Therapy
General Measures
In patients with venous thrombosis due to external compression or neoplastic infiltration of a dural sinus, treatment of the underlying cause is, of course, necessary. Likewise, a thrombosis of infectious origin, such as those due to spreading of disease from a middle ear infection, requires prompt antibiotic treatment and often surgical removal. If increased blood coagulation is due to a hematological or neoplastic pathology, such as leukemia, appropriate treatment should be taken as soon as possible. In patients with reduced consciousness levels, appropriate nursing care and a good fluid homeostasis, as well as management of intercurrent complications, such as infections, is, of course, essential.
Anticoagulants
Since the pathogenic mechanism responsible for CVT is increased blood coagulation, administration of anticoagulants to affected patients seems to be a promising approach. Anticoagulants may prevent clot growth, which can further impair venous blood drainage from the brain and lead to worsening of the clinical conditions, and could, in theory, shift the balance of the anticoagulation systems, increasing the chance of sinus recanalization. This potential benefit needs to be balanced with the possible increase in the rate of cerebral and systemic hemorrhage. In a model of chemically induced occlusion of the superior sagittal sinus in rats,[42] low-molecular-weight heparin did not lead to an increase in the rate of recanalization, but was nevertheless associated with a better functional outcome, suggesting that the clinical effect of the drug is mainly due to prevention of occlusion of collateral vessels. In this model, no increase in the rate of bleeding was associated with the therapy.
Heparin and low-molecular-weight heparin have long been employed for the treatment of CVT, and many case descriptions or nonrandomized case series are present in the literature. However, only two relatively small randomized trials of sufficient methodological quality have so far been reported. The first study tested endovenous heparin against placebo (saline solution) and was stopped early, after the recruitment of 20 patients, because a planned interim analysis showed an increased death rate in the placebo group. In total, three patients died and six survived, with a minor deficit in the placebo group, while only two patients had minor deficits in the heparin group and none died.[43] The second trial used fractioned heparin and enrolled 60 patients, showing a nonsignificant trend in favor of nadroparine (poor outcome: 13 vs 21% of the placebo group).[44] In both studies no symptomatic brain hemorrhage was observed; one case of gastrointestinal bleeding occurred in the second trial. In the first trial, three patients with brain hemorrhage improved with heparin, whereas in the placebo group two patients with previous hemorrhage died and two new symptomatic hemorrhages were observed. Therefore, early concerns of a hemorrhagic risk connected with heparin therapy, based on anecdotal reports, are not confirmed by the randomized trials, demonstrating a high level of safety for the treatment. Thus, concomitant brain hemorrhage consequent to CVT is not a contraindication for heparin therapy. A second possible beneficial effect of anticoagulation may be prevention of pulmonary embolisms from the jugular veins, but no such events were observed. A third study conducted in India showed similar results, but its validity is questionable as the diagnosis of CVT was made on the basis of a CT scan only.[45]
The two trials have been pooled in a Cochrane meta-analysis,[46] which found a nonsignificant relative risk reduction of 0.46 (95% CI: 0.16-1.31) in death or dependency; the absolute risk reduction was 13% (95% CI: −3-30). The relative risk of death was 0.33 (95% CI: 0.08-1.21). Although the two trials employed different drugs (unfractioned or fractioned heparin), the meta-analysis was considered possible because of consistent demonstration of the equivalence of the two drugs in other settings. Therefore, anticoagulation should be started in all patients with established CVT, either with unfractioned heparin or low-molecular-weight heparinoids, and then continued with oral anticoagulants. The decision of when to stop therapy is often a difficult one, as most recurrent event take place in the first year,[11] thus continuing the treatments beyond this limit does not seem justified. Although the optimal duration of anticoagulation is unknown, the common clinical practice is to continue treatment for at least 3 months in cases of CVT due to intercurrent disease or condition, 6-12 months in idiopathic cases or in cases of mild hereditary thrombophilia, and indefinitely in those with severe thrombophilia.[47]
Thrombolysis
Some patients continue to worsen and have a negative outcome despite anticoagulation. In this setting, systemic or local thrombolysis could be considered, with the aim of opening the occluded vessel and reducing cerebral hypertension. Indeed, some authors reported a dramatic improvement after thrombolytic treatment,[48,49,50,51,52] and its use as an alternative to anticoagulants in selected patients is increasing. In particular, local (intra-arterial) thrombolysis could be better suited than systemic treatment, as venous clots are larger than arterial ones and are more easily accessible for mechanical revascularization and for injection of the drug directly into the thrombus. In two open uncontrolled trials, one in Korea and one in the USA,[49,52] a total of 21 patients were treated with local thrombolysis, with good results. In total, 15 patients had a complete recanalization of the occluded vessel and 14 recovered completely. However, four patients had major extracerebral bleeding and two who had pretreatment intracerebral hemorrhage worsened. Evidence of brain hemorrhage might represent a contraindication to intra-arterial thrombolysis, although this concept would need to be confirmed by further data from clinical studies.
The patients most likely to benefit from thrombolysis are probably those who present with a coma and those with documented occlusion of the deep venous system, as both of these features, which frequently coexist, are associated with a worse prognosis despite anticoagulation. In addition, patients with occlusion of multiple sinuses have an unfavorable outcome and might be good candidates for a more aggressive treatment. In these patients, the main therapeutic goal is not to prevent a further extension of the thrombotic process, but to re-establish venous outflow in a critical district, thus modifying a condition that is already threatening the patient's survival. In fact, in a review on 38 comatose patients treated with thrombolysis, the observed mortality was 13% (six cases);[53] as a comparison, the death rate of patients in coma in the ISCVT was 38%.
Despite these preliminary results, at present, no clinical trial to test the safety and effectiveness of this procedure has been reported.[54] The conduction of a randomized controlled trial comparing anticoagulation with thrombolysis is, therefore, needed urgently and may provide significant information that could alter the clinical management of CVT. This will probably represent one of the most likely evolutions in this field (see 'Five-year view' section).
Antiepileptics
Cerebral venous thrombosis is associated with a much higher risk of epilepsy than arterial stroke. In the ISCVT, nearly 40% of patients had a seizure as the presenting symptom of the disease. Furthermore, the same study showed that 6.9% of the patients had seizure in the first 2 weeks after the diagnosis (these were called 'early seizures').[55] The latter are particularly relevant from a therapeutic point of view as they may represent a serious complication that may be prevented by the administration of antiepileptics. In the patients of the ISCVT, early seizures were present more often in patients with presenting seizures, motor deficit, superior sagittal sinus or cortical vein thrombosis and the presence of any cerebral lesion.[55] A logistic regression analysis demonstrated that the risk of early seizures was significantly increased in the patients with supratentorial lesions at CT scan or MRI (OR = 3.09; 95% CI: 1.56-9.62); patients with presenting seizures had a higher risk without statistical significance (OR = 1.74; 95% CI: 0.9-3.37). Both of these indicators have a biological plausibility, since the presence of a supratentorial ischemic or hemorrhagic lesion is a trigger of epileptic activity and since a seizure at presentation reflects an underlying condition that may facilitate further epileptic events. These prognostic data were confirmed in another study on 194 patients: motor deficit (OR = 5.8; 95% CI: 2.98-11.42; p < 0.001), intracranial hemorrhage (OR = 2.8; 95% CI: 1.46-5.56; p = 0.002) and cortical vein thrombosis (OR = 2.9; 95% CI: 1.43-5.96; p = 0.003).
The identification of patients at increased epileptic risk may be useful to select those most likely to benefit from antiepileptic therapy. By combining the two indicators, Ferro et al. divided a pooled population from the ISCVT and other smaller studies into four groups: those with neither presenting seizures nor supratentorial lesions, those with either the first or the second feature and those with both.[55] The patients in the first group were largely constituted of patients with isolated intracranial hypertension who presented with headache and no other clinical symptom; these patients had a low natural risk of early seizures (2.5%) and benefited little from antiepileptics. The patients with either presenting seizure or supratentorial lesions had a higher rate (7.1 and 8.2%, respectively); although antiepileptic treatment in these groups did not reach statistical significance for effectiveness, a clear trend toward a reduction of the crises can be appreciated (Table 3). Patients with both indicators have a consistent risk of recurrence of seizures and show a clear benefit from therapy (51% without therapy vs 0.7% with therapy; OR = 0.006%; 95% CI: 0.001-0.05). These data confirm earlier reports on smaller cohorts, in which only patients who had both presenting seizures and brain lesions had recurrence of seizures.[13]
The data presented should be considered with caution as they are derived from nonrandomized and nonblinded studies and, thus, suffer from several methodologic limitations, such as a possible unbalancing in clinical severity between patients treated or not treated with antiepileptics. However, since no evidence-based guidelines on this topic are currently available, these results are indeed valuable and have clinical implications. Patients with no brain lesions and who never had seizures should probably not be given antiepileptics, while those with both factors certainly benefit from treatment and are at risk of a worse outcome if not treated. Some uncertainty still exists regarding the indication of patients with a brain lesion but no presenting seizures or who have a first seizure but no parenchymal damage. Although conclusive evidence to treat these patients is currently lacking, the data available seem to indicate a trend towards reduction of crises. We believe, therefore, that the current clinical tendency to administer antiepileptics to patients in these two groups is justified and should be continued until more evidence is available. The decision of which antiepileptic to use is not supported by randomized trials; however, drugs with a good activity in focal epilepsy and with low or no interaction with oral anticoagulants should be preferred.
Treatment of Intracranial Hypertension
Some degree of brain edema is observed in up to 50% of patients with CVT and is responsible for some of the most frequent symptoms, such as headache and loss of vision. Anticoagulants are often sufficient to reduce brain swelling by increasing the venous outflow; however, further treatment may be need in patients with visual-field reduction and in those with impaired consciousness.
In the first case, lumbar puncture to reduce cerebrospinal fluid pressure before anticoagulant treatment is established can be useful, but if visual impairment progresses, surgical procedures, such as optical nerve fenestration or ventricular peritoneal shunting, must be considered. In the second instance, general measures to reduce intracranial hypertension should be taken: the patient's head should be raised by 30° and intravenous osmotic diuretic should be initiated. If symptoms progress, hyperventilation with a target partial pressure of CO2 must be established. Treatment with steroids has long been considered an option as it could reduce vasogenic edema; on the other hand, steroids have thrombotic properties and may, therefore, be harmful in CVT. This uncertainty is reflected in current clinical management; in the centers participating in the ISCVT a high variation in the use of steroids was observed (3.3-72%). The effectiveness of steroids was tested in a case-control retrospective analysis on 300 cases from the ISCVT,[56] showing no benefit from treatment (OR = 1.7; 95% CI: 0.9-3.3; p = 0.119). When patients were divided into those with or without lesions at CT-MRI scans, lack of effect was confirmed in the first group (brain lesion: OR =1.2; CI: 0.6-2.7; p = 0.675), while a trend towards a detrimental effect of steroid was demonstrated in the second group (no brain lesion: OR = 4.8; 95% CI: 1.2-19.8; p = 0.078). The authors conclude that there is no evidence to recommend steroid use in CVT patients with brain lesions and that they should be avoided in patients without lesions (level III recommendation).
In patients with large hemorrhagic infarctions and transtentorial herniation, decompressive craniotomy is necessary to save the patient's life; some authors reported survival with only minor sequelae even in such severe cases.[57] The hemorrhage itself should not be removed as the neuronal damage is limited and may be more easily reversible than in arterial infarction.[47]
Expert Rev Neurother. 2009;9(4):553-564. © 2009 Expert Reviews Ltd
Cite this: Cerebral Venous Thrombosis - Medscape - Apr 01, 2009.
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