Cerebral Venous Sinus Thrombosis in Children: A Study from a Tertiary Care Hospital of Eastern India.

CONTEXT: Cerebral venous sinus (sinovenous) thrombosis (CVST) in childhood is a rare, but under recognized, disorder, typically of multifactorial etiology, with neurologic sequelae apparent in up to 40% of survivors and mortality approaching 10%. AIM: The aim of this study was to enlist the patients diagnosed as CVST younger than 14 years of age and to diagnose the etiology along with radiological correlation. SETTINGS AND
DESIGN: This prospective clinical study was conducted for 2 years in the Department of Neurology, Srirama Chandra Bhanja Medical College & Hospital (SCBMCH), Cuttack, Odisha, India.
MATERIALS AND METHODS: All the patients were enlisted in a prestructured format with detailed clinico-radiological evaluation. Treatment was performed according to recent guidelines. Outcome after 3 months was analyzed. Ethical clearance was obtained from institutional ethics committee. STATISTICAL ANALYSIS: Data were statistically analyzed using IBM SPSS Statistics for Windows, version 20 (IBM Corp., Armonk, N.Y., USA).
RESULTS: The total number of patients included in the study was 30. Of them, six were neonates. The most common provocative factor was tuberculous meningitis. Phototherapy after neonatal hyperbilirubinemia was prominent cause in neonatal age group. Multiple sinus involvement was seen in most of the patients. Transverse sinus was the most common sinus to be involved.
CONCLUSION: CVST is an underdiagnosed but important cause of stroke in childhood, occurring most often in the neonatal period. Mortality and morbidity are significant. Infections hyper coagulative disorders are the two primary associations. Magnetic resonance venography is the investigation of choice. Early diagnosis with management along with plan for secondary prevention can save from catastrophic consequences. Copyright:

INTRODUCTION

Cerebral venous sinus (sinovenous) thrombosis (CVST) is one of the most common causes of pediatric and neonatal stroke. The incidence is estimated at 0.6/100,000/year, with 30%–50% occurring in newborns.[1] Generally, it is seen with a male predominance (60%–70%).[1] In CVST, thrombotic occlusion of these venous structures can create regional or diffuse increased intracranial pressure (ICP), cerebral edema, and venous infarction or hemorrhage (venous stroke). CVST is common in children than in adults, and risk is greatest in the neonatal period.[2] In neonates, CVST is often present with encephalopathy and seizures. Children may present with symptoms such as progressive headache, papilledema, diplopia secondary to sixth cranial nerve palsy, progressive loss of vision, or with acute focal deficits. Seizures, lethargy, and confusion are common.[2] Causes and risk factors for CVST are age dependent and highly variable. Infection, hypercoagulative states, and prothrombotic conditions are several causes in the reported literature.[1] Computed tomographic (CT) venography or magnetic resonance (MR) venography is necessary to show filling defects in the cerebral venous system. Magnetic resonance imaging (MRI) offers better parenchymal imaging as compared with CT.[2] Anticoagulation therapy plays an important role in childhood CVST treatment. Substantial indirect evidence has led to a consensus recommendation for anticoagulation with unfractionated or low-molecular-weight heparins (LMWHs) in most children.[3] The objectives of this study were to enlist the patients diagnosed as CVST under 14 years of age, to know the etiology and clinical syndromes along with radiological correlation, to treat according to recent guidelines, and to compare the outcomes.

SUBJECTS AND METHODS

This prospective clinical study was conducted for 2 years in the Department of Neurology, Srirama Chandra Bhanja Medical College & Hospital (SCBMCH), Cuttack, Odisha, India. Patients with a diagnosis of CVST, confirmed by imaging of brain with MRI/MRV (1.5 T), were included in the study. Detailed general and neurological examinations were performed in all patients. The patients were evaluated for demographic data, onset of symptoms, disease manifestations, severity, disability, duration of hospitalization, and treatments used. Various clinical manifestations such as signs of intracranial hypertension, papilledema, headache and its distribution, vomiting, blurring of vision, diplopia, ocular palsy, dizziness, nuchal rigidity, aphasia/dysphasia, focal motor deficit, sensory deficit, cerebellar signs, cranial nerve deficit, alteration of sensorium, seizures (focal, generalized, status epilepticus), and other neurologic deficits were examined and recorded.

The patients were categorized as per duration of symptoms into acute (<48h), subacute (>48h to 30 days), and chronic (>30 days) for analysis and comparison. As per clinical manifestations, patients were grouped into four CVST syndromes for the purpose of comparison of various parameters.[4] These syndromes are classified in Table 1. They were evaluated for antecedent cause of thrombosis along with thrombophilia profile. Treatment was performed according to recent guidelines.[6] Outcome after 3 months was analyzed. Data were statistically analyzed using IBM SPSS Statistics for Windows, version 20 (IBM Corp., Armonk, N.Y., USA). Ethical clearance was obtained from institutional ethics committee.

Table 1

CVST syndromes[45]

Clinical syndromes of CVST	Features
Syndrome of increased ICP	Patients with signs and symptoms of only headache, papilledema without any cranial nerve involvement, focal neurologic deficit, or seizure
Syndrome of focal neurologic deficit with or without increased ICP	Patients with signs and symptoms such as limb weakness, seizure, other focal neurologic deficit with or without headache, and papilledema
Syndrome of cavernous sinus thrombosis	Patients with signs and symptoms of conjunctival redness, chemosis, progressive swelling of eyelid, ophthalmoparesis, headache, and papilledema
Syndrome of unspecific diffuse encephalopathy	Patients presenting with signs and symptoms of generalized encephalopathic illness without a localizing signs or recognizable features of increased ICP, with a depressed level of consciousness being the most constant finding (varying from drowsiness to deep coma)

The total number of patients included in the study was 30. Of them, six were neonates. Male-to-female ratio was 1.5:1. Mean age was 5.7 years[Table 2].

Table 2

Salient clinical pictures

Characteristics	Observations
Numbers of patients	30 (pediatrics, 24; neonates, 6)
Male:female	1.5:1
Mean age	5.7 years
Most common provocative factors
In pediatrics patients	TB meningitis
In neonates	Phototherapy
CVST syndrome––the most common	Type 2 (50%)
Lobar involvement	Parietal lobe
Sinus involvement	Transverse sinus

The most common provocative factor was tuberculous meningitis (TBM) in eight (26%) cases, followed by phototherapy in six (20%) cases. All neonates had hyperbilirubinemia and were treated by phototherapy. Prothrombotic states were identified in 12 (67%) cases of 18 patients. In thrombophilia profile, combined protein C and protein S abnormality was most common in five (41%) cases. Isolated protein S was abnormal in seven (58%) cases. Hyperhomocysteinemia and sickle-shaped red blood cells were observed in four cases each.

A total of 18 (60%) cases were having subacute presentation. Blurring of vision was the most common clinical presentation in 17 (58%) cases. Seizure was observed in 14 (46%) cases. Headache was the primary presentation in 10 (33%) cases.

The syndrome of focal neurologic deficit with or without increased ICP was the most common syndrome found in 15 (50%) cases. It was followed by syndrome of unspecific diffuse encephalopathy seen in eight (26%) cases. Five (16%) cases were diagnosed as syndrome of increased ICP. Two cases were having syndrome of cavernous sinus thrombosis.

Parietal lobe was most common in 24 (80%) cases, followed by frontal lobe involvement in 67% cases. Lobar ischemia with edema was the most common pathology.

Transverse venous sinus involvement was most common in 18 (67%) cases. Multiple sinus involvement was seen in 12 (40%) cases [Figure 1].

Figure 1

MRV—transverse sinus thrombosis with collaterals in a nephrotic syndrome child

LMWH was used as primary modality of treatment followed by acenocoumarol therapy with the use of Prothrombin time international normalized ratio (PTINR) as control.

The average modified rankin score (mRS) score was 3 before treatment and 1 after treatment. One child succumbed due to re-stroke with history of sickle cell anemia.

DISCUSSION

Pediatric CVST occurs due to both intravascular and vascular factors, and dehydration is a common risk factor for all ages. Venous thrombosis in children is one of the most common causes of pediatric stroke. In several studies, it is wide apparent that the incidence is much higher in neonatal age-group. In our study also, several neonates were included. In several studies, males were found to be predominant.[1] Provocative CVST was more common in this study. Infection and other prothrombotic conditions are the primary causes of pediatric CVST. According to several studies, the most frequent etiologies were underlying chronic diseases (especially tumors, followed by hematologic disorders and autoimmune diseases) and infections, the most frequent of whom being head–neck infections.[12,7] In our cohort, TB meningitis was the most common provocative factor. Other factors such as phototherapy, nephrotic syndrome, sickle cell disease, and leukemia were also found. In terms of observed frequency, infection appeared to be the most common condition associated with CVST in pediatric age group excluding neonates.[7] Prothrombotic states have been identified in 24%–64% of children.[7] In our case, 53% cases had positive thrombophilia profile. Combined protein C and S were most common. It varied according to geographical location. Many previous studies revealed high protein C in Indian subcontinent.[78]

Because of the different etiologies and locations of the affected sinus, the clinical manifestations of CVST are diverse and lack specificity. Thus, it is extremely difficult to diagnose CVST based on clinical manifestations alone. The disease could present with an onset that is acute, subacute, or chronic. The literature reports that the early diagnosis and treatment of CVST could reduce the mortality rate to 5%–15%.[9] But as the knowledge of CVST is low in primary care physicians, most of the patients presented with subacute presentation. Similar trends were seen in a study performed in China.[8]

According to a study conducted by Wang et al.,[8] uncharacteristic headache is a common clinical symptom in 25 of 28 children with headache followed by visual symptoms. But in our study, visual symptom was the most common presentation.[8] As the numbers of neonates were high in this cohort, seizure was also a common symptom. As we belong to different geographical area where we have high case load of TB meningitis, the high incidence of increased ICP and blurring of vision can be explained.

The syndromic approach to CVST is rarely reported in previous pediatric cohort. Several adult studies have taken account of it.[45] We have carried out mild change in the syndromic classification in pediatric age-group. The encephalopathy and coma syndromes are clubbed into type 4 syndrome. Features of cavernous sinus thrombosis were isolated to classify it to a separate group. This is because of it’s differential presentation and treatment. In this study, the syndrome of focal neurologic deficit with or without increased ICP was the most common syndrome found in 50% cases. In another Indian study, similar presentation was observed in adult population.[4] High incidence of type 4 syndrome may be explained by the inclusion of neonates. In neonates, the disease presents as seizure and diffuse encephalopathy.

Neuroimaging is the principal basis for the diagnosis of CVST.[10] Typically, an initial CT scan is performed; however, only a few cases present with characteristic features on CT scan such as the high-density shadow of the strip. After contrast enhancement, the delta sign (also called the empty triangle sign) features can be seen.[8] Brain MRI and MRV diagnose CVST with high sensitivity and specificity. Digital subtraction angiography is the “gold standard” for the diagnosis of adult CVST. However, it is an invasive examination; thus, the compliance of pediatric case examination is limited.[11] In this study, parietal lobe and transverse sinus involvement were most common. The involvement of sinus may be different according to different geographical areas. According to a study conducted by Wang et al.,[8] the involvement of superior sagittal sinus was most common, followed by transverse sinus involvement.

At present, the treatment for CVST is based primarily on adult cases.[8] The purpose of CVST anticoagulant therapy is to avoid thrombus enlargement and contribute to spontaneous thrombolysis.[12] According to the current consensus, older children diagnosed with CVST without bleeding should receive anticoagulant therapy. It is safe and effective to administer subcutaneous injections of LMWH oral warfarin (180 Units/kg/day in two divided doses) for 2 weeks, then switch to oral warfarin (0.1-0.2 mg/kg/day) for 3 months to maintain an PTINR of 2.0–3.0.[8] The data from descriptive cohort studies suggest that outcomes are worse among in neonates as compared to children with CVST.[1] Moreover, in one observational study of neonates, there was a significant incidence of clot propagation and related new infarction in neonates who were not treated with anticoagulants (AC).[3] Recent data suggest that AC therapy in children and neonates is generally safe, but the efficacy is not established.[3] In this study, all patients were treated by LMWH followed by acenocoumarol in adequate dose according to recent consensus statement.[1] Outcome is good according to MRS scoring. Several studies depict good outcome in pediatric CVST with limited mortality and morbidity.[9] One child succumbed due to recurrent thrombosis causing acute encephalopathy. He had a definite risk factor in form of sickle cell disease. In a study conducted by Wang et al.,[8] two children succumbed. The mortality is low in venous thrombosis.

CONCLUSION

CVST in children is a very common cause of pediatric stroke. It is an emergency condition causing significant disability. The etiology of this disease is complex with wide spectrum. Early diagnosis prevents from gross disability. Primary care pediatricians and neurologists must suspect CVST in the following clinical situations: (1) patients who have high risk factors for venous sinus thrombosis such as infections and prothrombotic conditions, (2) those with progressive intracranial hypertension with normal imaging, (3) sudden onset of focal deficit, but imaging does not reveal involvement of arterial territory, and (4) progressive blurring of vision with headache and vomiting that cannot be explained by other known causes such as encephalitis, meningitis, or bleeding. LMWH and AC are primary modalities of therapy. Early treatment provides very good outcomes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.