427-430
29. Lee SK, Kim BS, Terbrugge K. Clinical presentation, imaging and treatment of cerebral venous thrombosis (CVT). Intervent Neuroradiol. 2002;8:5-14
30. Therapy for sinovenous thrombosis in the pediatric age group [Full text]

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

November 23, 2009 — Therapy for sinovenous thrombosis includes nonantithrombotic and antithrombotic therapy. In the acute phase of cerebral sinovenous thrombosis, nonantithrombotic therapy is aimed at maintaining adequate perfusion of the brain and minimizing the metabolic demands within cerebral tissue in order to minimize the extent of cerebral damage. Approaches include maintenance of blood pressure, correction of hyper- or hypo-glycemia, and prevention of recurrent seizures. In addition, specific primary treatment for all reversible underlying risk factors, including mastoiditis or meningitis, is important in order to prevent propagation of the thrombosis.

Older children with diffuse cerebral swelling at the onset of cerebral sinovenous thrombosis  may require treatment for persistent intracranial hypertension in the subacute and chronic phase. The latter can persist for many weeks or months. Treatments include acetazolamide (Diamox®), and serial lumbar punctures with removal of CSF. In resistant cases, placement of a lumbo-peritoneal shunt may be necessary. In addition to monitoring patient symptoms of headache and visual deficits, objective monitoring of the degree of papilloedema and status of visual field defects is important. If visual loss is progressing in spite of maximal treatment for intracranial hypertension, optic nerve sheath fenestration is sometimes required.

• Anticoagulant treatment

The objectives of anticoagulant therapy are to prevent the propagation of existing thrombus, and to enable the unopposed dissolution of existing thrombus by the activity of the fibrinolytic system. The recanalization of sinovenous channels reduces the congestion of brain tissue, reducing the risk of permanent venous infarction. In neonates and children with cerebral sinovenous thrombosis , there is a complete absence of clinical trials assessing the efficacy of anticoagulant therapy. In the past decade, in the Canadian Registry [1], 37% of neonates and 67% of older infants and children with CSVT received anticoagulant medications without significant hemorrhagic complications. The medications used were Low molecular weight heparin [LMWH] in 32%, unfractionated heparin (UFH) in 22%, and warfarin in 39% [1].

The increasing tendency to treat infants and children with cerebral sinovenous thrombosis with anticoagulants has been based on several lines of evidence. These include the established risk of propagation or recurrence of the thrombosis in childhood cerebral sinovenous thrombosis, compelling data on the efficacy and safety of heparin in adults with clinical trials, and evidence supporting the safety of anticoagulants in children. Four randomized controlled trials and several large cohort studies have supported the efficacy and safety of anticoagulants in adults with cerebral sinovenous thrombosis  [2–6]. Case reports and nonconsecutive cohort studies, such as the Canadian Registry, cannot establish the efficacy of anticoagulants in children with cerebral sinovenous thrombosis , as treatment is selected by individual treating physicians. Cohort studies in which consecutive children with cerebral sinovenous thrombosis  are treated with anticoagulants using standardized protocols can however, establish the safety of anticoagulants. One large prospective consecutive cohort study has assessed the safety of anticoagulants for a variety of childhood thrombotic events [7]. In that study, 146 children (33% neonates, 15 with cerebral sinovenous thrombosis , and 29 with arterial ischemic stroke) were treated with therapeutic doses of Low molecular weight heparin. The study showed a 5% rate of major bleeds, which occurred primarily in neonates [7]. A second consecutive cohort study assessed the safety profile for anticoagulant therapy in children with cerebral sinovenous thrombosis  [8]. In the latter study, 30 children were screened. 8 of whom were ineligible for anticoagulation due to the presence of intracranial hemorrhage. Ten children were treated with unfractionated heparin and twelve with Low molecular weight heparin during the acute stages of cerebral sinovenous thrombosis. Eighteen went on to receive warfarin for an additional 3 months. In the latter study, no child had an extension of the cerebral sinovenous thrombosis , although two children experienced recurrent CSVT during the chronic phase of anticoagulation. One child had a clinically silent intracranial hemorrhage during therapy with unfractionated heparin.

Given the frequency of hemorrhagic venous infarction in cerebral sinovenous thrombosis , there has been a concern about anticoagulant treatment for this condition. Data from the published trials in adult patients has shown, however, that even with hemorrhagic infarction those patients who were treated benefited from heparin therapy [9,10].

On balance, the data from the adult trials and childhood consecutive cohort studies suggest that anticoagulant therapy should be considered in children with cerebral sinovenous thrombosis . But clinical trials assessing the efficacy of anticoagulant therapy are urgently needed, particularly in neonates in whom the risk-to-benefit ratio of anticoagulants cannot be extrapolated from adult studies. Large multi-national randomized controlled trials will be necessary to establish efficacy. In older children, randomization to nonanticoagulants would be problematic given the strong evidence for efficacy in adult studies. As neonates differ markedly from older age groups, however, and the risks and benefits are truly unknown, randomization to a nonanticoagulant arm for neonates with cerebral sinovenous thrombosis  would be more feasible.

In the decision to treat individual children with cerebral sinovenous thrombosis  and decisions regarding treatment duration, several factors must be considered. These include the extent and location of the thrombus, the presence of intracranial hemorrhage, the reversibility or irreversibility of risk factors for the cerebral sinovenous thrombosis , and the ability to monitor anticoagulant therapy. Because subclinical propagation of the thrombus occurs, the clinical symptomatology is less relevant, particularly in neonates [11]. Our current approach while awaiting more definitive evidence on which to base therapy has been to treat neonates without intracranial hemorrhage with initial unfractionated heparin or Low molecular weight heparin, followed by Low molecular weight heparin or warfarin for 6 weeks. At that stage, the infant undergoes reassessment with a CT venogram or a MR venogram. If full recanalization has been achieved, anticoagulants are discontinued. If there is persistent thrombus, anticoagulants are continued for an additional 6 weeks [12]. During the anticoagulant treatment, cranial ultrasound can be used to monitor for the development of hemorrhage, and power Doppler ultrasound, when available, can monitor for extension or resolution of the thrombus. For older infants and children, the treatment approach for adults is followed and includes unfractionated heparin or Low molecular weight heparin for seven days followed by warfarin or Low molecular weight heparin for a total of six months, with reassessment of re-canalization at three months. Following cessation of anticoagulant therapy, a repeat radiographic assessment is conducted to determine the extent of recanalization. In all cases, we perform a CT scan several days following the initiation of anticoagulants to detect the development of subclinical intracranial hemorrhage.

• Thrombolytic therapy

In adults, direct catheter thrombolysis of cerebral sinovenous thrombosis  is being used with increasing frequency. Reperfusion has been observed in the majority of cases. There is, however, a risk of selection and publication bias. To date, the risk of hemorrhage and the functional outcome following thrombolytic therapy has been compared with that with heparin in only one study, and that was uncontrolled [13]. In that study, neurologic function at discharge was better in the thrombolysis group; however, hemorrhagic complications were observed in 10% (n = 2) in the thrombolysis group (subdural hematoma, retroperitoneal hemorrhage) and none in the heparin group (P = 0.49). There were no deaths. Although some authors advocate thrombolytic therapy for sinovenous thrombosis as an early intervention, most authors suggest limiting its use to patients who have clinical deterioration despite appropriate anticoagulant therapy.

There are several case reports highlighting the successful thrombolytic treatment of CSVT in neonates or children [14–16]. Major hemorrhagic complications have also been reported with this treatment [17]. A consecutive cohort study of seven children with systemic venous thrombosis reported successful lysis in only one of them, with major complications in three [18]. A large population-based study of children with deep vein thrombosis reported a failure of thrombolytic therapy in one third of the children in whom it was used [19]. The hemostatic system in children differs significantly from that in adults. Neonates have reduced plasminogen levels, and, in children, levels of PAI-1, the primary inhibitor of TPA, and alpha 2 macroglobulin, a plasmin inhibitor, are increased [20]. These differences may result in a relative resistance to fibrinolytic therapy in childhood.

In the Canadian Registry, [1] in the 85 children treated with anticoagulant, one child died from sinovenous thrombosis, and no child experienced major hemorrhagic complications. The five other deaths attributable to sinovenous thrombosis occured in four patients who received no anticoagulants and one who was treated with catheter directed urokinase. We reserve catheter-directed thrombolytic therapy in infants or children for patients in whom there is progression of the cerebral sinovenous thrombosis  in spite of maximum systemic anticoagulation. The risk/benefit ratio of thrombolytic therapy is not known in children with cerebral sinovenous thrombosis . The hemorrhagic risk of thrombolytic therapy may be considerable. Based on the current evidence, we would recommend against this method of treatment as first-line therapy outside of carefully designed cohort studies or randomized controlled trials.

References

1. deVeber G, Andrew M. Canadian Pediatric Ischemic Stroke Study Group: cerebral sinovenous thrombosis in children. N Engl J Med. 2001;345:417-423
2. Chakrabarti I, Maiti B. Study on cerebral venous thrombosis with special references to efficacy of heparin. J Neurol Sciences. 1997;150:S147[abstract]
3. de Bruijn SF, Stam J. Randomized, placebo-controlled trial of anticoagulant treatment with low molecular weight heparin for cerebral sinus thrombosis. Stroke. 1999;30:484-488
4. Einhaupl KM, Villringer A, Meister W, et al. Heparin treatment in sinus venous thrombosis. Lancet. 1991;338:597-600
5. Nagaraja D, Rao BSS, Taly AB, et al. Randomized controlled trial of heparin in puerperal venous sinus thrombosis. NIMHANS J. 1995;13:111-115
6. Preter M, Tzourio C, Amen A, et al. Long term prognosis in cerebral venous thrombosis: follow-up of 77 patients. Stroke. 1996;27:243-246
7. Dix D, Andrew M, Marzinotto V, et al. The use of low molecular weight heparin in pediatric patients: a prospective cohort study. J Pediatr. 2000;136:439-445
8. deVeber G, Chan A, Monagle P, et al. Anticoagulation therapy in pediatric patients with sinovenous thrombosis: a cohort study. Arch Neurol. 1998;55:1533-1537
9. Hartmann A, Wappenschmidt J, Solymosi L. Clinical findings and differential diagnosis of cerebral vein thrombosis. In: Einhaupl K, ed. Cerebral sinus thrombosis. Experimental and clinical aspects. New York: Plenum Press 1987:171-186
10. Ameri A, Bousser M. Cerebral venous thrombosis. Neurol Clin. 1992;10:87-111
11. Khurana DS, Buonanno F, Ebb D, et al. The role of anticoagulation in idiopathic cerebral venous thrombosis. J Child Neurol. 1996;11:248-250
12. Andrew M, deVeber G. Pediatric thromboembolism and stroke protocols. (ed 2) Hamilton, Ontario: BC Decker, Inc. 1999
13. Wasay M, Bakshi R, Kojan S, et al. Nonrandomized comparison of local urokinase thrombolysis versus systemic heparin anticoagulation for superior sagittal sinus thrombosis. Stroke. 2001;32:2310-2317
14. Griesemer DA, Theodorou AA, Berg RA, et al. Local fibrinolysis in cerebral venous thrombosis. Pediatr Neurol. 1994;10:78-80
15. Higashida RT, Helmer E, Halbach VV, et al. Direct thrombolytic therapy for superior sagittal sinus thrombosis. AJNR. 1989;10:S4-S6
16. Wong VK, LeMesurier J, Franceschini R, et al. Cerebral venous thrombosis as a cause of neonatal seizures. Pediatr Neurol. 1987;3:235-237
17. Horowitz M, Purdy P, Unwin H, et al. Treatment of dural sinus thrombosis using selective catheterization and urokinase. Ann Neurol. 1995;38:58-67
18. Monagle P, Phelan E, Downie P, Andrew M. Local thrombolytic therapy in children. Thrombosis Haemostasis. 1997;77(Suppl):504Abstract
19. Andrew M, David M, Adams M, et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood. 1994;83:1251-1257
20. Andrew M, Vegh P, Johnston M, et al. Maturation of the hemostatic system during childhood. Blood. 1992;80:1998-2005
21. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 10.4a October 2009 [Click to have a look at the home page]
22. Cerebral sinus thrombosis [Full text]
23. Neuroimaging of cerebral veno-sinus thrombosis (An introduction) [Full text]
24. Neuroimaging of cerebral veno-sinus thrombosis [Full text]
25. Pathophysiology of cerebral sinus thrombosis and its parenchymal changes [Full text]
26. Management of cerebral sinovenous thrombosis in adults [Full text]

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

November 23, 2009 — In sinovenous thrombosis, the mechanism for venous infarction is obstruction of venous drainage with increasing venous pressure in the affected region of the brain. The venous congestion results in significant extravasation of fluid into the brain, producing focal cerebral edema and hemorrhage. The edema may be transient, if venous flow is re-established, or be associated with permanent tissue infarction if the increased venous blood pressure eventually exceeds the arterial blood pressure. In the latter situation, there is insufficient delivery of arterial blood and regional ischemic infarction [1,2]. Recently, MR imaging studies utilizing diffusion-weighted imaging (DWI) have demonstrated cytotoxic edema early in acute CSVT, preceding the onset of vasogenic edema. These findings support the presence of primary neuronal injury early in venous infarction [3].

Once the initial thrombus has formed, the resultant obstruction and venous stasis can promote propagation of the initial thrombus. Anticoagulant therapy is aimed at preventing extension of the initial thrombus and allowing the fibrinolytic system to achieve dissolution of the existing thrombus. Unlike an arterial ischemic stroke, relief of venous obstruction, even if very delayed, may relieve the circulatory congestion in CSVT with clinical benefit.

Figure 1. Deep venous thrombosis: male newborn born at term developed hypernatremia, dehydration, and seizures at day 8 of life; axial noncontrast CT shows bilateral thalamic hemorrhagic infarction secondary to deep venous thrombosis. Note increased density in the internal cerebral veins and the vein of Galen (arrow). (Click to enlarge figure)

Thrombotic occlusion of the superior sagittal sinus or the dominant lateral sinus interferes with the absorption of cerebrospinal fluid (CSF) through impaired function of the “arachnoid granulations” that line the superior sagittal sinus. The latter mechanism further increases the extent of cerebral swelling and results in a communicating hydrocephalus [1].

In addition to the intracerebral and intravascular events in CSVT, pressure on the optic nerves secondary to raised intracranial pressure initially causes papilloedema, which if unrelieved over time can progress to permanent visual loss.

• Imaging of venous infarction

Venous infarction may be evident on CT as a diffuse low-attenuating lesion (Fig. 2). Mass effect is common, and, in one study, 40% of symptomatic patients showed CT evidence of hemorrhage (Fig. 3) [4]. Bilateral, parasagittal, hypoattenuating lesions on CT is a common feature of venous thrombosis in the superior sagittal sinus. These lesions do not conform to an arterial distribution but do involve the cortex. Early changes are often subtle, with edema and swelling of the frontal/parietal gyri. In addition, isolated involvement of the temporal lobe is common and found in cerebral sinus thrombosis of the transverse sinus. Bilateral thalamic hypoattenuating lesions on CT may be evident in deep venous thrombosis and on non-contrast-enhanced CT, thrombus may be seen in the straight sinus.

Figure 2. Deep venous thrombosis in a 27-year-old woman with antiphospholipid antibody syndrome who presented with headache, nausea, and vomiting that progressed to aphasia and a decreased level of consciousness. Axial noncontrast CT (A) and T2-weighted MRI (B) show bilateral thalamic ischemia or infarction (open arrow). On CT, a small hemorrhage is seen in the right lateral ventricle (solid arrow). (C) T1-weighted sagittal MRI demonstrates subacute thrombus in the vein of Galen and straight sinus. (Click to enlarge figure)

Figure 3. Bilateral parasagittal hemorrhages secondary to superior sagittal sinus thrombosis (A) Axial noncontrast CT shows a high attenuation in the superior sagittal sinus (solid arrow) and bilateral parasagittal hemorrhages (open arrows). (B) Fluid-attenuated inversion-recovery sequence in another patient shows mixed-signal-intensity lesions in both frontal lobes with a fluid-fluid level (arrow) in a hematoma cavity on the left. (Click to enlarge figure)

MRI is sensitive to the parenchymal changes seen in cerebral sinus thrombosis. Cortical and subcortical high-signal-intensity lesions on fluid-attenuated inversion-recovery sequence and T2-weighted imaging may highly suggest cerebral sinus thrombosis when the lesions do not correspond to an arterial territory (Fig. 4) [4]. Restriction of diffusion on diffusion-weighted imaging (DWI) with a corresponding decrease in the apparent diffusion coefficient (ADC) value is often irreversible in arterial infarction and correlates with a permanent neurologic deficit [4]. Diffusion techniques have been used in cerebral sinus thrombosis to differentiate reversible ischemic tissue from irreversible ischemia [4]. Preliminary results have shown some potential in predicting the prognosis of the cerebral sinus thrombosis [4]. Recent investigations of cerebral sinus thrombosis have revealed that mixed signal intensity on DWI (see Fig. 4) may represent both cytotoxic and vasogenic edema [4]. A reduced ADC value in CVT may not correlate with neuronal death and a permanent neurologic deficit [4]. Therefore, a decrease of ADC in cerebral sinus thrombosis may not have the same prognostic value as it does in arterial stroke [4], and venous ischemia may be reversible despite decreased ADC values. This correlates with the important clinical improvement that may occur after an initial major cerebral sinus thrombosis-related neurologic deficit.

Figure 4. Diffusion imaging. T2-weighted (A) and fluid-attenuated inversion-recovery sequence (B) MRIs show scattered high-signal-intensity lesions (arrows). (C) Diffusion-weighted imaging demonstrates a mixed-signal-intensity area (arrow) suggesting both cytotoxic and vasogenic edema. (D) ADC map reveals that the lesions are predominantly hyperintense (arrows). (Click to enlarge figure)

 References

1. Bousser MG, Russell RR. Cerebral venous thrombosis. Toronto: WB Saunders Company Ltd. 1997
2. Ungersbock K, Heimann A, Kempski O. Cerebral blood flow alterations in a rat model of cerebral sinus thrombosis. Stroke. 1993;24:563-569
3. Forbes KP, Pipe JG, Heiserman JE. Evidence for cytotoxic edema in the pathogenesis of cerebral venous infarction. Am J Neuroradiol. 2001;22:450-455
4. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 10.4a October 2009 [Click to have a look at the home page]
5. Cerebral sinus thrombosis [Full text]
6. Neuroimaging of cerebral veno-sinus thrombosis (An introduction) [Full text]
7. Neuroimaging of cerebral veno-sinus thrombosis [Full text]
8. Pathophysiology of cerebral sinus thrombosis and its parenchymal changes [Full text]

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

November 23, 2009 — In childhood CSVT, thrombosis results from a combination of intravascular and vascular factors. Within individual patients, certain underlying risk factors including prothrombotic states may predispose to thrombosis, and other states including acute illnesses or prothrombotic medications act as triggering factors. Dehydration is a major intravascular risk factor at all ages. Vascular malformations including vein of Galen or cerebral arteriovenous malformations can also be associated with CSVT.

• Major risk factors for pediatric sinovenous thrombosis

Risk factors are identifiable in most children with CSVT.(Table 1).

• Neonates, older infants and children

Idiopathic CSVT occurred in only 3% of children in the Registry, compared with an estimated 10–25% of adults [1]. Common risk factors for CSVT in adults, such as pregnancy [2], malignancy [3,4]. and exogenous steroids are reported only rarely in children [5].

Risk factors are age-related in childhood CSVT. Neonates are uniquely susceptible to CSVT because of a number of physiologic factors. The maternal hypercoagulable state associated with pregnancy and the peri-natal period may contribute to neonatal thrombosis [6,7]. During delivery, molding of the cranial bones with deformation of the cranial sutures can damage the underlying dural sinuses, resulting in sinus thrombosis. Additional factors predisposing to neonatal CSVT include a relatively high hematocrit and slowing of dural venous flow compared with older ages and a decrease in the normal levels of protective clotting factors including Protein C, Protein S, and antithrombin [8]. In the neonate, venous flow within sinuses is dependent on head positioning [9].

Table 1. Major risk factors for pediatric CSVT

Pre- or peri-natal disorders are reported in 51% of neonates with CSVT and include maternal infections, gestational diabetes, and prolonged rupture of membranes or placental abruption. Asphyxia is a frequent concomitant diagnosis in neonates with CSVT, and there is often diagnostic confusion between the two conditions. In neonates with documented asphyxia, CSVT is frequently present [10]. In the Registry, asphyxia or hypoxic-ischemic encephalopathy were reported in 51% of neonates [1]. Other neonatal illnesses associated with CSVT include dehydration (present in nearly one third of neonates), bacterial sepsis, meningitis, and prothrombotic disorders [1]. Hypernatremic dehydration in exclusively breast-fed neonates has been associated with neonatal CSVT [11,12]. Prothrombotic abnormalities have been reported in 15–20% of neonates with CSVT [1,13,14]. The persistence and contribution of these abnormalities to neonatal CSVT have not been defined, however [1]. A strong association has been reported among pre-eclampsia, prothrombotic disorders, and neonatal venous sinus thrombosis [15].

In older infants, iron deficiency anemia is occasionally associated with CSVT [16]. Head and neck infections resulting in “septic” CSVT are present in 23% of older infants and children, and they are particularly common when related to otitis media and mastoiditis in preschool children [1]. In septic CSVT, head and neck infections directly invade adjacent dural sinuses resulting in a thrombophlebitis.

In older children head trauma or cranial surgery may damage the dural sinuses leading to CSVT. Chronic systemic diseases are an underlying risk factor in approximately 60%. These consist of connective tissue disorders including systemic lupus erythematosus, nephrotic syndrome, inflammatory bowel disease, hematologic disorders, underlying cardiac disease, and others [1,13,14]. The mechanism for sinovenous thrombosis in most chronic diseases is that of an acquired prothrombotic state. For example, nephrotic syndrome causes renal loss of antithrombin, resulting in an acquired antithrombin deficiency, and systemic lupus erythematosus may be associated with a lupus anticoagulant—both prothrombotic states. Acute illnesses including sepsis or dehydration are present in nearly one third of children with CSVT. Dehydration is frequently found in the setting of a viral gastroenteritis.

Prothrombotic disorders are reported in 33–96% of children with CSVT, the latter figure representing children with otherwise idiopathic CSVT. Congenital prothrombotic disorders are relatively rare and include factor V Leiden; prothrombin gene G20210A; dysfibrinogenemia; deficiencies of protein C, protein S and antithrombin; factor XII deficiency; and a thrombomodulin mutation [8,9,15–22]. These figures exceed the estimates in adults with CSVT, in whom the incidence of prothrombotic disorders is 15–21% [23,24]. Acquired prothrombotic states are frequently found, and multiple abnormalities may coexist in individual patients. Acquired prothrombotic states include anticardiolipin antibody; lupus anticoagulant; acquired activated protein C resistance; acquired deficiencies of protein C, protein S and antithrombin; and hyperhomocystinemia [11,12,25,26]. These acquired abnormalities are frequently transient, however, and whether they are associations with CSVT is still being explored. At all ages, superimposed acute illnesses frequently combine with prothrombotic disorders in the development of CSVT. [27,28,29,30]

 References

1. Bousser MG, Russell RR. Cerebral venous thrombosis. Toronto: WB Saunders Company Ltd. 1997
2. Cantu C, Barinagarrementeria F. Cerebral venous thrombosis associated with pregnancy and puerperium. Review of 67 cases. Stroke. 1993;24:1880-1884
3. Brown MT, Friedman HS, Oakes WJ, et al. Sagittal sinus thrombosis and leptomeningeal medulloblastoma. Neurology. 1991;41:455-456
4. Hickey WF, Garnick MB, Henderson IC, et al. Primary cerebral venous thrombosis in patients with cancer–a rarely diagnosed paraneoplastic syndrome. Report of three cases and review of the literature. Am J Med. 1982;73:740-750
5. Dindar F, Platts ME. Intracranial venous thrombosis complicating oral contraception. Can Med Assoc J. 1974;111:545-548
6. Ballem P. Acquired thrombophilia in pregnancy. Semin Thromb Hemost. 1998;24(Suppl 1):41-47
7. Delorme MA, Burrows RF, Ofosu FA, et al. Thrombin regulation in mother and fetus during pregnancy. Semin Thromb Hemost. 1992;18:81-90
8. Andrew M, Paes B, Johnston M. Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hematol Oncol. 1990;12:95-104
9. Cowan F, Thoresen M. Changes in superior sagittal sinus blood velocities due to postural alterations and pressure on the head of the newborn infant. Pediatrics. 1985;75:1038-1047
10. Lee BC, Voorhies TM, Ehrlich ME, et al. Digital intravenous cerebral angiography in neonates. Am J Neuroradiol. 1984;5:281-286
11. Gebara BM, Everett KO. Dural sinus thrombosis complicating hypernatremic dehydration in a breastfed neonate. Clin Pediatr (Phila). 2001;40:45-48
12. van Amerongen RH, Moretta AC, Gaeta TJ. Severe hypernatremic dehydration and death in a breast-fed infant. Pediatr Emerg Care. 2001;17:175-180
13. Bonduel M, Sciuccati G, Hepner M, et al. Prethrombotic disorders in children with arterial ischemic stroke and sinovenous thrombosis. Arch Neurol. 1999;56:967-971
14. deVeber G, Monagle P, Chan A, et al. Prothrombotic disorders in infants and children with cerebral thromboembolism. Arch Neurol. 1998;55:1539-1543
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The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

November 22, 2009 —  Summary of neuroimaging findings in cerebral sino-venous thrombosis

References

1. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 10.4a October 2009 [Click to have a look at the home page]
2. Cerebral sinus thrombosis [Full text]
3. Neuroimaging of cerebral veno-sinus thrombosis (An introduction) [Full text]
4. Neuroimaging of cerebral veno-sinus thrombosis [Full text]
5. Pathophysiology of cerebral sinus thrombosis and its parenchymal changes [Full text]