|Ahead of print
A study on the distinctive clinical profile and thrombophilia in pediatric cerebral venous sinus thrombosis
Nevine Ismail1, Ray Clarke2, Cheri Mathews John3, Ravi K Anadure4
1 Mid Cheshire Hospital Foundation NHS Trust, Liverpool, United Kingdom
2 Department of ENT Surgery, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK
3 Angels Speciality Clinic, Chennai, Tamil Nadu, India
4 Army Hospital Research & Referral, New Delhi, India
|Date of Submission||17-May-2020|
|Date of Decision||04-Jul-2020|
|Date of Acceptance||27-Aug-2020|
|Date of Web Publication||02-Jul-2021|
Cheri Mathews John,
Angels Speciality Clinic, AL-190, 1st Street, 12th Main Road, Anna Nagar, Chennai 600 040, Tamil Nadu.
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Aim: The objective of the study was to systematically bring out the clinical presentations, neuro-imaging features, treatment given, and long-term outcomes of children with cerebral venous sinus thrombosis (CVST). Materials and Methods: Data were obtained by retrospective analysis of electronic records spanning 13 years, of children (<18 years) with a confirmed diagnosis of CVST based on magnetic resonance imaging of the brain and managed at a tertiary care children’s hospital in the UK. Results: Seventeen patients with pediatric CVST were identified over a 13-year study period, highlighting the uncommon prevalence of this entity. This study comprised 10 males and seven females. The age range at presentation was between 2 days and 17 years with a median age of 5.5 years. Headache was the commonest presenting symptom in 10 of 17 children and focal neurological signs were seen in 11 of 17 patients. Among risk factors, six patients had an antecedent infection of the ear/mastoid, three children had acute leukemia, and two patients had central venous catheters. Para-infectious CVST (seven of 17 patients) responded well to appropriate antibiotic therapy. Thrombophilia screens were available in 10 of 17 patients with noninfectious CVST and returned abnormal in four patients (two with Factor V Leiden mutations and one each with deficiency of protein C and anti-thrombin III). Anticoagulants were used in only six of 17 cases and were generally well tolerated. Follow-up data revealed, 11 of 17 patients had a complete recovery and four of 17 patients had residual neurological deficits. Two children died in the entire cohort. Conclusion: Pediatric CVST is uncommon and has a different spectrum from adults, with unique clinical triggers and thrombophilic states. Management varies significantly among clinicians, due to the paucity of trial evidence and also due to the heterogeneity of this condition in children.
Keywords: Cerebral venous sinus thrombosis, pediatric, thrombophilia
| Introduction|| |
The incidence of childhood cerebral venous sinus thrombosis (CVST) varies between 0.4 and 0.7 per 100,000 children per year with more than 40% presenting within the neonatal period. This is more than likely an underestimate of the true incidence because neonates often present with nonfocal neurological signs and symptoms and, hence, CVST may not even be suspected. Venous sinuses are located between two rigid layers of dura mater. This prevents their compression when intracranial pressure rises. As the cerebral veins and sinuses lack both valves and tunica muscularis, blood flow is possible in different directions. In addition, the cortical veins are linked by numerous anastomoses, allowing the development of a collateral circulation, and this may explain the good prognosis of cerebral venous thrombosis.
In addition to draining most of the cerebral hemisphere, the superior sagittal sinus (SSS) also receives blood from diploic, meningeal, and emissary veins. This explains the frequent occurrence of CVST as a complication of infective pathologies in the catchment areas, e.g., cavernous sinus thrombosis in facial infections, lateral sinus thrombosis in chronic otitis media, and sagittal sinus thrombosis in scalp infections. The dural sinuses, especially the SSS, contain most of the arachnoid villi and granulations, in which absorption of cerebro spinal fluid (CSF) takes place. Dural sinus thrombosis blocks these villi and causes CSF back pressure, which leads to intracranial hypertension and papilloedema.
The outcome of pediatric CVST is a bit unpredictable as it is not unusual to see dramatic recovery in a deeply comatose child and sudden worsening in a stable patient due to rapid extension of thrombosis. Early diagnosis and aggressive treatment are critical and life-saving in any form of CVT. We, therefore, attempted to fill the gaps in our understanding of pediatric CVST, by conducting this study at a tertiary care children’s hospital in the UK. It was aimed at specifically capturing the clinical presentations, etiologies, radiological features, and treatment outcomes of CVST in a pediatric population.
| Materials and Methods|| |
The study was carried out at a tertiary care children’s hospital in the UK. The study design was a retrospective review of case records, with patient data retrieved from our electronic database for 13 years (January 1997 to December 2009).
Only patients with age below 18 years and with a firm diagnosis of CVST based on clinical profile of raised intracranial pressure, seizures, with or without focal neurological deficits, and further confirmed on magnetic resonance imaging (MRI) of the brain with magnetic resonance venography (MRV) were included in the study. Patients were excluded in cases of (i) inconclusive neuro-imaging, (ii) arterial strokes, (iii) space occupying lesions, and (iv) insufficient data.
All the patients underwent MRI and MRV of the brain on a 1.5 Tesla MRI system (Symphony; Siemens, Erlangen, Germany). The scan protocol included an axial fluid attenuated inversion recovery (FLAIR), axial and coronal T2W, T1 3D sagittal, diffusion-weighted images with the generation of apparent diffusion coefficient map and axial gradient sequence. All details of clinical examination, laboratory investigations, pattern of venous sinus involved, and therapy given were captured in a detailed predesigned performa for analysis. The study protocol was approved by the institutional ethics committee.
All patients at our center with infection-triggered CVT (para-infectious CVST) were managed usually with broad-spectrum or culture-sensitive antibiotics as per protocol, and anticoagulation was avoided in such cases. However, in other cases of CVST without any obvious infective focus, the use of anticoagulation with heparin or vitamin K antagonists was based on the discretion of the treating team. Antiepileptics, anti-edema, and other supportive therapy were used wherever required. Follow-up records were available in all cases for periods ranging from 6 months to 8 years. A pro-coagulant workup was done, usually 3–6 months after the ictus, to avoid false lowering of ant-coagulant factors in the acute phase of a thrombotic event. The workup included a standard testing panel of protein C and S, anti-phospholipid antibody (APLA) panel, and anti-thrombin III. The genetic testing panel included Factor V Leiden (FVL) mutation and MTHFR mutation studies.
The retrospective data thus collected were entered into Microsoft Excel worksheets. Analysis of the data was carried out using appropriate descriptive statistics.
| Results|| |
A total of 17 patients were identified as confirmed CVST in the pediatric age group (<18 years). This group comprised 10 males and seven females. The age range at presentation was between 2 days and 17 years with a median age of 5.5 years. Among these, five were <1 year old (two neonates), three were 1–5 years, and nine were over 5 years old. The commonest predisposing factors were otitis media/mastoiditis which was seen in six patients. Three patients had acute leukemia, while two critically ill neonates had central line-related thrombosis. Two patients with CVST were felt to be secondary to nonaccidental head injuries (NAHIs). The details of the wide spectrum of clinical triggers for CVT in the pediatric population are summarized in [Table 1].
The clinical setting peculiar to five babies (<8 weeks) with CVST were peri-natal hypoxia, IUGR (intra-uterine growth retardation), insertion of central venous lines, and cyanotic congenital heart disease.
Headache was the commonest symptom in nine children who were old enough to communicate. This was followed by vomiting in five patients and visual disturbance in three patients. Focal neurological signs were seen in 11 patients and included limb weakness (seven), cranial nerve palsies (five), and focal seizures (three). Papilledema confirmed by a pediatric ophthalmologist was seen in five patients [Table 2].
There were five babies aged between 2 days and 8 weeks in this cohort. Of this group, two neonates presented with seizures and peri-natal hypoxia. Two babies had IUGR with respiratory distress and feeding difficulties. The fifth baby was diagnosed with CHARGE (Coloboma, Heart defects, Atresia choanae, Retarded growth, Genital and Ear abnormalities) syndrome.
Systemic infections were identified in seven of 17 children in the study, which included ear/mastoid infections in six children and pneumonia in one child. The children who had an obvious infection as the predisposing cause for CVST (seven children) were considered to have a para-infectious, pro-thrombotic state, and did not have a thrombophilia screen. Thus, only 10 children with other noninfectious provoking events underwent detailed screening for markers of thrombophilia, because thrombosis in these children is considered as a complex interplay between genetic and acquired causes. (It included protein C and S levels, anti-thrombin III, APLA, FVL mutation, and MTHFR mutation.) The screen was abnormal in four children, of which two were heterozygote for FVL mutation and one each had deficiency of protein C and anti-thrombin III. The contribution of such abnormalities to the etiology of childhood thrombosis remains unclear, and many other metabolic factors and genetic mutations could be at play, in the pediatric population.
MRI of the brain and contrast MRV are most useful in the diagnosis of CVT. In the T2W images, there will be an absence of flow voids in the effected venous sinuses [Figure 1]. MRV classically reveals nonfilling of the effected dural venous sinuses [Figure 2]. When this is associated with an infarct which does not follow the conventional arterial territory, it becomes the classical imaging description of a venous infarct [Figure 3]. Contrast venography images can show filling defects in the thrombosed sinuses [Figure 4]. All the patients in this study had MRI of the brain and MRV to diagnose sinus thrombosis. [Table 3] shows the frequency of different sinuses involved. The commonest venous sinus involved were the transverse sinus in 10 cases followed by the SSS in six cases and the sigmoid sinus in five cases. Four children had features of mastoiditis on MRI of the brain, with thrombosis of adjacent transverse and/or sigmoid sinuses.
|Figure 1: Axial T2 and T1 magnetic resonance imaging of the brain showing subacute thrombus (thin arrow) in right transverse sinus|
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|Figure 2: MRV (TOF) showing nonvisualization of bilateral transverse and proximal sigmoid sinuses|
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|Figure 3: Axial FLAIR image of the brain showing thrombus in superior sagittal sinus with left parietal venous infarct|
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|Figure 4: Contrast MRV showing thrombus in superior sagittal sinus and bilateral transverse sinuses|
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In the two cases where NAHI was the most likely explanation, one presented at 7 weeks of age with difficulty in breathing and feeding, and subsequently became unresponsive with seizure activity. Imaging revealed bi-frontal contusions and SSS thrombosis. The second child presented at 4.5 years of age with a prolonged afebrile seizure and a large right subdural hemorrhage on computerized tomography (CT) brain. Subsequent MRI and MRV showed traumatic brain infarct and ischemia of the right hemisphere with SSS thrombosis.
One child who presented at 6 weeks of age with transposition of great vessels developed nonfebrile seizures and MRI revealed multiple venous infarcts in frontal and temporal lobes with dural thrombosis in the right transverse sinus and SSS.
Treatment and outcomes
Although all children were managed in the same tertiary care hospital, the management varied, based on the discretion of the treating team and also the clinical setting. Medications used varied between antibiotics for suspected or proven infections in seven of 17 cases, low molecular weight heparin (LMWH) in six of 17, and warfarin in only three of 17 cases. Supportive therapy with anti-edema and anticonvulsants was used in the majority of cases (15 of 17).
Of the 17 patients in this series, 11 children had a complete recovery, four had a residual neurological sequel, and two kids died in the cohort. Death was attributed to NAHI in one patient and in the other patient was due to the underlying CHARGE association.
Of the patients with abnormal thrombophilia screens, two children were heterozygote for FVL mutation. One of these had a residual weakness with spasticity of one arm, while the other one had recurrent internal jugular vein thrombosis with partial resolution on follow-up imaging. Notably, two patients each who had deficiency of protein C and anti-thrombin III recovered completely with no residual deficits.
| Discussion|| |
Stroke due to either arterial or venous occlusion has been increasingly recognized in children in recent years, but diagnosis and management can be difficult. Children and adolescents with stroke have remarkable differences in their presentations when compared with older patients. Children with CVST commonly present with headaches or seizures. About half of the children presenting with an acute focal neurological deficit have a previously identified risk factor. The list of associated conditions ranges from head and neck infections to systemic conditions such as inflammatory bowel disease, nephrotic syndrome, and autoimmune disorders. Head trauma, sickle cell disease, and congenital or acquired heart disease appear to be a trigger for arterial stroke, whereas dehydration, cyanotic heart disease, and chronic anemia predispose to venous strokes. Infections and pro-thrombotic disorders are probably risk factors for both. In addition to these risk factors, one needs to consider peri-natal hypoxic insults in neonatal strokes.
Diagnosis of CVST in children is challenging. The clinical manifestations of CVST in children are at times nonspecific, particularly in neonates. Presentation with seizures, increased intracranial pressure, and headache has been well documented. Some children develop hydrocephalus, subdural effusions, and subarachnoid hemorrhage as a presentation of CVST.
CT scanning is relatively easy and quick to acquire, but it accurately depicts only hemorrhagic lesions. Venous thrombosis is easily missed on CT scans of the brain, especially if parenchymal lesions are nonhemorrhagic. MRI with MRV accurately defines the site of venous thrombosis or occlusion. Catheter angiography is technically more difficult in babies and children and tends to be done only when endovascular intervention is anticipated. The British Committee for Standards in Haematology has recently given out comprehensive guidelines for venous thrombosis in children.
Unlike the Bristol study, we included neonates with CVST in our study. The commonest underlying illness in neonates was perinatal hypoxia, surgical intervention, and/or the presence of central lines. Similar to the Bristol study, the most common risk factor for CVST in older children was infection (particularly middle ear or mastoid infection). Other studies have also reported higher frequencies of both systemic and local infections in children with CVST, as compared to adults., A previous study on CVST in neonates identified the predisposing factors as dehydration, sepsis, and cardiac defects.
In our study, of the 10 children tested for thrombophilia, only four had abnormal results and none of these patients died. However, in the Bristol study, of the three children with abnormal thrombophilia screens, two with a heterozygous FVL mutation died. In the same study, one child was found to have low anti-thrombin III and low protein S levels, similar to our study where one child each was deficient in protein C and anti-thrombin III activity.
The FVL mutation is the most common cause of resistance to natural anticoagulant Activated protein C and consequently of venous thrombosis. It is present in 1% to 7% of Caucasians and rarely affects Blacks. The presence of the FVL mutation increases the risk for venous thrombosis, 7-fold in heterozygotes and 80-fold in homozygotes. This risk is increased still further in situations such as pregnancy, oral contraceptive use, malignancy, and surgery. In children with CVST without underlying comorbidities or provoking events, a higher incidence of prothrombotic risk factors has been reported. Hence, a more thorough investigation for thrombophilia may be needed in children with apparently “idiopathic” or “unprovoked” CVST.
In our study, there were seven children with an obvious infection (para-infectious CVST) as the provoking cause for venous thrombosis. They were treated with broad-spectrum antibiotics, and resolution of infection usually coincided with neurologic recovery. Supportive therapy with anti-edema measures and anti-epileptic drugs were used as and when indicated. Only six of 17 children in this cohort received anticoagulation with LMWH and further only three of these 17 children were transitioned to oral anticoagulation with vitamin K antagonists. Unlike in adults, the rationale for treatment with anticoagulants in CVST is not yet well established due to the paucity of data in this age group and hesitancy among clinicians in starting anticoagulants when hemorrhagic lesions are seen on brain imaging. A study which was conducted in 2007 on adults concluded that anticoagulation on its own appears to be an adequate treatment for patients with acute dural sinus thrombosis. Intra-dural thrombolytics via invasive angiography is required only for treatment-refractory cases or those with large venous hemorrhage. No patient in this study needed digital subtraction angiography or intra-dural thrombolytics.
In a systematic review in 2009, the recommendation for all patients with CVST without contraindications for anticoagulation suggested that patients should be treated either with body weight-adjusted subcutaneous LMWH or dose-adjusted intravenous heparin. Concomitant intracranial hemorrhage related to CVST is not a contraindication for heparin therapy. The optimal duration of oral anticoagulation after the acute phase is still unclear.
In patients having CVST with large parenchymal lesions causing herniation, de-compressive surgery has been lifesaving and often results in good functional outcomes, even in patients with severe clinical conditions. Consultation with a neurosurgeon is indicated in patients with subdural empyema or brain abscess. Consultation should also be considered for patients who have severe neurologic deterioration, despite aggressive medical management.
In our study, 11 of 17 children recovered completely while 4 had residual neurological deficits, and only two died. In the Bristol series, almost half of the 21 cases had an adverse outcome from CVST, although cognitive outcome was not assessed in this study. In another study, almost 40% of children with CVST had cognitive difficulties. Other studies have found fewer or no cognitive difficulties and much better outcomes.,
Two of the 17 children in our study developed chronic intracranial hypertension, with recurrent headaches and papilledema, requiring lumbar punctures and cerebral decongestants with close ophthalmic monitoring. This number was much higher in the Bristol study, where eight of 21 children had significant chronic intracranial hypertension. Children with confirmed CSVT require monitoring for neurological and ophthalmological symptoms and signs related to raised intracranial pressure and optic nerve compression. This is particularly the case in nonverbal patients as visual impairment may go undetected by parents.
| Conclusion|| |
Pediatric CVST continues to remain a clinical challenge, with a wide spectrum of presentations and unique provoking events. It is important to maintain a high index of suspicion to diagnose this relatively uncommon condition in children, especially where the risk factors for venous thrombosis are not evident. MRV remains the imaging modality of choice even in the pediatric age group, although sedation and anesthesia support are usually needed in most children. The management of these children also poses challenges, as evidence on the safe use of anticoagulants is not as robust, as in the adult population. The long-term outcomes appear favorable, and mortality is mainly due to underlying comorbidities. This case series highlights the need for larger studies to define the optimum levels of thrombophilia testing and anticoagulation in pediatric cerebral venous thrombosis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]