Caring for cerebral venous sinus thrombosis in children.

Cerebral venous sinus thrombosis in children is increasingly recognized as diagnostic tools and clinical awareness has improved. It is a multifactorial disease where prothrombotic risk factors and predisposing clinical conditions usually in combination constitute the underlying etiology. Clinical features range from headache, seizures to comatose state. Although symptomatic treatment involving control of infections, seizures and intracranial hypertension is uniform, use of anticoagulation and local thrombolytic therapy is still controversial. Morbidity and mortality can be significant and long-term neurological sequelae include developmental delay, sensorimotor and visual deficits and epilepsy.

INTRODUCTION

Cerebral venous sinus thrombosis (CVST) is thrombosis of intracranial venous sinuses and cerebral veins, which leads to impaired venous drainage and consequently to intracranial hypertension and/or venous infarcts. An estimated incidence of CVST in children derived from the largest pediatric CVST registry is 0.67 per 100, 1000 children. A higher incidence in neonates, however, has been reported by different studies (2.6-12 per 100 000 newborns a year).[1-3]

The actual occurrence is presumed to be much high as diagnosis is difficult, delayed and missed altogether in some cases because of highly variable clinical presentation in children and lingering onset.[4]

Clinical features range from seizures, headache and respiratory distress to threatening focal neurological deficits and comatose state. The risk factors are age-dependent, frequently multiple and different from those reported in adults.[1]

Infections are the most common predisposing factor both in neonates and older children, followed by hypercoagulable/hematological states, dehydration and various other conditions. In majority of cases, it results from combination of prothombotic risk factors with or without underlying clinical condition.[5]

Greater awareness and better availability of non-invasive diagnostic techniques, has led to increasing identification of the disease. Magnetic resonance imaging (MRI) and MR venography (MRV) are considered as the best tools for diagnosis and follow-up.[5]

Although symptomatic treatment i.e., control of seizures, intracranial hypertension and infections remains more or less uniform.[5] Regional practices demonstrate considerable variability and uncertainty about the indications for antithrombotic therapy in children especially in neonates.[6] Recent retrospective studies on safety and outcome of systemic anticoagulation therapy (ACT), showed anticoagulation is safe in pediatric population especially in the absence of initial intracranial hemorrhage, and non-treatment was associated with thrombus propagation.[7]

Long-term neurological sequelae include developmental delay, sensorimotor and visual deficits and epilepsy.[58-10]

Given the increasing incidence of sinovenous thrombosis in children, the variations in treatment and the adverse outcomes in half of the children with this disorder, studies are needed to identify more effective immediate and secondary preventive therapies.

PATHOGENESIS

CVST cause symptoms and signs by two different mechanisms: Thrombosis of the cerebral veins, with local effects caused by venous obstruction, and thrombosis of the major sinuses, which causes intracranial hypertension. In the majority of patients, these two processes occur simultaneously.

The first mechanism involves occlusion of the cerebral veins, which causes localized edema of the brain and venous infarction. Pathological examination shows enlarged, swollen veins, edema, ischemic neuronal damage and petechial hemorrhages, the latter can merge and become large hematomas. Two different kinds of cerebral edema can develop. The first is cytotoxic edema, caused by ischemia, which damages the energy-dependent cellular membrane pumps, leading to intracellular swelling. The second type, vasogenic edema, is caused by a disruption in the blood-brain barrier and leakage of blood plasma into the interstitial space. Vasogenic edema is reversible if the underlying condition is treated successfully. MRI has shown that both cytotoxic and vasogenic edema occur in cerebral vein thrombosis.[11]

In the second mechanism, intracranial hypertension develops as the result of occlusion of the major venous sinuses. Thrombosis of the sinuses leads to increased venous pressure, impaired absorption of cerebrospinal fluid, and consequently increased intracranial pressure. It is assumed that increased intraluminal venous pressure causes decrease in cerebral blood flow and cerebral perfusion pressure. This might induce an energy failure and a disruption of the blood-brain barrier that results in vasogenic edema and hemorrhagic transformation from increased venous pressure.[12]

The protective mechanisms against the abrupt increase of intravenous pressure have been described in the literature. One of these mechanisms is the opening of reserve capillaries that causes an increase in cerebral blood volume during the early phase of sinus occlusion,[13] if the capillary reserve capacity does not function efficiently, a sufficient amount of cerebral blood volume may not be sustained, which may result in ischemic injury to the brain in the early stage of sinus thrombosis.[14-16]

Another protective mechanism is the opening of the venous collateral pathways, which if not readily open after sinus thrombosis, causes a rapid increase in intravenous pressure and may cause injury to the blood-brain barrier very quickly.[17]

RISK FACTORS AND ETIOLOGY

Causative and/or predisposing factor for CVST in children differs from adults [Table 1]. However, like in adults, pediatric CVST is also multifactorial and in most patients combinations of risk factors contribute to the development and future risk of recurrent thrombosis.[3]

Table 1

Risk factors and etiology of pediatric cerebral venous sinus thrombosis

CLINICAL DISORDERS

Dehydration and systemic and local infections of head and neck like mastoiditis and meningitis are the most common clinical conditions described in neonates and children by various pediatric CVST registries. Perinatal complication like hypoxia, Extracorporial membrane oxygenation, pre-eclampsia and gestational diabetes in neonates and cardiac defects both in neonates and non-neonates are the other most commonly found clinical conditions. Rare conditions include vascular trauma, connective tissue disorders, solid tumors, hematological malignancies and surgeries mostly of head and neck.[1819]

PROTHROMBOTIC DISORDERS

Genetic and acquired prothrombotic disorders are increasingly recognized as risk factors for CVST in pediatric population as in adults. Relative frequencies of prothrombotic conditions, reported among different countries and ethnicities vary more as compared to clinical conditions described.

Genetic

The most genetic prothrombotic disorders are lipoprotein A, high levels of factor VIII, mutation in factor V Leiden and G20210A mutation in factor II and homozygosity for thermolabile methylene tetrahydrofolate reductase polymorphism (tMTHFR).

Acquired

Among acquired causes, raised anticardiolipin antibodies with connective tissue disorders and deficiencies of antithrombin III, protein C and protein S, fibrinogen and plasminogen by an acquired disorder such as liver disease, the nephrotic syndrome, or disseminated intravascular coagulation has been variably reported.

Anemia with or without microcytosis due to iron deficiency or chronic hemolysis as in thalassaemia or sickle cell disease is a common observation in these patients and might predispose to CVST.

Treatment with chemotherapeutic agents, L-asparginase, steroids and oral contraceptic agents are also recognized as acquired prothrombotic risk factors.[31318-21]

The majority of children (65%) have at least two risk factors with 40% having more than three risk factors. In about one-third of these patients, no obvious cause or underlying disorder can be diagnosed.[3]

CLINICAL FEATURES

Clinical presentation is highly variable and symptoms mostly result from intracranial hypertension or from damage to brain tissue due to venous infarcts. An equal sex distribution to male preponderance has been reported, with no ethnic predisposition.[222]

Generalized or focal seizures are the most common presentation in both neonates and non-neonates. Rests of clinical features vary among the two groups. Lethargy, feeding difficulties, apnea or respiratory distress and hypotonia predominate in neonatal group whereas focal neurological signs and symptoms like headache, motor and cranial nerve deficits, papilledema and decreasing level of consciousness are more commonly encountered in non-neonatal group. Involvement of deep cerebral venous thrombosis is characterized by altered consciousness, decerebrate posturing, changes in extrapyramidal tone and psychiatric symptoms such as confusion as a result of infarction in the thalami and basal ganglia and white matter structures. Some of the clinical features can in part be attributed to associated underlying clinical condition.

Although isolated pseudo-tumor cerebri is a common presentation of CVST, its prevalence in convulsive or non-convulsive status epilepticus is not known.[518]

Estimation of exact duration of symptoms and diagnosis is sometimes difficult to determine both in neonates and non-neonates because of non-specific features, so diagnosis requires a high-degree of clinical suspicion by treating physician. Salient features of neonatal CVT are given in Table 2.

Table 2

Salient features of neonatal cerebral venous sinus thrombosis

DIAGNOSIS

Laboratory

A thorough workup should be done to rule out all possible genetic and acquired prothrombotic disorders, anemia and investigations required for any associated clinical condition.

If no obvious cause or underlying disorder can be diagnosed, constant search should be continued and looked for with repeated investigations on follow-up.

Radiology

Computed tomography (CT)/CT venogram (CTV) of brain can be the imaging of choice for scanning neonates because of its advantages of a very short scanning period and its easy availability. However, CT scans have been shown to miss lesions in 10-26% of patients and can give false positive results in neonates. Cranial ultrasound may be helpful in neonatal cerebral venous thrombosis, but its findings often need to be confirmed by MRI and MRV.[11418]

MR in combination with MRV is the single most sensitive diagnostic technique for CVST. The MR appearance of the thrombus within the dual sinus or cortical vein is variable and largely dependent on its age. The loss of the normal flow void on spin echo T2 images is a sensitive parameter. Focal parenchymal changes occur in approximately 50% of cases and are due to edema and infarction, with or without hemorrhage. T2-MRI sequence is superior to spin echo in detecting CVST and small hemorrhages. MRV is considered the technique of choice for diagnosis and follow-up of CVST, but in certain cases, MRI could be superior as it shows the thrombus itself and not just the absence of signal as seen on MRV.[2324]

Diffusion and perfusion MRI may play a role in detecting venous congestion in cerebral venous thrombosis and in the differentiation of cytotoxic and vasogenic edema but does not differentiate venous from arterial infarction.[25]

The most common locations for CVST in both neonates and older children are the transverse sinuses, the superior sagittal sinus and followed by the straight sinus in the neonates and infants and the sigmoid sinus in older children.[14] Majority of the children presents with involvement of multiple sinuses. Lesser involvement of deep cerebral veins may reflect the current difficulties in diagnosing thrombosis in the deep system or cortical veins, which may require conventional angiography.[2627]

Focal brain abnormalities have been identified in approximately 50-60% of patients with sinus venous thrombosis despite the reported protective role of the venous collateral pathways in preventing parenchymal injury during sinus occlusion.[2829]

The most common location of brain lesions in neonates were the frontal and parietal lobes, whereas the most common location of brain lesions in the older children were the frontal lobe and the thalamus. The parenchymal lesions in infants were mostly seen in the frontal lobe and the cerebellar hemisphere. The location of brain lesions correlated with the corresponding venous drainage territory in children as compared to adults.[14]

A higher percentage of brain lesions and intraventricular hemorrhage has been observed in neonates by some studies. It has been suggested that CVST is not well-tolerated in children, particularly in neonates and the reason for this result may be the deficiency of the protective mechanisms because of immaturity.[14]

Treatment

Treatment of CVST remains controversial more so in neonates. Results of the published International Pediatric Stroke Study showed considerable variability and uncertainty in the regional antithrombotic practice, regarding the indications for antithrombotic therapy.[6]

Supportive treatment is more or less uniform for all pediatric age groups and includes rehydration, antibiotics for suspected sepsis, antiepileptic drugs for seizure control and measures to reduce intracranial hypertension.[18]

The American College of Chest Physician guidelines, published in 2004 and updated in 2008 suggest anticoagulation for neonates without significant intracranial hemorrhage, while the American Heart Association (AHA) guidelines published in 2008 recommend anticoagulants only when there is evidence of thrombus propagation, multiple cerebral or systemic emboli or a severe prothrombotic state is present.[30-32]

In one of the largest pediatric CVST registry, 85 out of 160 children including 25 neonates received ACT with no reported complications; however, treatment dosing, monitoring and outcomes were not standardized.[1]

A recent 7-center Portuguese study reported no influence of ACT on the outcome of 37 children but did not discuss safety of ACT in children. However, therapeutic regimens varied in different study centers.[33]

In another recent large single-center retrospective study on safety and outcome of ACT, 99 pediatric patients including 46% neonates and 77% children were treated with low molecular weight heparin (LMWH) either alone or following unfractionated heparin (UFH). Intravenous UFH was initiated without loading dose using 28 U/kg/h in infants of 1-year-old and 20 U/kg/h in older patients. LMWH was injected subcutaneously twice daily, 1.5 mg/kg/dose for children 2-months-old and 1.0 mg/kg/dose for older patients. The warfarin dose for children 1 year of age was 0.2 mg/kg/day, titrated to an international normalized ratio of 2.0-3.0.[7]

In their study major ACT-related complications were limited to intracerebral hemorrhage (ICH) and were observed in 6% of treated pts, at similar rates in neonates and children. Pretreatment ICH emerged as a strong predictor of ICH in both age groups, as new/increased ICH occurred 14% of patients with pretreatment ICH. Hence, ACT in the setting of pretreatment ICH requires careful consideration.

To support the use of ACT safety in the presence of pre-existing ICH in pediatric CSVT, prospective studies are needed.[7]

CVST propagation was noted in 30% of untreated patients, a finding that has been previously reported in untreated neonates and children. By preventing new thrombus formation, ACT enables unopposed fibrinolysis to dissolve thrombi, relieving venous congestion. Therefore, in CVST the potential ability of ACT to reduce ICH caused by severe or persistent thrombosis may balance the risks of ACT dependent bleeding.[7]

These observations, however, need confirmation in a controlled, adequately powered prospective trial. They further come up with suggestions including shorter duration ACT treatment in neonates.[7]

Till the evidence from randomized clinical trials is available, we suggest that anticoagulation should be considered in all children and neonates with CVST without intracranial hemorrhage, and with caution in the presence of intracranial hemorrhage. An early repeat venous imaging to screen for CVST propagation in untreated children and a vigorous follow-up is needed.

The experience with thrombolytic therapy and mechanical thrombectomy in pediatric CVST is limited to individual case reports or case series. Despite its effectiveness in achieving recanalization or patency of thrombosed intracranial sinuses, safety and availability are the main limitations of thrombolysis.[3435]

Surgical treatment of cerebral venous thrombosis is generally reserved for intracerebral hematomas with mass effect and for hydrocephalus.[18] Figure 1 provides flow chart for management of pediatric CVT.

Figure 1

Flow chart showing management plan for pediatric CVST

Outcome

Morbidity and mortality can be significant and associated with extent and localization of thrombosis and associated parenchymal lesions. Complete recovery was noted more in children as compared to neonates, whereas mortality ranges around 8-12% in either group. Long-term neurological sequelae include cognitive impairment, sensorimotor and visual deficits and epilepsy.[18-101819]

Presence of infarcts, younger age, seizures at presentation, decreased level of consciousness, focal neurological signs and thrombosis of the straight sinus have been found to be associated with poor outcome and long-term major neurological deficits in both neonates and older children.[833]

Whereas age at CVT onset (age equal to and younger than 2 years), non-administration of anticoagulation, persistent venous occlusion and presence of G20210A mutation in factor II predict recurrent thromboembolic events in children.[3637]

Secondary prophylactic anticoagulation should be given on a patient-to-patient basis in children with CVT, and at high risk of recurrent CVST. A practical approach could be coverage with anticoagulation in these patients in high-risk situation e.g., postoperatively, if prolonged immobilization is needed, or if the patient becomes dehydrated rather than indefinite therapy. While indefinite therapy may be considered in children with recurrent events of CVST.[3638]

SEARCH METHODOLOGY AND TERMS

References were selected from an electronic Medline, Google scholar and Cochrane library search from 1994 till 2010 using key words “cerebral vein thrombosis in children”, and “cerebral vein thrombosis in neonates” and terminologies like risk factors, clinical features, outcome etc. Only references in English were included. Some of the references for this review came from the authors’ files.

CONCLUSIONS

CVST in children is associated with significant morbidity and mortality although chances of recovery are better in children than in neonates. Diagnosis is difficult and requires high clinical suspicion because of non-specific, highly variable clinical presentation and lingering onset. As symptomatic treatment remains more or less uniform among different treatment groups, role of anticoagulation or thrombolytic therapy still remains controversial. Evidence from large multicenter randomized trial is needed to establish the role of anticoagulation and thrombolytic therapy in pediatric CVST.