FormalPara Key Summary Points

Each pediatric patient without typical otomastoid complaints but presenting symptoms of raised intracranial pressure and otitis media should be suspected for otogenic CVST (OCVST).

The extent of the sigmoid sinus pathology is not proportional to the involvement of the bony sinus plate.

The role of contralateral compensatory drainage as a factor predisposing to OCVST needs further studies.

The routine screening for thrombophilia is disputable and requires further objective verification.

The benefits of anticoagulant therapy appear to outweigh the potential risks, but there is no established regimen concerning indications, the duration, or form of the treatment.

Introduction

Cerebral venous thrombosis (CVT) is a rare entity but with the potentially serious consequences. Headaches, neurologic deficits, and seizures have been reported in more than 50% of children, whereas death has occurred in 9–29% of pediatric cases [1,2,3]. CVT remains a diagnostic challenge due to various clinical manifestations and a wide variety of causative agents. Local infections, such as acute (AOM) or chronic otitis media (COM), can play a role in the pathogenesis of CVT. It is considered that CVT may be triggered by the release of inflammatory cytokines and the activation of the coagulation pathway in the middle ear space in response to infection [4]. The proximity of the tympanic cavity and temporal bone air cells to the dural venous sinuses predisposes them to secondary thrombosis [5]. The incidence of acute mastoiditis (AM) is estimated at 3.5–4.2 per 100,000 people/year. Septic lateral sinus thrombosis (LST) develops in 0–3% of patients with AM [6,7,8,9]. Among all the pediatric patients with CVT, otogenic causes are responsible for less than 10% of cases. In contrast, a primary thrombus formation within the dural sinus is called a nonseptic LST [5, 10]. This difference is of utmost importance, as the therapy strategies are not the same. There is no consensus in the literature concerning the treatment of otogenic cerebral venous sinus thrombosis (OCVST). Both the extent of the surgery and the use of anticoagulants are disputable.

The aim of this study was to provide a thorough analysis of the literature concerning cerebral venous sinus thrombosis (CVST) in patients with AOM and AM. The current surgical and conventional treatment strategies have been presented. Special attention has been attached to the role of anticoagulants in septic CVST.

Methods

A review of the literature concerning cases with OCVST was carried out. PubMed database was searched for literature published in English on the subject. Databases were searched using Medical Subject Headings (MeSH) terms “acute otitis media” or “mastoiditis” with one of the following terms: “cerebral venous thrombosis”, “lateral sinus thrombosis”, “sigmoid sinus thrombosis”, “transverse sinus thrombosis” or “petrosal sinus thrombosis” and combined with the term “children”. The following exclusion criteria were implemented: publication before 2000, isolated case reports, and series of cases of < 5 patients, primary CVT, reports concerning solely adult patients, studies providing no data or insufficient data on the type of intracranial complication, studies providing no data or insufficient data on the method of treatment, animal reports, non-English language, or only abstract available.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Results

The search process in the PubMed database identified a total of 204 results. Forty-four of them met the inclusion criteria and were included for further analysis (Fig. 1). The main disputable issues concerning pediatric OCVST have been identified, discussed, and summarized. The list of the most important articles included in our analysis is presented in Table 1.

Fig. 1
figure 1

Diagram of the searching process

Full size image
Table 1 Summary of the most important articles referenced
Full size table

Discussion

Nomenclature

The literature analysis revealed a significant inconsistency in the nomenclature regarding the cerebral venous system. Many authors customarily used the term “lateral sinus” to describe the sigmoid sinus (SS) or the transverse sinus (TS). The term lateral sinus (LS) was also used as a description of a complex of sigmoid and transverse sinuses. Such an inconsistency influences the unequivocal interpretation of the published data. According to Tubbs [13], the sigmoid sinus and the transverse sinus are anatomically different structures and terms. Therefore, these terms should be distinguished and the nomenclature respected in further studies.

General Characteristic and Demographics

Septic otogenic CVST in children is a rare entity but with potential devastating neurological consequences. Nevertheless, only one mortality was reported in a group of reviewed 104 patients [14]. Wong et al. stressed that CVST was twice as common in males [9]. The lateral sinus thrombosis is thought to occur slightly more commonly on the right side [9, 14]. The average time from the onset of symptoms to hospital admission was 11 days [14].

Symptoms and Clinical Findings

The symptomatology of septic CVST is uncharacteristic. Severe headache is the most common presenting symptom. Except from that, otalgia, “picket-fence” fever, vomiting, pain in the neck or neck stiffness, and papilloedema may be observed [5, 14, 15]. Typical otoscopic findings confirm AOM, whereas an oedema in the postauricular region with tenderness over mastoid are pathognomonic of mastoiditis. Internal jugular vein thrombosis can be suspected during the palpation of the neck along the sternocleidomastoid muscle [5]. Examining the fundus oculi reveals papilloedema, and sometimes retinal hemorrhage. Symptoms of intracranial hypertension in the case of CVT include headache, vision deterioration, and vomiting [15]. Strabismus and sixth cranial nerve palsy were also reported among neurologic findings [15].

A wide variety of bacterial flora including bacteroides, Staphylococcus, Enterobacteriaceae, Proteus, Pseudomonas, and other species have been identified as etiological factors [5]. The conclusion from the review by Au et al. was that only 46% of cultures were positive [14]. Vishawanatha et al. stated that a high percentage of negative cultures could stem from preadmission antimicrobial therapy [5], which may mask the typical symptoms of septic CVST.

Recent studies of Coudert et al. have revealed a significant association between Fusobacterium necrophorum and thrombotic complications of AM [16]. F. necrophorum presented a specific prothrombotic activity by producing cytokines and hemagglutinin supporting inflammation and aggregation of platelets [17, 18]. Ziv et al. revealed that F. necrophorum was statistically associated with multiple intracranial complications of AM [19]. Ichord regarded F. necrophorum as a main risk factor for CVST in children [20].

Imaging

Many researchers agree that magnetic resonance imaging or magnetic resonance venography (MRI or MRV) should become a gold standard in cases suspected of CVT [8, 21,22,23]. According to a study by Au et al., MRI is more specific than CT in thrombus detection (sensitivity 100% vs 87%) [14]. Due to the essential role of surgery in treatment of AM and OCVST, it seems reasonable to perform MRI with contrast-enhanced CT for the supreme evaluation of both cerebral and otologic pathology [5]. Moreover, MRI enables the differential diagnosis and visualization of some dural venous sinus anatomical variants, including not only hypoplasia or aplasia of the sinus but more challenging cases with intrasinus septum or prominent arachnoid granulations [8]. The importance of serial imaging with MRI, MRV, or CT venography in patients suspected of thrombus progression is emphasized [24].

Unfortunately, the main disadvantage is the availability of the emergency MRI which has been highlighted in the literature by numerous authors [1, 11, 25]. Ghosh et al. stressed that the high index of suspicion is required in children with raised intracranial pressure (ICP) and a history of prior ear pain or AOM even in the absence of typical otomastoid complaints [8]. This remark is extremely important to make clinicians aware that AM is not necessary for OCVST to occur.

Predisposing Factors and Controversies

Knowing that sigmoid sinus thrombosis may be a silent complication [24, 26], the predisposing factors should be taken into consideration.

Venous Drainage Pattern Asymmetry (VDPA)

VDPA is frequently revealed on imaging. Csákányi et al. claim that atresia or hypoplasia of the transverse sinuses is not uncommon [11]. In cases of a dominant sinus occlusion, the clinical signs of elevated ICP are more severe. Durgun et al. reported that right-sided sinuses are the dominant ones in 41% of the population [27]. Similar observations were published by Widjaja and Gritffiths [28]. The anatomic study conducted by Leach et al. revealed asymmetric transverse sinuses were in 49% of participants, with a complete or partial absence of one transverse sinus in 20% of individuals [29]. The other attribute of cerebral sinuses influencing the potential course of the CVT is the lack of valves, which favors thrombus propagation to other sinuses and to the internal jugular vein [25]. Zanoletti et al. regard the form of protective mechanism as showing that the cerebral sinuses invert their venous flow when an acute obstruction occurs in the sigmoid-jugular system [6]. They claim that a compensatory drainage guarantees the function of the whole system. Moreover, the authors conclude that very few cases of unplanned sigmoid sinus occlusion have had serious clinical consequences, and even unplanned sacrifice of the sigmoid sinus has never reportedly been a problem per se [6].

Thrombophilia

Some authors have claimed that 50% of patients with CVST had a previously asymptomatic prothrombotic state related to one or more of the following: protein C and S deficiency, anticardiolipin antibodies, antithrombin III, or prothrombotic gene mutations (MTHFR, factor V Leiden, prothrombin 20210) [3, 30]. In contrast, the favored role of thrombophilia in CVST was considered controversial in other studies [8, 31, 32]. Scorpecci et al. reported that more than 90% of children in their study had genetic abnormalities associated with thrombophilia [12]. Other authors have assessed the prevalence of thrombophilia among children with OLST ranging from 10 to 78% [33] or even higher [34]. Some authors consider the favored role of polymorphism of the MTHFR gene still controversial [8, 31, 32], but others recognize it as a significant prothrombotic factor in OLST [34, 35]. The type of thrombophilia did not appear to be predictive of short- or long-term OLST resolution [12].

Others

A few more preoperative non-anatomical conditions have been indicated in the literature as factors predisposing to OCVST: cardiac disease, collagen tissue disorders, and other than thrombophilia hematological abnormalities [3, 24].

Treatment

The literature review revealed no controlled studies concerning this issue of OCVST. Due to the lack of evidence-based reports, Scorpecci et al. are skeptical to recommend surgical treatment [9, 12]. Christensen et al. considered the variable clinical manifestation and the rarity of CVST unfavorable factors in establishing the optimal therapeutic management in these patients [36].

Surgical Treatment

Most authors consider surgery to be mandatory [11, 32, 37], but the extent of the surgery differs between them. Many ENT surgeons have performed prompt cortical mastoidectomy with removal of the SS plate (or its remnants) and granulation tissue adjacent to the SS [11, 14, 36], with subsequent conservative therapy [11, 37,38,39]. In contrast, Scorpecci et al. stated that mastoidectomy should no longer be indicated in cases where lateral sinus thrombosis is associated with a non-erosive mastoiditis [12]. It sounds controversial in relation to the study of Ooi [37]. That author highlighted that the extent of the SS pathology is not proportional to the involvement of the bony sinus plate. These observations are consistent with the results of Csákányi al., as they revealed that an epidural abscess can frequently be identified under an apparently intact SS plate [11]. The facts mentioned above shed a new light on the potential recommendations concerning the extent of the surgical procedure with the obligatory decompression of the SS during mastoidectomy.

Surprisingly, one of the studies reported that < 50% of patients had concurrent myringotomy with ventilation tube insertion [14]. The reason is unclear as this procedure is considered a natural step in the treatment of AM.

Au et al. reported surgical manipulations of the thrombosed sinus in almost 50% of individuals [14]. In that group, a needle aspiration was performed in 54.9% of patients, thrombectomy in 47.1%, and internal jugular vein ligation in 7.8%. Recently, the role of these procedures has apparently diminished. Csákányi et al. argued that surgical confirmation of the thrombus was unnecessary in children without persisting septicemia because of the wide availability of imaging [11]. In cases of signs of persisting septicemia, some authors advise removal of the infected clot [38].

The literature also indicates the marginal role of internal jugular vein (IJV) ligation. Recent authors consider IJV ligation redundant in cases of mastoidectomy and SS exposition supported by adequate antibiotic therapy [23]. Some authors see the role of IJV ligation in cases of embolization or septicemia not responding to conventional and initial surgical treatment [5].

Conventional Treatment and Anticoagulants

Some authors support a less invasive therapeutic approach [40] or even question operative management [12].

Guidance on the management of CVST in children was published by the British Society of Haematology in 2009 [33]. Anticoagulation treatment with low-molecular-weight heparin (LMWH) was recommended in each case apart from the situation of associated intracranial hemorrhage. Researchers have stressed that anticoagulants prevented thromboembolic events, decreased the risk of death and severe neurologic consequences, and reduced the recurrence of thrombosis within 6 months [32, 41, 42]. Nevertheless, the guidance of the British Society of Haematology refers to all causes of pediatric CVST and is unspecific as to otological cause, which is the major limitation of this document.

Anticoagulation with heparin followed by oral anticoagulation is considered the traditional therapy for CVT [24], and is recommended by pediatric neurologists and hematologists [31,32,33]. Surprisingly, a recent systematic review revealed that only 60% of children with OLST received anticoagulation [9], and, in the report by Au et al., 57.4% patients received it [14]. The routine use in otogenic septic CVST is still disputable among otorhinolaryngologists [8, 14].

A distinctive position on this issue was presented by Scorpecci et al. [14]. The authors proposed a treatment protocol including intravenous broad-spectrum antibiotics and anticoagulation with LMWH in all patients. They recommended mastoidectomy only on a case-to-case basis because of insufficient evidence on the effectiveness of surgical treatment [14].

Several authors have questioned the importance of anticoagulation, due to the possible risk for hemorrhage [8, 31, 32, 39]. Other researchers recommend their use only in cases of OCVST with proximal (to IJV) or retrograde thrombus progression (to TS, petrosal sinus or cavernous sinus) or the presence on initial imaging [37, 43]. Bradley et al. suggested introducing anticoagulants in the presence of persistent fever, neurologic changes, and embolic events [43].

The recommended therapy duration with anticoagulants is still disputable in the literature. Scorpecci et al. suggested continuing the treatment for at least 2 months to the first MRI control [14]. They advised basing the decision of treatment duration on comprehensive thrombophilia screening (including MTHFR mutations) in patients with OCVST. This allows the estimation of the risk for thrombosis recurrence and establishes future antithrombotic prophylaxis [14]. Coudert et al. claim that the duration of therapy should depend on the initial extent of the thrombosis and imaging studies performed 6 and 12 weeks after surgery [16]. Nevertheless, the type of thrombophilia does not influence the perspectives of otogenic CVST resolution, hence international guidelines do not recommend any modifications of treatment protocols [1, 33].

Endovascular Treatment

The endovascular treatment of CVST using thrombolysis (urokinase, streptokinase) and mechanical thrombectomy have been reported in a few case reports or small case series. Dentali et al. claim that there is a severe risk of intracranial hemorrhage and mortality in this method [44]. Capecchi et al. indicated that the published data were unconvincing regarding the safety of thrombolysis and endovascular treatment in cases of CVST [45]. No data concerning endovascular treatment of otogenic CVST are available in the literature.

Treatment Outcome and Recanalization

Zanoletti et al. claim that symptoms of CVST are usually self-limiting and rarely life-threatening, with a good response to conservative treatment [6, 24]. Many authors have reported the rapid resolution of symptoms after initial treatment [14, 26]. An interesting observation was published by Rosdy et al. in 2014. The authors revealed that clinical signs of elevated intracranial pressure had transiently worsened postoperatively [25]. Considering the results of these studies, a more reliable indicator of recovery should be sought. Recanalization of the affected venous sinus after 6 months seems to be widely recognized in the literature. In the majority of cases, recanalization may be expected in 2–5 months [11]. Scorpecci et al. proposed scheduled postoperative monitoring with imaging studies to assess the resolution of thrombosis [14].

Some authors have stated that sinuses usually recanalize spontaneously even without clot evacuation after simple mastoidectomy and antimicrobial treatment [46]. According to a study published by Neilan et al., spontaneous sinus recanalization was observed in 52.9% of cases. These rates were higher (although insignificantly) for patients with additional anticoagulation in their group (66.7%) [46]. Au et al. presented higher percentages of 75% and 84% for non-anticoagulated and additionally anticoagulated patients, respectively [14]. In contrast, Chalmers et al. stated that there was no evidence that anticoagulation improves the rate of recanalization [33]. Nevertheless, some limitations for the interpretation of these data exist. The degree of recanalization (partial or complete), unstandardized timing of imaging during follow-up, and the lack of standard protocols for anticoagulation treatment should be taken into consideration.

Conclusions and Future Studies

The extent of sigmoid sinus pathology is not proportional to the involvement of the bony sinus plate. Each pediatric patient without typical otomastoid complaints but presenting symptoms of raised intracranial pressure and otitis media should be suspected for otogenic CVST. The role of contralateral compensatory drainage as a factor predisposing to OCVST needs further studies. The routine screening for thrombophilia is disputable and requires further objective verification. The use of anticoagulant therapy in otogenic CVST remains controversial. The benefits appear to outweigh the potential risks, but there is no established regimen concerning indications, the duration, and the form of the treatment.