Benefits of Prolonged Anticoagulant Treatment in a Series of Cerebral Venous Thrombosis in Pediatric Patients

Abstract

Background: Cerebral sinus venous thrombosis (CSVT) is a rare complication in children, usually secondary to an underlying condition. Recent guidelines recommend treating all pediatric patients with CSVT, but also suggest that treatment longer than three months should not be justified in provoked cases in which the risk factor has disappeared.

Methods: Retrospective observational study analyzing data of CSVT in children (1-18 years-old) admitted in a single hospital. Demographic data, clinical presentation, etiology, extension, treatment and outcome were evaluated.

Results: Thirty-one patients had a confirmed CSVT. Sixteen were girls, mean age was 7.3 years (SD 4.39). Sigmoid sinus (n=17) and transverse sinus (n=14) were the most frequent sinuses affected. Multiple sinus thrombosis was found in 20 patients (64.5%). Underlying condition was described in 29 cases: infectious disease (n=20), major head trauma (n=4), chemotherapy (n=3), arteriovenous malformation (n=2). More frequent symptoms were: headache (n= 15), decreased level of consciousness (n=5), seizures (n=3), focal neurological deficit (n=2), papilledema (n=2), diplopia (n=2), vision impairment (n=1), and coma (n=4). All patients received anticoagulant treatment. Complete vein recanalization after 3 months was achieved in 53.3% of the cases. Treatment was prolonged up to 6 months in those patients with partial or no response (n=14). Seven of them improved radiological findings. Complete and partial vein recanalization were reported in 73.3% and 20% of the patients.

Conclusion: Anticoagulation was useful to achieve complete vein recanalization in this series. Extending anticoagulation up to 6 months could be useful to improve outcome of pediatric patients with CSVT in selected cases.

Keywords: Sinus thrombosis; Pediatric; Anticoagulant treatment; Treatment outcome

Background

Cerebral sinus venous thrombosis (CSVT) is a rare condition in pediatric patients (0.7 cases per 100,000 children and year) [1]. Most of them are secondary to well known risk factors: head and neck infections, cranial traumatism, chemotherapy treatment (steroids and asparaginase), inherited or acquired thrombophilia, and hormonal treatment with estrogens [2-4]. Headache and other neurological manifestations as seizures, decreased level of consciousness, or focal neurologic deficits are frequent but unspecific symptoms of CSVT [4,5]. In fact, diagnosis is exclusively radiological: computerized tomography angiography (CT) and/or magnetic resonance imaging angiography (MRI) [2].

Treatment approach to CSVT in pediatric population is still controversial and relies on recommendations with a low level of evidence [6-8]. Anticoagulation reduces thrombus progression, mortality, and recurrence risk with a low rate of hemorrhagic complications [9,10]. Thus, last American Society of Hematology guidelines for management of venous thromboembolism strongly recommends using anticoagulation in children with CSVT without hemorrhage and suggest using it in patients with hemorrhage. The authors also suggest that those patients with a provoked deep venous thrombosis should receive treatment for three months (or less in selected cases) if the risk factor is resolved. Treatment should be longer (6-12 months) in unprovoked cases [7].

Treatment efficacy varies depending on the published series and CSVT etiology. Complete or partial recanalization occurs up to 83% of patients with CSVT secondary to head or neck infections after 3-12 months under anticoagulant treatment [11,12]. However, a recent randomized study of 114 patients with CSVT and different etiologies described a lower recanalization rate after a 3-month period of treatment. Complete or partial sinus recanalization as observed in 78% of the patients treated with rivaroxaban and 64% in those treated with standard anticoagulants [5].

The aim of this study was to evaluate the efficacy of prolonged antithrombotic treatment in a pediatric series of CSVT while describing clinical presentation, radiological findings, and outcome.

Methods

Observational retrospective study to evaluate the efficacy of antithrombotic treatment in a series of pediatric patients (age 1 month-18 years) diagnosed with CSVT treated in a single tertiary pediatric hospital from January 2011 to December 2021. CSVT diagnosis was based on clinical presentation and confirmed by neuroimaging studies in all cases.

Medical charts were revised to collect: age at diagnosis, gender, family history of thrombosis, clinical presentation, etiology, neuroimaging studies and radiological findings at onset and during follow-up, surgical approach (if needed), anticoagulation treatment (type, dose, duration), laboratory test (including treatment control evaluations), hemorrhage associated to treatment and long-term outcome related to CSVT.

Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS Statistics, version 27.0). Descriptive statistics included frequencies and percentages for categorical variables and means, standard deviations, confidence intervals, medians, and interquartile ranges for continuous variables. Categorical variables were assessed by Chi2-test and continuous variables by t-test or Mann-Whitney test. p values were considered statistically significant when <0.05.

Results

A total of 31 patients had a confirmed CSVT during the study period. Sixteen were girls and mean age was 7.3 years (SD 4.39). All of them were diagnosed by imaging, CT in 21 cases, MRI in other 10. The most common sites of CSVT were sigmoid sinuses (n=17) and transverse sinuses (n=14). The superior sagittal sinus was affected in seven cases and superior ophthalmic vein in three cases. Of note, internal jugular vein was also thrombosed in eight cases, but no central venous device was associated to this finding. Whereas CSVT involving one sinus occurred in 11 patients (35.5 %), multiple localizations were found in 20 (64.5%). Those patients with CSVT in more than one sinus did not have a higher incidence of intracranial complications as cerebral abscesses or meningitis comparing to those with only one sinus affected.

Twenty-nine cases had an underlying condition: infectious disease (n=20), major head trauma (n=4), chemotherapy during acute lymphoblastic leukemia (ALL) induction phase (n=3), arteriovenous malformation (n=2). CSVT were idiopathic in two patients. Headache was the most frequent symptom (n= 15), followed by decreased level of consciousness (n=5), seizures (n=3), focal neurological deficit (n=2), papilledema (n=2), diplopia (n=2), vision impairment (n=1). Four patients presented with coma (those with major head trauma as risk factor). CSVT was a radiological finding in two patients with mastoiditis.

All patients received anticoagulant initial treatment with low molecular weight heparin (LMWH) (enoxaparin n=27, enoxaparin + acenocoumarin n=4). Anti X activated was evaluated in 50% of the patients. Relevant dose modifications were not necessary in any case. None received thrombolytic therapy. Mastoidectomy and/or cerebral abscess drainage was needed in 17 patients. Of them, seven patients had not started anticoagulant treatment, but ten patients had already received enoxaparin. Anticoagulation was withdrawn before surgery in these cases and reinitiated 24-48 hours later. Five patients had an associated hemorrhage at diagnosis (those with major head trauma and a patient with mastoiditis and cerebral abscess). Enoxaparin was administered at low doses (0.5 mg/kg every 12 hours) during the first 7-14 days of treatment in four patients and during 6 weeks in another one. No hemorrhagic events related to treatment were described in any patient.

Anticoagulation efficacy was evaluated in thirty patients as a boy with a CSVT secondary to major head trauma was referred to another hospital and follow-up was lost. Risk factors disappeared or improved in all cases except in those patients under chemotherapy for ALL. Anticoagulation was stopped after three months of treatment in those patients with complete sinus recanalization (n=16; 53.3%). However, patients with partial or without recanalization (n=14; 46.6%) continued anticoagulants administration up to a total of six months. Seven of them improved their radiological results. In summary, complete recanalization after three or six months of treatment was achieved in 73.3% of the patients and partial in 23.3%. Treatment only failed in one case. Table 1 resumes CSVT outcome after 3 and 6 months of anticoagulant administration according to etiology, thrombosis extension and treatment characteristics. Statistical significant differences between groups were not found.

  

    
 
    
Recanalization outcome after 3 months of    treatment
    
Patients with treatment continuation
    
Recanalization outcome in patients with prolong    treatment up to 6 months 
  
  

    
 
    
Complete n (%)
    
Partial n (%)
    
Absence n (%)
    
 
    
Complete n (%)
    
Partial n (%)
    
Absence n (%)
  
  

    
Etiology
    
 
    
 
    
 
    
 
    
 
    
 
    
 
  
  

    
Infectious disease (n=20)
    
11 (55%)
    
8 (40%)
    
1 (5%)*
    
9
    
5 (55.5%)
    
4 (44.5%)
    
-
  
  

    
Major head trauma (n=3)
    
3 (100%)
    
-
    
-
    
-
    
-
    
-
    
-
  
  

    
Chemotherapy (n=3)
    
2 (66.6%)
    
1 (33.3%)
    
-
    
1
    
1 (100%)
    
-
    
-
  
  

    
A-V malformation (n=2)
    
-
    
-
    
2 (100%)
    
2
    
-
    
1 (50%)
    
1 (50%)
  
  

    
Idiopathic (n=2)
    
-
    
2 (100%)
    
-
    
2
    
-
    
2 (100%)
    
-
  
  

    
Extension
    
 
    
 
    
 
    
 
    
 
    
 
    
 
  
  

    
Only one SV affected (n=19)
    
11 (57.9%)
    
6 (31.6%)
    
2 (10.5%)
    
8
    
3 (37.5%)
    
4 (50%)
    
1 (12.5%)
  
  

    
More than one SV affected (n=11)
    
5 (45.5%)
    
5 (45.5%)
    
1 (9.1%)
    
6
    
3 (50%)
    
3 (50%)
    
-
  
  

    
LMWH    withdrawal/delayed due to surgery necessity in patients with underlying    infectious disease
    
 
    
 
    
 
    
 
    
 
    
 
    
 
  
  

    
Yes (n=17)
    
8 (47.1%)
    
8 (47%)
    
1 (5.9%)
    
9
    
5 (55.5%)
    
4 (44.5%)
    
-
  
  

    
No (n=3)
    
3 (100%)
    
-
    
-
    
-
    
-
    
-
    
-
  
  

    
Initial    LMWH dose
    
 
    
 
    
 
    
 
    
 
    
 
    
 
  
  

    
Anticoagulant dose (n=26)
    
13 (50%)
    
10 (38.5%)
    
3 (11.5%)
    
13
    
5 (38.5%)
    
7 (53.8%)
    
1 (7.7%)
  
  

    
Prophylactic dose (n=4)
    
3 (75%)
    
1 (25%)
    
-
    
1
    
1 (100%)
    
-
    
-
  
  

    
A-V: Arteriovenous. The total number of patients    is 30 as follow-up was lost in one patient. *A patient with no    recanalization after 3-month period treatment achieves a complete    recanalization 3 months later. 
  

Table 1: CSVT global outcome after 3 and 6 months of treatment according to etiology, thrombosis extension and treatment characteristics.