Cerebral sinus venous thrombosis

Introduction

Cerebral sinus venous thrombosis (CSVT) is a rare form of venous thromboembolism (VTE).[1] CSVT represents almost 0.5%[2] -3%[2] of all the types of stroke, affecting predominantly younger people,[3] with an estimated incidence for adults of 3-4 per million, and for children 7 per million.[4]

In the pre-antibiotics era, the leading cause of CSVT were the septic processes, currently the aseptic form of CSVT is the most common cause.[5] An autopsy finding can represent 10% of death causes from cerebrovascular diseases.[6]

CSVT is characterized by a highly variable clinical spectra, difficult diagnosis, variable etiologies and prognosis. Of interest, in poor countries, there is an association with the puerperium, with no clear arguments, but probably related to factors such as inappropriate perinatal care, metabolic derangements, and infections associated to childbirth.[5] The peripartum-associated CSVT has been established to be of 11.6 cases per 100 000 deliveries.[7] There is sex predominance (hormonal?); 75% of all CSVT patients are women, with a 3:1 ratio compared to men.[8]

This work aims to review current knowledge about CSVT including its pathogenesis, etiology, clinical manifestations, diagnosis, and treatment.

Anatomy

Cerebral venous drainage is comprised of two systems, the superficial and the deep venous systems. The drained blood runs into the major dural sinuses: Superior sagittal sinus (SSS), inferior sagittal sinus (ISS), lateral sinus (LS), cavernous sinus and straight sinus, and then to the internal jugular vein (IJV). Due to its high proportion of anastomoses, the superficial venous system is difficult to diagnose in cases of occlusion, this system predominantly drain the SSS and the LS. Deep white matter and basal ganglia are drained by the deep venous system toward the vein of Galen. Many anastomoses can be found between these two cerebral venous systems.

Dural sinuses are divided classically into posterior superior (P-S) and anterior inferior groups (A-I). P-S comprises the SSS, ISS, LS, straight sinus, and occipital sinus. The A-I group comprises the superior and inferior petrosal sinuses and the cavernous sinus. Inside of dural sinuses are found the Pacchioni's or arachnoid granulations, which play an essential role in the cerebrospinal fluid (CSF) physiology. SSS is located anatomically in the attached margin of falxcerebri, and drains almost all cerebral cortex.

LS have two sections, the transverse and the sigmoid, which drain cerebellum, brain stem, and the posterior portions of brain hemispheres. In the skull base are located the cavernous sinuses, into these sinuses, run oculomotor, trochlear, the ophthalmic and maxillary branches of the trigeminal nerves, through the petrosal sinuses, the cavernous sinuses drain the blood to the IJV.

Pathogenesis

Clinical findings of CSVT can be product of two main mechanisms:

1. Occlusion in cerebral veins

This occlusion can cause outflow obstruction and venous congestion, increasing the capillary hydrostatic pressure[9] and then producing edema, but this not necessarily means focal venous infarctions.[10] Histological analysis reveals dilated and enlarged veins, edema and ischemic neuronal damage, petechial hemorrhages that can converge and transform into hematomas. Two types of edema can develop, cytotoxic and vasogenic edema, the magnetic resonance (MR) could differentiate the type of edema present during the CSVT event.[1112]

2. Occlusion of venous sinuses

Derived from this phenomenon, the intracranial hypertension (ICH) is the predominant characteristic. Normally, the CSF drains into the SSS through the Pacchioni's or arachnoid granulations. When the thrombosis happens, the venous pressure raises due to delaying in the venous emptying, altering the CSF absorption, and thereby raising the intracranial pressure.[45]

The sufficiency of the collateral blood drainage will determine the symptoms. When collaterals are sufficient, symptoms are related to ICH; when they become insufficient, the venous congestion causes ischemia and infarctions.[5] In the case of younger patients, the CSVT spectrum can range from venous congestion detectable or not on neuroimaging, to the parenchymal cortical or subcortical ischemic injury,[9] lesser frequently is observed the CSVT-related sub-arachnoid and subdural hemorrhages.[9]

The International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) determined the frequency of the sites of SCVT as follows: Transverse sinus 86%, superior sagittal sinus 62%, straight sinus 18%, cortical veins 17%, jugular veins 12%, vein of Galen and internal brain veins 11%.[8]

Causes and Risk Factors

CSVT is a multifactorial condition with sex-related specific causes.[1] As in any thrombotic process, risk factors are associated with the classical Virchow triad of thrombogenesis: hypercoagulability, vessel wall damage and blood stasis.[1314] It may be associated with inherited and acquired risks factors (see Table 1); however, this categorization is fairly artificial, because they have additive effects and CSVT is multifactorial.[15] By far, in developed countries, the most frequently associated factor is congenital thrombophilia.[2] Inherited prothrombotic risk factors include homocysteinemia, factor V Leiden homozygous mutation, G20210A prothrombin gene and Methylene- Tetra-Hydro-Folate-Reductase 677TT mutations, protein C and S and anti-thrombin III deficiency, and positive anti-cardiolipin or anti-phospholipid antibodies.[1617]

Table 1 Risk factors associated to CSVT

Acquired risks factors include all the usual causes of VTE and additionally causes such as brain tumors,[18] head trauma,[19] central nervous system infections (bacterial meningitis, cerebral malaria,[20212223] intracranial hypotension,[242526272829] any local head infection,[2] extracerebral neoplasias,[3031] dural fistulas,[32] hematological conditions,[3334353637] nephrotic syndrome,[38394041] systemic vasculitis,[424344] medicaments (cisplatin,[45] methotrexate,[46] steroids), neurological surgery, lumbar puncture,[47484950] pregnancy,[151525354] Puerperium.[35556] The Table 1 summarizes the risk factors associated to CSVT.

The IJV represent the main outflow pathway for the cerebral venous system.[57] IJV abnormalities may change the hemodynamics of cerebral venous outflow, leading to insufficient venous drainage, and subsequently causing CSVT. In a study performed by Jia et al.,[14] found that among 51 consecutive CSVT cases with unknown etiologies, 61% of the cases (31/51) had an IJV abnormality; furthermore, almost all the CSVT occurred on the same side as the IJV lesions, which strongly suggests a close association between IJV abnormalities and CSVT. However, a predisposing factor may not be identified in up to 20–35% of cases.[1758]

The marked sex preference is usually attributed to gender-specific risk factors, especially oral contraceptives use (OC) and to a lesser extent, pregnancy, puerperium, and the hormone replacement therapy. Conclusions have been obtained from researches in age groups that lack of these gender-specific risk factors (i.e., children and elderly patients), and have showed no gender predilection.[5960] Furthermore, epidemiological studies performed before OC era do not show a difference in gender distribution.[60] Strikingly, evidence has shown that contraceptive products that delivers a lower systemic estrogen dose like NuvaRing® has at least as much prothrombotic potential as combined OC, doubting the theoretical benefits of non-oral route of steroid hormone delivery.[61] Case-control studies showed a significant association between use of OC and CSVT, which was confirmed in a meta-analysis (pooled OR, 5.59).[62]

In the ISCVT registry,[8] 44% of the patients had one risk factor, and congenital or genetic thrombophilia was present in 34.1% of the patients. Gender-specific risk factors were present in 65% of the women. Near to 85% of the patients with CSVT have prothrombotic risk factors or direct causes. Inherited or acquired thrombophilia and the OC use were the commonest risks factors.[8] In the group of acquired thrombophilia, the anti-phospholipid syndrome was the most frequent (5.9%), followed by hyperhomocystinemia.[8] OC use was in 54.3% of the patients;[8] thus, keeping relationship with the results of Bruijin et al,[63] 85% of women in their study used OC, from which 56% were third generation OC, containing gestodene or desogestrel.

The RENAMEVASC study (from a registry conducted between 2002 and 2004 in 25 Mexican hospitals) found that gender-specific risk factors explained the majority of cases, and as suboptimal the thrombophilia assessment and acute treatment. Those findings make a big difference regard registries conduced in developed countries, where is performed a standard protocol for thrombophilia and active seeking of oncology and hematology patients.[3]

The fluctuations of ICP during delivery and the hypercoagulability state of pregnancy due to enhanced platelet adhesion and to increased coagulation factors could be an explanation for the augmented risk of CSVT in the peripartum. In two clinical reports, one from the Hospital Militar Nueva Granada in Bogotá,[64] and another from the University Hospital of North Staffordshire,[65] both patients had persistent cephalea during more than two weeks after epidural anesthesia, with evidence of dural accident in one of the cases, unresponsive to blood patches, and with diagnosis of lately CSVT. The group of University Hospital of North Staffordshire proposes that obstetric units should have protocols for the management of post-puncture headache, which includes thromboprophylaxis for patients with low mobility and an earlier multidisciplinary approach with neurologists and radiologists when cephalea persists after dural blood patch.[65]

Not all CSVT involve venous infarction; SanzGallego et al.[10] studied the influence of risk factors in patients with CSVT regard the probability of developing venous infarction, they included 52 patients, and found that the most frequent risk factor in those who had venous infarction was thrombophilia (40.9%), whilst in those without venous infarction the use of OC predominated (26.7% of the total sample; 38% of females), with thrombophilic states only being detected in 16.5%. No cases of venous infarction were found in the group of patients with OC but without an associated thrombophilic state. They concluded that appears to be a different profile of risk factors in patients who develop venous infarction associated to CSVT, with thrombophilia prevailing. In conclusion, CSVT is a multi-factor consequence, and the identification of one of them should not prevent the intentional search for co-existing causes that may potentially increase the probability of recurrence.[3]

Clinical Manifestations

Clinical data of CSVT is extraordinarily variable, and such variability depends on different factors, such as the location and extension of the thrombosis, the extent of the venous occlusion, patients age, and the nature of the underlying disease or predisposing cause.[66] Although a few differences have been identified between men and women in the clinical presentation of CSVT, these differences are minor, and the diagnostic work up and treatment strategies are roughly similar in both groups.

In 30% of CSVT cases, it presents in an acute fashion and the symptoms appear in less than 48 h. In up to 50% of cases, it presents in a sub-acute fashion and the symptoms appear between 48 h and 30 days. The chronic form corresponds to 20% of cases, and the symptoms develop over a period greater than 30 days and up to 6 months,[5] see Table 2.

Table 2 Presentation fashion of CSVT

Clinical findings in CSVT usually are due to the impaired venous drainage, ICH, focal brain injury from venous ischemia/infarction or hemorrhage, or mix of them; however, it is not necessarily to be together at presentation.[13] Bousser et al.[2] described 4 clinical patterns for CSVT, see Table 3:

Table 3 Clinical patterns of CSVT

Headache is the most common symptom in CSVT. In the SCVT, it was present in almost 90% of patients; in fact, in CSVT, this symptom is more frequent than in cerebrovascular ischemic arterial disease. Its physiopathology lies in the ICH syndrome, in the venous walls distension or due to local inflammation or the blood leakage over the brain surface irritating dural sensitive fibers.[66] Similar headache frequency has been reported in other populations studied, see Table 4.[313]

Table 4 Analysis of risk factors and clinical presentation of CSVT

Typically, the cephalea is described as diffuse and often progressive in severity over days to weeks,[13] but, in a minority of patients may present as a thunderclap headache, suggesting an hemorrhagic process (i.e., sub-arachnoid hemorrhage), oras migraine cephalea,[13] that difficult diagnosis, because can be confusing to distinguish due to its unilateral character, intermittent course and for the usual visual abnormalities.[66] Diffuse or anterior/posterior bilateral headache has been reported.[67]

Isolated headache without focal neurological findings or papilledema occurs in up to 25%-40% of patients with CSVT, confusing the diagnostic process.[1337] Even in the absence of neurological focal signs suggestive of idiopathic ICH, in all patient with headache and papilledema or diplopia (caused by sixth nerve palsy), should be considered as differential diagnosis the CSVT.[13] Since ICH can be present in an isolated way, the idiopathic ICH should be considered among differential diagnosis; clinically, the main difference between ICH secondary to CSVT and idiopathic ICH is that the latter predominates in obese women.[5]

Near to 12-31.9% of patients have seizures as the presenting feature of CSVT, but 44.3% of patients may have seizures in the early stage of the disease.[68] Similar proportions have been found in other studies.[6970] Focal sensory and motor deficits are very common and occasionally suggest the location site, especially when there is a paralysis of cranial nerves such as in IV paralysis.[5] Focal or generalized seizures are frequent, occurring in near 40% of patients.[13] In patients with seizures, Todd's paralysis can be presented in near 54% of cases.[69]

According to the SCVT, the course of clinical manifestations can be summarized as follows: intensive and progressive cephalea, the main symptom; seizures (39.3%); paresis (37.2%); papilledema (28.3%); altered mental state (22%), aphasia (19.1%), stupor or coma (13.9%), diplopia (13.5%), and visual deficits (13.2%).[8]

In cases of septic CSVT, the clinical pattern is characterized by cephalea, fever, ophtalmoplegia due to paralysis of oculomotor, abducens and trochlear nerves, all, making compatible with orbital cellulitis, which is the most common antecedent in these cases.

Diagnosis

This entity should be considered in all young women who have unusual headache that can be progressive in time, with focalized neurological deficits and without vascular risk factors. Because the variability in the clinical presentation, it should be excluded by using available neuroimaging studies when there is clinical suspicion. Due to the wide availability of magnetic resonance venography (MRV) and CT-scan venography (CTV), the invasive procedures (i.e., cerebral angiography and direct cerebral venography) are less commonly needed for making diagnosis. Generally, invasive modality of diagnosis is reserved when MRV or CTV results are inconclusive or if an endovascular procedure is being considered.[13]

CT and MR venography

Due to its vascular detail and ease interpretation, CTV can provide a rapid and reliable diagnosis of CSVT.[79] CTV has proved to be a reliable method to investigate the structure of the cerebral veins, with a reported sensitivity of 95% with multiplanar reformatted (MPR) images when compared with digital subtraction angiography (DSA) as the gold standard.

Some disadvantages of conventional CTV are the time-consuming and operator-dependent editing needed to remove over projecting bone for the angiographic display of intracranial vessels,[79] radiation exposure, and problems related to use of contrast in the setting of poor renal function, or in patients with contrast material allergy, because of these concerns, MRV have being preferred to CTV. CTV is much more useful in sub-acute or chronic situations because of the varied density in thrombosed sinus. As previously mentioned, the dense cortical bone adjacent to dural sinus made prone bone artifact interfering with the visualization of enhanced dural sinus.

The combination of abnormal sinus signal and the corresponding absence of venous flow in the MRV confirm the diagnosis, but in front of a chronic CSVT with unclear MRI, the angiography could be the first diagnostic tool.[8687] Besides of allow the CSVT diagnosis, the MRI and the MRI angiography obviate the use of invasive angiography, and furthermore, they are useful for the follow up of CSVT patients.[88]

CT-contrasted angiography and the Gadolinium-enhanced MRI or the MRI angiography has 100% sensitivity and specificity for identification of CSVT;[8889] thus, CTV is at least equivalent to MRV in the diagnosis of CSVT.

MRV features include non-visualization of the vessel (i.e. no flow), flow defect, and presence of collaterals at the site of occlusion,[84] see Figure 1. In the first 5 days, the thrombus is highly hypointense in T2- weighted MRI and isointense in T1- weighted MRI. Until the 15^th day, the hyperintense thrombus signal in T1- and a T2- weighted image persists. This could be the most important period of time because is when most diagnosis are made. The thrombus signal diminishes at the third week, and the imagenological evolution is toward the re-establishment of the blood flow or to a residual blood clot. Venous infarction on MRI is a significant predictor of clinical deterioration in patients with CSVT (P = 0.001).[90] Diffusion-weighted image (DWI) hyperintensity indicating diffusion restriction is also predictive of clinical deterioration in patients with CSVT.[90]

Close

Figure 1

3D-MIP (reformatted by 2D-TOF) sequence of a 40-year-old female patient with CSVT. Sequence obtained after 2 months does not show changes at the level of straight sinus; the transverse sinus is still absent of flow near the confluence of the sinuses.

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Treatment

Treatment strategies are aimed to control or resolve the underlying pathology, controlling ICH and treatment of seizures or focal deficits caused by cerebral edema or infarction.[93] Anti-coagulation is used almost universally and in selected cases, endovascular and surgical techniques have been employed to remove the clot. Surgical techniques are further used to treat the sequelae of CSVT such as hydrocephalus, ICH, hemorrhagic stroke, among others.

Medical Management

Anticoagulation

Heparin has been used to treat CSVT since 1941.[93] The use of heparin and oral anticoagulants (OA) is based basically on the rationale of reversing the causal thrombotic process and on preventing complications. Due to the presence of a hemorrhagic element in 40% of CSVT, the administration of anticoagulant treatment stills controversial.[5]

In the metanalysis performed by Coutinho et al.,[97] where only were included the only two random studies with the minimum methodological standards, heparin was associated with an absolute reduction in mortality of 13% (CI 95%: 27-1%; P = .08) and a reduction in absolute risk of death or dependence of 15%, without causing an increase in new hemorrhagic lesions, also was observed a greater frequency of pulmonary embolism in those patients who did not receive anticoagulation.

Further evidence for support the use of heparin derive from the finding that 39% of cases in the SCVT cohort had intracerebral hemorrhage before treatment, no prognosis worsening was observed in the 83% of all patients treated with heparin.[8] Other concern related to heparin is that currently there are no precise instructions on which type of heparin to use [Unfractioned heparin (UFH) vs. Low Molecular Weigh Heparin (LMWH)]. The “European Federation of Neurological Societies” (EFNS) guideline recommends LMWH because of practical advantages. The main advantage of this heparin use is that it is easy to antagonize in situations such as the need for surgical intervention[598] and based upon data from randomized trials in leg-vein thrombosis,[99] but in the ISCVT, the UFH was used in almost the majority of patients.[8] An international survey performed with the aim to determine how physicians worldwide treat CSVT showed that physicians worldwide consider heparin the primary therapy for CVT patients. However, while evidence-based guidelines advocate the use of LMWH, the majority uses UFH.[100] Other advantages of LMWH in therapeutic doses are that it provides more steady anticoagulation and does not require dosage adjustment based on coagulation times.[5] UFH is administered intravenously at an initial dose of 5000 UI, and then the infusion is maintained at 1000 UI/h or a response dose to achieve an activated partial thromboplastin time of 60-80s.[101]

Guenther et al.[5] recommends that after the acute phase of CSVT, to use OA unless there is a clear contraindication and in cases of CSVT associated with a transient risk factor such as infection, trauma or pregnancy, a treatment period of 3 months is enough, but in the case of being present a greater risk of recurrence, such as pro-thrombotic states, the duration of anticoagulation should be longer (6-12 months). Also recommend a suggest maintaining anticoagulation with an international normalized ratio (INR) of between 2.0 and 3.0.

Endovascular and Surgical Management

Conclusion

CSVT is a multifactorial condition with gender-related specific causes, with a wide clinical presentation, furthermore, the leading causes differ between developed and developing countries, i.e., congenital thrombophilia vspuerperium or OC use respectively.

CSVT is a condition characterized by a highly variable clinical spectra, difficult diagnosis, variable etiologies and prognosis that requires fine medical skills and a high suspicious index. Patients who present with CSVT should underwent to CVT and to the proper inquiry of the generating cause. It is imperative an intentional search for co-existing causes, as well as the management of post-puncture headache.

Correcting the cause, generally the complications can be prevented. Mortality trends have diminished, and with the new technologies, surely it will continue. Treatment strategies are aimed at treating the underlying pathology, controlling ICH, and management of seizures or focal deficits caused by cerebral edema or infarction.

Fifty years ago, CSVT was a mortal condition, but with the introduction of neuroimaging, the mortality rates have become minimal; however, it is needed further impulse because still persist great blanks, especially regard to clarification of its management.