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23 Focal Suppurative Infections of the Central Nervous System in Children…
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Fig. 23.5 The danger
triangle of the face;
infections involving the
middle third of the face
(e.g., the areas around the
eyes and nose) may,
although rarely, be
complicated by septic
cavernous thrombosis as
the vessels in this area are
without valves. (Courtesy
Taylan Çelik, MD)
23.3.3 Epidemiology
309
In an 11-year study in children, it was reported that 8% (10/121) of 121 cases with
pediatric CST had CavST. In this retrospective study, 10 pediatric patients were
evaluated, and bilateral CavST was detected in 50% of the cases [9]. In another
retrospective study conducted on children, 12 pediatric CavST cases (3–16years,
mean age 10years, 58% male) between 2000 and 2013 were evaluated; 83% of the
cases were bilateral, and sinusitis was found as a risk factor in 32% [10]. Although
aseptic CavST is usually seen due to trauma or a prothrombotic etiology, infection
associated with septic CavST draws attention [11]. Conditions that cause immunosuppression may also be risk factors for septic CavST [1].
23.3.4 Pathogenesis
The cavernous sinuses receive blood from the facial veins and pterygoid plexus via
the facial and ophthalmic veins. Therefore, infections on the face, including the
paranasal sinus, nose, orbit, tonsils, and soft palate, can easily spread to the cavernous sinus due to the absence of valves in these veins [1, 11]. Infections in the danger
triangle around the nose on the face pose a greater risk in this respect (Fig.23.5).
Bilateral CavST development due to intercavernous spread is common in delayed
CavST cases. In addition, orbital involvement, meningitis, subdural empyema, and
sepsis may accompany due to proximity [11].
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Primary infection sites most likely to cause septic CavST are sphenoid and/or
ethmoid sinus, facial, and dental infections. Sphenoid and/or ethmoid sinus infections are increasingly reported together with cavernous sinus thrombosis [1, 2, 9].
Sphenoid sinusitis is the most common predisposing factor for cavernous sinus
thrombosis. Because sphenoid sinus infection is challenging to diagnose, treatment
is often delayed, allowing the infection to spread into the cavernous sinus. Infection
from sphenoid sinusitis can spread directly through the emissary veins (thin-walled,
valveless veins in the skull that pass through the bone tissue through small foramina
and empty into the venous sinuses) or by destroying the porous sphenoid sinus lateral wall due to infection. Ethmoid sinus infection may extend laterally into the
orbit and then spread to the cavernous sinus via the superior ophthalmic vein [1, 2].
Infections involving the danger triangle area of the face (Fig. 23.5), especially
around the nose, drained by the ophthalmic vessels, may cause septic cavernous
sinus thrombosis. Squeezing or emptying the nasal furuncles is one of the most
common facial infections that cause complications. Dental abscesses/infections
cause this complication less frequently; the infection spreads to the cavernous sinus
via the pterygoid venous plexus and the emissary veins that cross the bone. Otitis
media and its associated complication, mastoiditis, rarely cause CavST. Mastoid
infection may spread to the lateral and sigmoid sinuses before reaching the cavernous sinuses via the inferior and superior petrosal sinuses, leading to septic LST
more commonly. However, since the dural sinuses do not have valves, the infection
may also spread retrogradely into the cavernous sinuses due to pressure gradients [1, 2].
Many previous case reports reported reversible narrowing of the ICA associated
with CavST due to its adjacent relationship with the cavernous sinus (Figs.23.4,
23.6, and 23.7). It is reported that 70% of the cases with ICA stenosis in the acute
phase of the disease resolve within 6months. The clinical signicance of ICA stenosis is uncertain, but it may raise concerns about the potential for arterial ischemic
stroke [10].
Fig. 23.6 Gradenigo
syndrome. A 5-year-old
patient complained of
headache, diplopia, and
restricted right eye
movement. Axial
T1-weighted contrastenhanced MR image shows
inammation causing
enlargement of the right
cavernous sinus (double
arrows) and diminished
diameter of the right
internal carotid artery
(arrow). (Courtesy Zeynep
Yazıcı, MD)
23 Focal Suppurative Infections of the Central Nervous System in Children…
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Fig. 23.7 Rhino-orbital mucormycosis causing cavernous sinus and internal carotid artery thrombosis. A 14-year-old patient with type 1 diabetes and ketoacidosis. Axial T1-weighted contrastenhanced MR image shows enlargement and heterogeneous enhancement of the right cavernous
sinus and absent ow void in the right internal carotid artery (white arrow) compared with the
normal left cavernous sinus and left internal carotid artery (black arrow). Soft tissue inammation
and abscess formations involving the right orbit and ethmoid sinus are also seen. (Courtesy Zeynep
Yazıcı, MD)
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23.3.5 Clinical Manifestations
Headache is the most common early symptom in CavST and usually begins a few
days before fever and periorbital edema. The character of the headache is typically
sharp; the pain gets progressively worse, disrupts sleep, and is not relieved by painkillers. The pain is usually unilateral, occasionally reected in the occipital region,
but is more prominent in the retroorbital and frontal areas. In addition to headache,
patients may have fever (94%), periorbital swelling (73%), and diplopia, which
starts unilaterally but can spread to the other side via the intercavernous sinus connection within 24–48h. Following eye-related symptoms, the infection may spread
to the meninges; it may present with changes in mental status, such as sleepiness,
confusion, or coma [1]. In a literature review for CavST in children covering the
years 2003–2014, of 10 children with CavST between the ages of 11 and 17, half
were boys. Headache (70%), fever (60%), and vomiting (60%) were reported as the
most common symptoms [9]. Less common complaints may include photophobia
and tearing [1]. Typically, symptoms progress within a few days. Cavernous sinus
infection may rarely be a subacute or chronic process with an unexplained headache
that begins a few months before the onset of ocular ndings.
Cavernous sinus thrombosis classically presents as a clinical syndrome involving
a combination of proptosis and chemosis of the involved eye and cranial nerve palsies and/or sensory loss [9]. In septic CavST, most patients present with fever and
classical bilateral ptosis, proptosis, chemosis, and ocular muscle paralysis. However,
physical ndings may be subtle when patients are seen early. So, careful eye and
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neurological system examination, especially paying attention to the cranial nerves,
is necessary for early diagnosis.
Periorbital edema may be the earliest physical examination nding, and if it is
accompanied by a headache, a more detailed physical examination should be performed on these patients. A fundoscopic examination is abnormal in two-thirds of
patients. Papilledema or enlarged coiled retinal vessels occur in almost two-thirds
of patients. Extraocular muscle weakness is an important nding in 50–88% of
cases and is caused by dysfunction of the adjacent CN-III, CN-IV, and CN-VI
(Fig.23.4). Lateral gaze palsy (isolated CN-VI dysfunction) draws attention, especially in cases of chronic sphenoid sinusitis. Ptosis, mydriasis, and eye muscle
weakness are caused by CN-III dysfunction. Complete paralysis of the nerve causes
downward and lateral gaze. Proptosis and chemosis are thought to result from
occlusion of the ophthalmic vessels and usually occur just before or at the same
time as ophthalmoplegia. Mild hypo/hyperesthesia may occur in dermatomes innervated by the ophthalmic and maxillary branches of the CN-V.
T. Çelik et al.
23.3.6 Laboratory
In case of suspicion with clinical ndings, it is important to conrm the diagnosis
with laboratory methods, including imaging. Cavernous sinus thrombosis can lead
to serious neurological sequelae if not detected on time. Cranial imaging is the most
important laboratory approach in diagnosis.
23.3.6.1 Imaging
Although the diagnosis of CavST was made clinically in the past, imaging methods
are required for diagnosis today [10]. The diagnosis of CavST should be considered
in patients who present with signs of cranial nerve involvement localized to the
cavernous sinus in addition to the symptom triad of progressive/continuous headache, mental status change, and vomiting and who have signs of infection and neuroimaging, specically targeting this condition should be considered urgently [1, 2].
In this respect, various imaging methods can be used. Contrast-enhanced cranial
magnetic resonance (MR) imaging and MR venography are the imaging modalities
of choice. It has been reported that MR imaging is superior to computed tomography (CT) in septic CavST because it can detect all stages of thrombus and evaluate
the extent of parenchymal damage. If MR imaging is unavailable, contrast-enhanced
orbital CT and CT venography usually provide high sensitivity to identify thrombosis; however, they are less specic and less sensitive to characterize brain damage.
If CT is used, it is preferred that the CT be a high-resolution CT (≤3mm slice thickness) [12]. Early venous phase, thickened cavernous sinus walls, and decreased/
irregular intrasinus contrast can be demonstrated following contrast administration
[1, 2, 9]. Contrast-enhanced MR or CT is considered the gold standard in diagnosing CavST [10]. Contrast-enhanced MR and CT venography are 100% sensitive in
detecting CavST, while non-contrast MR and CT are not [11]. Computed
23 Focal Suppurative Infections of the Central Nervous System in Children…
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tomography and MR can also detect underlying ethmoid and sphenoid sinusitis and
may guide the treatment. Other venous structures should also be evaluated in
patients with CavST, as additional vein thrombosis is observed in 70% of the
patients besides CavST [9]. If there is no other explainable cause, narrowing of the
ICA accompanied by signs of surrounding cavernous sinus inammation can be
considered a nding that supports septic CavST. Computed tomography and MR
imaging can also detect paranasal sinus infection with high sensitivity and contribute to determining the etiology and guiding the treatment. The presence of paranasal
sinus infection may also be a guide for possible surgical intervention [1].
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23.3.6.2 Other Laboratory Tests
Two sets of blood cultures should be sent before starting antibiotic therapy, which
may be positive in approximately 70% of cases [13]. Peripheral white blood cell
count is usually elevated (leukocytosis), which favors acute bacterial infection [1].
Studying acute phase reactants (such as CRP, procalcitonin, and ESR) may be benecial in necessary cases. The tendency of high acute phase reactants to improve
with treatment may be a guide in therapy. A prothrombotic examination is recommended in all patients to identify additional risk factors that may predispose them
to thrombosis (prothrombotic genetic conditions such as antithrombin deciency,
protein C and protein S deciency, factor V Leiden mutation, MTHFR gene mutation, and investigation of nephrotic syndrome and antiphospholipid antibodies) [9].
If the patient has no signs of supporting meningitis, a lumbar puncture is not
required [1].
23.3.7 Differential Diagnosis
Many conditions are considered in the differential diagnosis of septic CavST,
including headache, periorbital swelling, chemosis, and painful ophthalmoplegia.
Orbital occlusion symptoms (proptosis, conjunctival injection, and chemosis) often
accompany eye diseases. Most of these can be distinguished by neuroimaging
assessment and/or clinical symptoms.
23.3.7.1 Periorbital andOrbital Cellulitis
Periorbital/orbital cellulitis and septic CavST have overlapping symptoms such as
periorbital swelling, chemosis, and ophthalmoplegia. Also, septic cavernous sinus
thrombosis is a complication of orbital cellulitis. For differential diagnosis of these
patients, mydriatic pupil/pupillary, vision loss, papilledema, CN-V dysfunction,
bilateral eye involvement, and detection of inammatory cells in the CSF are clinical features that increase the possibility of cavernous sinus involvement. Cavernous
sinus thrombosis should also be considered in cases where periorbital/orbital cellulitis is unresponsive to optimal treatment, and cranial nerve ndings persist.
Computed tomography or MR imaging can easily distinguish between the two diseases by demonstrating cavernous sinus involvement.
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23.3.7.2 Intraorbital Abscess
The intraorbital abscess typically presents acutely with periorbital swelling, proptosis, chemosis, ophthalmoplegia, fever, decreased vision, and pain; however, there is
usually no papilledema or pupillary involvement. Imaging studies can distinguish
abscesses from cavernous sinus thrombosis.
23.3.7.3 Intracavernous Carotid Artery Aneurysm or
Arteriovenous Fistula
These formations are usually accompanied by proptosis and pulsating pain. Patients
do not have a fever or other signs of infection. Neuroimaging ndings are
distinctive.
23.3.7.4 Aseptic Cavernous Sinus Thrombosis
Aseptic CavST is distinguished from septic CavST, typically by the presence of
aseptic disease, without fever on examination or history, as well as the absence of
signs of sinus, mastoid, or facial infection on physical examination and/or laboratory, including imaging investigations.
23.3.8 Treatment
Antibiotics are the mainstay of septic CavST treatment. In selected cases, anticoagulants and surgery are additional treatments that can be applied. Early diagnosis
and treatment are critical. Delays in treatment may be associated with morbidity and
mortality [1, 2]. However, no clinical studies evaluated the risks and effects of
CavST therapies in children.
23.3.8.1 Antibiotics
Empirical intravenous (IV) antibiotics should be started urgently to cover possible
organisms expected to cause infection (Table23.1). Treatment changes can be made
according to blood culture results and treatment response. Empirical treatment
should also include community-acquired MRSA.It would be appropriate to choose
the antibiotics with high CSF penetration in septic CavST. First- and secondgeneration cephalosporins should be avoided in treating CNS infections due to poor
CSF penetration. It is appropriate to plan the empirical parenteral initial regimen as
vancomycin plus third-generation cephalosporins such as cefotaxime and ceftriaxone. If Pseudomonas coverage is desired (e.g., in patients with chronic sinusitis and
known sinus colonization by Pseudomonas), cefepime should be used instead of
ceftriaxone. An antibiotic with anaerobic coverage, such as metronidazole, should
be added if a tooth or sinus infection is suspected. If a cephalosporin or metronidazole cannot be used, the combination of vancomycin plus meropenem is a reasonable empirical regimen for most patients. If meropenem is unavailable, imipenem
can be used; however, since it may increase the risk of seizures, it is recommended
to prefer meropenem. Antifungal therapy is rarely necessary and should only be
used if a biopsy proves an invasive fungal infection.
23 Focal Suppurative Infections of the Central Nervous System in Children…
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Table 23.1 Antibiotics are used in the treatment of cerebral sinus thrombosis in children
Antibiotics
Cefotaxime 300mg/kg/day 6 12,000 g/day
Ceftriaxone 100mg/kg/day 12 4000mg/day
Cefepime 150mg/kg/day 8 6000mg/day
Vancomycin 60mg/kg/day 6–8 2000mg/day
Metronidazole 40mg/kg/day 6–8 4000mg/day
Meropenem 120mg/kg/day 8 6000mg/day
Nafcillin 200mg/kg/day 6 12,000mg/day
Oxacillin 200mg/kg/day 6 12,000mg/day
Ceftaroline 2month–2year: 24mg/kg/day 8 1200mg/day
Daptomycin 1–6year: 12mg/kg/day 24
Linezolid
Trimetoprim–
sülfametoksazol
a
Adapted and modied from Refs. [1, 14]
Dose Dose range (h)
≥2year: ≤33kg, 36mg/kg/day
>33kg, 1200mg/day
7–11year: 9mg/kg/day
12–17year: 7mg/kg/day
≤11year: 30mg/kg/day
>11year: 600mg 12
10–20mg/kg/day 6–12 320mg/day
8–12
8 1200mg/day
Maximum dose
a
If S. aureus is sensitive to methicillin in the antibiotic susceptibility test, the
treatment should be changed to nafcillin or oxacillin. If S. aureus is resistant to
methicillin, vancomycin treatment should be continued. Ceftaroline, daptomycin,
linezolid, or trimethoprim-sulfamethoxazole may be considered alternative agents
if vancomycin cannot be used or if there are clinical signs such as fever, bacteremia,
and mental status changes do not improve within 7days despite treatment.
Thrombus can reduce the penetration of antibiotics into the infection site, so longterm administration of IV antibiotics is recommended. A minimum of 3weeks of
treatment is usually required to achieve sterilization. The duration of treatment may
be further extended based on clinical response and individual assessment of the
patient’s additional factors. In the presence of S. aureus and/or serious ndings
considering bacteremia, or if signicant ophthalmoplegia or ocular edema persists
at the end of the planned treatment, the duration may need to be extended. Since the
recovery of cranial imaging ndings is usually late, clinical parameters should be
considered primarily for assessing the treatment duration.
23.3.8.2 Anticoagulation
The use of anticoagulants in septic CavST is controversial, and there are limited
data on this subject. Findings support that adding anticoagulant therapy generally
contributes to a more favorable prognosis in morbidity and mortality. In a retrospective study, a decrease in mortality was observed in patients with unilateral
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involvement who applied early and received heparin (14%) compared to those who
did not (36%) [15]. In another retrospective analysis, the addition of anticoagulant
therapy in the early period, within the rst 7days of hospitalization, and antibiotic
therapy, has been shown to reduce morbidity, including ophthalmoplegia, blindness,
paralysis, hypopituitarism, and seizures, although it did not affect mortality.
Although the exact duration of anticoagulant therapy is not precise, it is recommended to continue for 4–6 weeks, depending on the clinical response of the
patient [12].
In a study involving children, covering the years 2003–2014, in which cases of
ICA stenosis and arterial ischemic stroke were widely reported; therapeutic interventions, including anticoagulation, to prevent the progression of thrombosis or
vasospasm, have been reported to be associated with favorable outcomes, contributing to the prevention of progressive infarction, although not completely preventing
new infarctions [9]. Evidence-based data on the efcacy of anticoagulant therapy in
children in septic CavST are limited or unavailable. Published treatment guidelines
for children have been primarily estimated from data from adult studies [2]. In the
authors’ clinic, until new evidence-based data are available in children, it is recommended that anticoagulant therapy be given in addition to antibiotics in the treatment of septic CavST unless contraindicated.
The recommendations of the CavST treatment guidelines for adults can be summarized as follows [2]: Anticoagulant therapy is safe and may be benecial in
reducing mortality and long-term morbidity, even in intracranial hemorrhage. There
is insufcient evidence to show whether heparin or low molecular weight heparin
(LMWH) is superior. In critically ill patients who experience clinical worsening
despite anticoagulant therapy, brinolytic or endovascular therapy may be lifesaving. The addition of aspirin or steroids is not recommended because of its association with higher mortality rates and poor outcomes. Duration of anticoagulant
therapy should be at least 3–6months in patients with CavST secondary to an infection, 6–12months in patients with spontaneous CavST without persistent thrombophilia, on a lifelong basis in patients with severe thrombophilia such as severe
protein C, protein S or antithrombin III deciency, homozygous prothrombin or
factor V Leiden mutation, and antiphospholipid antibody syndrome.
The British Committee for Standards in Haemotology recommends that children
with CavST, and non-intracranial hemorrhage, receive anticoagulant therapy with
LMWH or heparin as in all age groups [16].
In patients considered for anticoagulation, dose-adjusting anticoagulation is recommended initially at the routine treatment dose (heparin or LMWH) and keeping
the thromboplastin time between 1.5 and 2.5. Warfarin should be avoided in the
acute phase of the disease because of the difculty in meticulously maintaining safe
levels of anticoagulation.
The duration of anticoagulation has not been determined. The presence of infection is a signicant risk factor for septic thrombosis. It is recommended to continue
anticoagulation until signs of infection (e.g., periorbital edema, fever, and leukocytosis) are resolved and signs of cavernous sinus thrombosis are signicantly resolved
[1]. In a study in children, therapeutic anticoagulation was initiated in 10 of 12
patients with CavST who had ICA abnormalities. In this study, the median
23 Focal Suppurative Infections of the Central Nervous System in Children…
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anticoagulation duration was 3 months; 80% were treated with LMWH, and no
bleeding complications were reported. These data are important to demonstrate that
anticoagulation is safe to use, at least in this population [10].
Complications associated with anticoagulation are rare. In a cohort of 57 patients
with CST associated with head or neck infections, the use of heparin was not associated with an increase in intracranial bleeding (26% vs. 25%) in patients receiving
heparin compared with patients not receiving heparin [17]. These data support the
safety of anticoagulation.
In the authors’ clinic, in cases with septic CavST, low molecular weight heparin
(enoxaparin 2 × 0.5–1mg/kg/dose, subcutaneous) is started by monitoring coagulation parameters in addition to appropriate antibiotics. By tracking the imaging ndings and clinical ndings of the patient, LMWH is administered as long as the
patient is using antibiotics and after all clinical ndings have resolved; also, after
the antibiotic therapy has been discontinued, LMWH is continued for a period,
which can vary individually, with the recommendation of pediatric hematology
experts. If there are no risk factors for thrombophilia or there has been no previous
signicant thrombotic attack in patients with clinical and radiological improvement,
this extra period after stopping antibiotics is usually 2–4weeks. If the patient has
risk factors for thrombophilia, anticoagulant therapy is recommended for a more
extended duration, with pediatric hematology consultation.
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23.3.8.3 Surgery
There is no clear recommendation for surgery in CavST; the literature results are
inconsistent. If a severe sphenoid sinus infection thought to cause CavST is detected
on imaging, emergency surgical drainage might be considered in the early phase of
treatment. Debridement of the infected sphenoid can accelerate healing [1]. In a
study involving children, surgical debridement, functional endoscopic sinus surgery
in 10 patients, and myringotomy in one patient were performed in 11 (92%) of 12
patients. However, the results were not different between children who had surgery
and those who did not. Whether early surgical intervention may prevent complications is unclear and requires further investigation [10]. The authors consider that
because the optimal response is usually assessed by the antibiotic and anticoagulant
therapy, surgical treatment is not recommended unless there is an additional indication to require surgery.
23.3.8.4 Lack ofRole forGlucocorticoids
There has been interest in using glucocorticoids to potentially reduce cranial nerve
edema and orbital inammation in patients with septic CavST; however, the limited
data available indicate that they are not helpful [1].
23.3.9 Outcome
Morbidity and mortality may be high in CavST cases associated with sphenoid
sinus infection [1]. Venous obstruction in severe cases can lead to infarction, malignant intracranial hypertension, herniation, and death. In surviving children,
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intracranial hypertension and papilledema can cause vision loss [2]. Morbidity and
mortality rates differ in different studies. Mortality associated with septic CavST
has been reported as up to 30%. In addition, severe permanent sequelae such as
oculomotor weakness, blindness, hemiparesis, or pituitary insufciency may
develop in 30% of cases [14]. More recent studies have reported mortality rates of
9–16% and morbidity rates of 15–38% [17, 18]. In another study and literature
review involving children, the overall mortality rate in 52 cases was reported as 8%
and the morbidity rate as 25% [10]. Signicant mortality and sequelae rates highlight the importance of early diagnosis and comprehensive treatment in CavST.
23.3.10 Complication ofHearing Loss
In contrast to LST, CavST is not a kind of septic dural sinus thrombosis causing
major HL.However, in the presence of accompanying recurrent/persistent acute or
chronic otitis media, conductive or SNHL (due to involvement of the cochlear system and CN-VII) may develop. In addition, SNHL may develop in cases complicated by meningitis.
23.4 Septic Lateral Sinus Thrombosis
Lateral (transverse) sinus thrombosis is a rare but potentially fatal disease that usually affects the pediatric population, occurring in the sigmoid and lateral sinuses
(Figs.23.1, 23.2, 23.8a–c, and 23.9) as a complication of AOM and mastoiditis. The
lateral sinuses are one of the major cerebral sinuses. They extend bilaterally from
the lower part of the posterior cranium, laterally and transversely, and then open into
the sigmoid sinuses, eventually draining into the internal jugular vein [19–21].
Fig. 23.8 (a–c) Purulent meningitis complicated with septic left sigmoid sinus thrombosis. A
15-year-old patient. (a) Axial T2-weighted MR image shows the absence of the ow void in the left
sigmoid dural sinus owing to the thrombosis (arrow). The normal blood ow void is seen in the
contralateral sigmoid sinus (double arrows). The left mastoid air cells are lled with uid (asterisk). (b, c) T1-weighted contrast-enhanced axial (b) and coronal (c) MR images show no enhancement of the left sigmoid sinus but with surrounding dural enhancement (arrow). The normal right
sigmoid sinus is enhanced vividly (double arrows). The left mastoid air cells (arrowhead) are
opacied; the right mastoid air cells (curved arrow) appear normal. (Courtesy Zeynep Yazıcı, MD)
b
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