Cerebral venous thrombosis in adolescence: Looking beyond the obvious

Abstract

Behçet's disease (BD) is a rare systemic vasculitis with multisystemic involvement. Neurological involvement, called neuro-Behçet's disease (NBD), mostly involves the central nervous system and cerebral venous thrombosis (CVT) is the predominant neurological manifestation in the pediatric age.

A 12-year-old female with a past medical history of a CVT, without an identifiable etiology, was admitted with a five-day right fronto-orbital headache. Neuroimage showed a subacute thrombosis of a right superficial sylvian vein, with indirect signs of intracranial hypertension and no imaging signs of vasculitis. Prothrombotic screening and immunologic study were normal. She was started on acetazolamide and hypocoagulation with progressively improving. She had a history of frequent oral aphthae and an episode of a genital ulcer three months before admission. Pathergy test was negative. HLA-B51 was positive. She was diagnosed with NBD and started therapy with colchicine and infliximab. After discharge, the patient remains without symptoms, hypocoagulated, and on infliximab regimen, without complications to report.

This case, only diagnosed in the second episode of CVT, is paradigmatic of the difficulty in establishing the diagnosis of BD.

1. Introduction

Behçet's disease (BD) is a rare systemic vasculitis that was first described as a disease causing recurrent oral and genital aphthae and uveitis [1,2]. However, we now know that the disease can course with many more manifestations and have a multisystemic involvement [3].

Its prevalence in Europe is low, and it is typically more prevalent in countries belonging to the historical Silk Road [3].

BD mainly affects young adults, but symptoms start at pediatric age in about 15–20% [2]. In these cases, the age of onset is usually between 5 and 12 years, and the delay in diagnosis can be up to 3 years [3].

The etiopathogenesis is still not well understood, considering that several infectious and environmental agents may play a causative role in genetically susceptible individuals. The mechanisms appear to be similar to autoimmune, autoinflammatory diseases, and seronegative spondyloarthropathies [2].

Neurological involvement in BD, called neuro-Behçet's disease (NBD), has an inconsistent prevalence in pediatric age (3.6%–59.6%), and the presentation can be very heterogeneous [2,3]. It most frequently involves the central nervous system and can be divided into parenchymal and nonparenchymal vascular forms [[2], [3], [4]]. The nonparenchymal vascular form is the most common in pediatric patients, has a better prognosis, and usually manifests as cerebral venous thrombosis (CVT) or pseudotumor cerebri [2,3].

Because the neurological manifestations of BD are nonspecific, the diagnosis can be initially challenging [4].

Here, the authors report the case of a female adolescent with NBD who was diagnosed in the context of recurrent CVT.

2. Case

A 12-year-old female with a past medical history of a CVT at the age of 10 years old, without an identifiable etiology, for which anticoagulation had been suspended 8 months before our observation was admitted. In recent years, she also had self-limited recurrent episodes of fever (<3 days), pharyngitis and cervical adenopathies, and frequent oral aphthae unrelated to the febrile episodes. She was studied for autoinflammatory syndromes that were excluded by molecular studies.

She was admitted to our hospital with a 5-day right fronto-orbital headache, sometimes with nocturnal awakenings, associated with photophobia, phonophobia, and nausea. On physical examination, she had fever and neck stiffness, without other abnormalities. Blood analysis showed the white blood cell count of 14 × 10⁹/μL, and the C-reactive protein level of 85.6 mg/L. Lumbar puncture was performed, and cytological and biochemical examinations of cerebral spinal fluid (CSF) were normal. Cerebral computed tomography (CT) and CT cerebral venography were performed, and showed a reduced caliber of the superior sagittal sinus, transverse sinus, and sigmoid sinus.

Because of the persistence of headache complaints, she was admitted to the pediatric department. Bacteriological and virological studies of the CSF were negative. Cerebral magnetic resonance (MR) and MR cerebral venography revealed subacute thrombosis of a right superficial sylvian vein with indirect signs of intracranial hypertension. No imaging signs of vasculitis were found (Fig. 1). Digital Subtraction Angiography (DSA) confirmed reduced caliber/patency of the superior sagittal sinus, transverse sinus, and sigmoid sinus, with compensatory venous drainage through alternative superficial and deep venous pathways (Fig. 2). Prothrombotic screening (protein C, protein S, antithrombin III, factor V Leiden, factor VIII, prothrombin, homocysteine, lupus anticoagulant, and homocysteine) and immunologic study (antinuclear antibodies (ANA), antibodies to double-stranded DNA (dsDNA), antineutrophil cytoplasmic antibodies (ANCA), anticardiolipin antibodies, anti-beta2-glycoprotein, antibodies against myeloperoxidase (MPO), antibodies against proteinase 3 (PR3), SSA/Ro and SSB, C3, C4, IgG, IgA, IgM) were normal. She was started on acetazolamide (25 mg/kg/day) and hypocoagulation with unfractionated heparin. In the following days, she improved progressively; however, she showed the onset of two oral aphthae.

Fig. 1.

Cerebral MRI depicted signs of subacute thrombosis of a right superficial sylvian vein. (A) Axial T1-weighted MR image showed an area of abnormally increased signal intensity, with a filling defect in the corresponding area on the axial contrast-enhanced MR image (B), and susceptibility effect on axial T2∗-weighted gradient-echo image (C). (D) Axial fat-saturated T2–weighted imaging showed indirect signs of intracranial hypertension, with prominent subarachnoid space around the optic nerves.

Fig. 2.

DSA: AP and sagittal view in venous phase. Reduced patency of the superior sagittal sinus, transverse sinus, and sigmoid sinus (arrowheads), with compensatory venous drainage through alternative superficial and deep venous pathways (white arrows).

Reviewing her past medical history, the adolescent had a history of frequent oral aphthae, especially in the last year (more than three episodes per year) and an episode of a genital ulcer 3 months before admission. She had no rashes, joint, eye, or gastrointestinal symptoms. After evaluation by ophthalmology, uveitis was excluded. Pathergy test was negative. HLA-B51 was positive. A thoracoabdominal CT angiography excluded pulmonary and aortic aneurysms.

She was diagnosed with NBD after meeting the criteria according to the consensus of the Pediatric Behçet's disease (PEDBD) group (Table 1). She started therapy with colchicine (1 mg/day) and, due to neurovascular involvement, started infliximab (5 mg/kg/dose), which she repeated every two, six, and eight weeks.

Table 1.

Diagnostic criteria for paediatric Behçet's disease according to PEDBD group.

PEDIATRIC CRITERIA FOR BEHÇET’S DISEASE
Recurrent oral aphthosis: At least three attacks/year
Genital ulceration or aphthosis: typically, with scar
Skin involvement: Necrotic folliculitis, acneiform lesions, erythema nodosum
Ocular involvement: anterior uveitis, posterior uveitis, retinal vasculitis
Neurological signs: with the exception of isolated headaches
Vascular signs: venous thrombosis, arterial thrombosis, arterial aneurysm
At least 3 criteria are required for the diagnosis.

After discharge, the patient remains without complaints and no new episodes of oral or genital aphthae. She remains hypocoagulated with warfarin, colchicine, and an infliximab regimen every eight weeks, with no complications to report.

3. Discussion

The reported case, which was only diagnosed in the second episode of CVT, is paradigmatic of the difficulty in establishing the diagnosis of BD, essentially due to the time it took (about 2 years) to develop the full spectrum of symptoms.

The diagnosis of BD is based on clinical criteria. Several classification criteria have been published, but so far, the only set of criteria recommended for diagnosis in pediatric age is the PEDBD group [5].

The spectrum of presentation of BD is highly variable. The onset can be insidious or in the form of an acute event, with the disease course being typically recurrent and unpredictable. Neurological manifestations are the presenting symptom in about one-third of pediatric patients [4,6]. CVT is the predominant neurological manifestation, and it may be the initial manifestation in up to 20% of cases [7]. It may present with symptoms of intracranial hypertension, such as headache, papilledema, sixth cranial nerve palsy, and rarely fever [8]. CSF findings are usually normal, except an increased pressure [9]. The onset is often subacute or chronic, which can help distinguish it from other etiologies [10,11]. The superior sagittal and transverse venous sinuses are usually the most affected [12]. We found over 50 cases described of CVT associated with BD in pediatric population, and in only three, there was a recurrence [4,7].

There are no published international recommendations regarding the treatment of pediatric BD. The main goal of treatment is to reduce inflammation, and prevent future recurrences and organ damage [2].

Soluble TNF-alpha receptor has been shown to play a role in the pathogenesis of BD as it is locally and systemically elevated in cases of active BD. In association, anti-TNF-alpha agents have been shown to be quite effective in the remission of different forms of BD [13]. Their use as a second-line option for refractory BD, and as a first-line treatment in severe ocular and neurological involvement, has been shown to be effective in improving the outcome of BD patients [3]. Its excellent tolerability and safety associated with rapid action have led some authors to recommend anti-TNF-alpha agents as first-line treatment in cases of NBD [2,3,13]. It seems to have good long-term results in terms of preventing future recurrences and stabilizing the disease [14,15]. Therefore, it was the treatment of choice for this patient.

Histologically, BD is a vasculitis of small and large vessels, with a greater tendency to venous involvement. Endothelial dysfunction has been shown to be the primary mechanism leading to thrombosis formation in BD [2,3]. Some studies have suggested that there may also be prothrombotic disorders associated with endothelial dysfunction in these patients, and that both play a role in the development of thrombosis, but the data are conflicting [10,11]. Recently, a meta-analysis on antiphospholipid antibodies revealed a significantly high prevalence of anticardiolipin and anti-beta2-glycoprotein antibodies [9]. An independent association between prothrombotic risk factors and the development of sequelae and thrombosis recurrence had been previously described [11].

Therefore, it is essential to carry out prothrombotic screening, and the main treatment involves the use of immunosuppressive drugs associated with hypocoagulation [10,11].

In our case, no prothrombotic risk factors were identified, despite being investigated. However, since the CVT recurred shortly after the discontinuation of hypocoagulation, their use is justified in the long term in this patient. Our patient can be an example of the need to use hypocoagulation to treat and prevent new thrombotic events in patients with NBD.

CVT associated with NBD, if treated promptly, tends to have a good prognosis. However, diagnostic delay can lead to neurological sequelae such as optic nerve atrophy [10]. HLA-B51 positivity had been associated with a worse prognosis and an increased risk of relapse [9].

The authors alert that in the presence of a CVT, whether isolated or recurrent, NBD should be considered.

Ethical statement

All authors listed have contributed sufficiently to the project to be included as authors. To the best of our knowledge, no conflict of interest, financial or other, exists.

The authors declare that informed consent was obtained from patient.

Declaration of competing interest

None.