10.14639/0392-100X-N1835
Objectives. Sinus venous thrombosis (SVT) is a rare complication of acute otitis media (AOM) with acute mastoiditis (AM), which during recent years has been associated with Fusobacterium necrophorum (Fn) infection. Our objective was to review clinical, microbiologic, and hematologic features of paediatric otogenic SVT, with a specific focus on the role of Fn. Methods. A retrospective database review in a tertiary paediatric hospital between 2000- 2019. Results. Fifty children aged 6-155 months were treated for AM with SVT. Forty-seven (94%) underwent cortical mastoidectomy. Forty-six children received low-molecularweight heparin (LMWH). Follow-up imaging revealed recanalisation in 92% of cases. No long-term neurologic or haematologic complications were observed. Since 2014, when anaerobic cultures and PCR were routinely used in our institute, Fn was isolated from 15/21 children with SVT. Their time to recanalisation was longer, and the rate of lupus anticoagulant antibodies (LAC) was higher than in the 6 non-Fn patients. Children positive for LAC also had a longer time to recanalisation. Conclusions. Fn is a common pathogen in AM with SVT; its thrombogenic role was demonstrated by a higher prevalence of LAC and a longer time to recanalisation.
text/xml
1827-675X
1835
en
David  Ulanovski
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
sinus thrombosis, mastoiditis, Fusobacterium necrophorum
Paediatric otogenic sinus venous thrombosis: the role of Fusobacterium necrophorum
Text.Serial.Journal
https://www.actaitalica.it/
42
Otology
2022-09-30
2021-09-28
2022-10-12
2022-10-12
388-394
1
David  Ulanovski
2022/09/30
10.14639/0392-100X-N1835
388
Schneider Children's Medical Center of Israel
1827-675X
sinus thrombosis, mastoiditis, Fusobacterium necrophorum
en
394
Paediatric otogenic sinus venous thrombosis: the role of Fusobacterium necrophorum
https://www.actaitalica.it/article/download/1835/857
42
ACTA OTORHINOLARYNGOLOGICA ITALICA 2022;42:388-394; doi: 10.14639/0392-100X-N1835




Otology


Paediatric otogenic sinus venous thrombosis:
the role of Fusobacterium necrophorum
Trombosi del seno venoso su base otogena in pazienti pediatrici:
il ruolo del Fusobacterium necrophorum
Eyal Yosefof1,2, Ohad Hilly1,2, Meirav Sokolov2,3, Eyal Raveh2,3, Joanne Yacobovich2,4, David Ulanovski2,3
1
  Department of Otorhinolaryngology and Head and Neck Surgery, Rabin Medical Center, Petach Tikva, Israel; 2 Sackler Faculty of
Medicine, Tel Aviv University, Tel Aviv, Israel; 3 Pediatric Otorhinolaryngology Unit, Schneider Children’s Medical Center, Petach Tikva,
Israel; 4 Pediatric Hematology Unit, Schneider Children’s Medical Center, Petach Tikva, Israel


SUMMARY
Objectives. Sinus venous thrombosis (SVT) is a rare complication of acute otitis media
(AOM) with acute mastoiditis (AM), which during recent years has been associated with
Fusobacterium necrophorum (Fn) infection. Our objective was to review clinical, micro-
biologic, and hematologic features of paediatric otogenic SVT, with a specific focus on the
role of Fn.
Methods. A retrospective database review in a tertiary paediatric hospital between 2000-
2019.
Results. Fifty children aged 6-155 months were treated for AM with SVT. Forty-seven
(94%) underwent cortical mastoidectomy. Forty-six children received low-molecular-
weight heparin (LMWH). Follow-up imaging revealed recanalisation in 92% of cases. No
long-term neurologic or haematologic complications were observed. Since 2014, when
anaerobic cultures and PCR were routinely used in our institute, Fn was isolated from
15/21 children with SVT. Their time to recanalisation was longer, and the rate of lupus
anticoagulant antibodies (LAC) was higher than in the 6 non-Fn patients. Children positive
for LAC also had a longer time to recanalisation.
Conclusions. Fn is a common pathogen in AM with SVT; its thrombogenic role was                  Received: September 28, 2021
demonstrated by a higher prevalence of LAC and a longer time to recanalisation.                 Accepted: June 6, 2022
KEY WORDS: sinus thrombosis, mastoiditis, Fusobacterium necrophorum
                                                                                                Correspondence
                                                                                                Eyal Yosefof
RIASSUNTO                                                                                       Department of Otorhinolaryngology and Head and
Obiettivi. La trombosi del seno venoso (SVT) è una rara complicanza dell’otite media acuta      Neck Surgery, Rabin Medical Center, Beilinson
(AOM) associata a mastoidite acuta (AM), che negli ultimi anni è stata associata all’infe-      Hospital, 39 Jabotinski St., Petach Tikva 4941492,
zione da Fusobacterium necrophorum (Fn). Il nostro obiettivo è stato rivedere le caratte-       Israel
                                                                                                Tel. +972 3 9376456. Fax +972 3 9376467
ristiche cliniche, microbiologiche ed ematologiche della SVT otogena pediatrica, con un
                                                                                                E-mail: eyalyos@gmail.com
focus specifico sul ruolo del Fn.
Metodi. Una revisione retrospettiva del database in un ospedale pediatrico terziario negli
anni 2000-2019.                                                                                   How to cite this article: Yosefof E, Hilly O,
Risultati. Cinquanta bambini di età compresa tra 6 e 155 mesi sono stati trattati per AM          Sokolov M, et al. Paediatric otogenic sinus venous
con SVT. Quarantasette (94%) sono stati sottoposti a mastoidectomia corticale. Quaran-            thrombosis: the role of Fusobacterium necropho-
tasei bambini hanno ricevuto eparina a basso peso molecolare. L’imaging di follow-up ha           rum. Acta Otorhinolaryngol Ital 2022;42:388-
                                                                                                  394. https://doi.org/10.14639/0392-100X-N1835
rivelato una ricanalizzazione nel 92%. Non sono state osservate complicanze neurologiche
o ematologiche a lungo termine. Dal 2014, quando nel nostro istituto sono state utilizzate di
                                                                                                © Società Italiana di Otorinolaringoiatria
routine colture anaerobiche e PCR, il Fn è stato isolato in 15/21 bambini con SVT. Il tempo     e Chirurgia Cervico-Facciale
alla ricanalizzazione è stato più lungo e il tasso di anticorpi lupus anticoagulanti (LAC) è
stato superiore rispetto ai 6 pazienti non Fn. Anche i bambini positivi per LAC hanno avuto                    OPEN ACCESS
un tempo più lungo per la ricanalizzazione.
Conclusioni. Fn è un patogeno comune in AM con SVT; Il suo ruolo trombogenico è stato           This is an open access article distributed in accordance with
                                                                                                the CC-BY-NC-ND (Creative Commons Attribution-Non-
dimostrato da una maggiore prevalenza di LAC e da un tempo più lungo alla ricanalizza-          Commercial-NoDerivatives 4.0 International) license. The
zione.                                                                                          article can be used by giving appropriate credit and mentio-
                                                                                                ning the license, but only for non-commercial purposes and
PAROLE CHIAVE: trombosi sinusale, mastoidite, Fusobacterium necrophorum                         only in the original version. For further information: https://
                                                                                                creativecommons.org/licenses/by-nc-nd/4.0/deed.en




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                                                                                            Paediatric otogenic sinus venous thrombosis




Introduction                                                      fluctuation was diagnosed, needle aspiration of the pus was
                                                                  performed at admission. According to our departmental
Otogenic sinus venous thrombosis (SVT) is a rare complica-
                                                                  imaging protocol for AM, CT was not routinely performed
tion of acute otitis media (AOM) and acute mastoiditis (AM),
                                                                  at admission. CT was performed only in patients with a
with potentially serious consequences. SVT can result from
                                                                  septic appearance at presentation (including high fever, in-
direct extension or haematogenic spread of infection through
                                                                  flammatory indices, haemodynamic instability, or altered
emissary veins that connect the mastoid with the sinus. The
                                                                  mental status), subperiosteal abscess with no response to
disease may then propagate to the internal jugular vein or oth-
                                                                  needle aspiration, or when no clinical or laboratory im-
er dural sinuses. In the era of antibiotics and surgical treat-
                                                                  provement was observed during 48 h of treatment. CT was
ment, the mortality rate from SVT has substantially decreased
                                                                  always performed with intravenous contrast enhancement.
and while in the past a rate of 5% was described, in recent
                                                                  CT findings determined the extent of surgical intervention
years mortality due to otogenic SVT has become rare 1-4.
                                                                  which included ventilation tube insertion and one of the
The current treatment approach to AM with SVT includes
                                                                  following options: 1) If CT demonstrated a confined, small
broad spectrum antibiotics, introduction of a ventilation
                                                                  abscess without intracranial involvement, we performed in-
tube and cortical mastoidectomy with the removal of the
                                                                  cision and drainage of the subperiosteal abscess; 2) If CT
bony plate covering the sigmoid sinus and epidural space.
                                                                  demonstrated SVT by signs of dural enhancement and a
Anticoagulant therapy is usually administered postopera-
                                                                  filling defect of the involved lateral sinus or epidural ab-
tively 3. Other approaches can include sinus incision and
                                                                  scess, the preferred surgical option was cortical mastoidec-
thrombectomy or sinus ligation 5.
                                                                  tomy with unroofing of the bony plate covering the sigmoid
Computerised tomography (CT) and magnetic resonance
                                                                  sinus and epidural space; and 3) all other cases that failed
imaging (MRI) are indispensable in the diagnosis, man-
                                                                  to improve underwent cortical mastoidectomy with drain-
agement and follow-up of patients with SVT. Contrast
                                                                  age of the subperiosteal abscess. MRI is not performed in
enhanced CT has a major role in diagnosis of SVT and
surgical planning. The duration of anticoagulant treatment        our institute at the diagnostic stage of AM with SVT and is
is directly influenced if recanalisation is demonstrated in       used mainly as the follow-up imaging modality of choice.
imaging follow-up with MRI 6,7.
The incidence of Fusobacterium necrophorum (Fn) mas-              Imaging follow-up
toiditis has been shown to increase in the last two decades       Follow-up imaging was mostly performed with MRI in-
and is strongly associated with an increased risk of devel-       cluding an MR venography (MRV) protocol at 3 months
oping SVT 8-12.                                                   after hospitalisation and at 3-month intervals until recanali-
The study reviewed our 20-year experience with SVT treat-         sation was demonstrated. Until 2010, follow-up imaging
ment and outcomes and to compare clinical characteristics of      was performed mainly with CT venography (CTV). Time
patients with Fn SVT and non-Fn SVT. The current study is         to recanalisation was defined as the time (days) between
a follow-up of our previous publication from 2014 that de-        initiation of anticoagulation treatment and the date of the
scribed our experience with a limited cohort of 24 children 13.   imaging exam showing complete or partial recanalization.

                                                                  Thrombophilic work-up
Materials and methods                                             Of 50 children included in the study, 46 had a documented
Patients                                                          haematologic work-up including: prothrombin time (PT),
We reviewed the records of all patients hospitalised and          partial thromboplastin (PTT), international normalised ratio
treated for otogenic SVT at a university-affiliated tertiary      (INR), factors IX, X, XI, XII, antithrombin, Lupus antico-
paediatric care centre from 2000 to 2019. Data collected          agulant (LAC), antiphospholipid antibodies (APLA) [an-
from medical charts included: symptoms and signs, microbi-        ticardiolipin (ACL) and β-2 glycoprotein], protein C, pro-
ologic evaluation, thrombophilic evaluation, radiologic find-     tein S, activated protein C resistance, lipoprotein (a), factor
ings, medical and surgical treatments and clinical outcome.       V Leiden, methylenetetrahydrofolate reductase (MTHFR)
                                                                  mutation and homocysteine. Children with partial data were
Treatment approach for AM                                         included only for the tests available. This work-up was per-
Children were diagnosed with AM by a paediatric otolar-           formed during or shortly after hospitalisation, and all were
yngologist in the presence of otalgia, fever, signs of AOM,       followed in our haematology clinic after discharge.
and retro-auricular redness and swelling. Tympanocentesis
was performed in cases without spontaneous discharge,             Microbiologic work-up
and culture was taken for microbiology. If retro-auricular        Microbiologic cultures were performed on middle ear ﬂuid



                                                                                                                                 389
E. Yosefof et al.




samples obtained from all children either by tympanocente-                    Results
sis or by collection of spontaneous discharge at admission,
                                                                              During the study period, 1280 children with AM were
and during the surgical procedure. Our institutional policy
                                                                              hospitalised in our institution. Fifty children (3.9%), aged
until the year 2013 was to obtain only aerobic cultures for                   6-155 months (median 25 months), had SVT. Of these, 37
children with AM, unless anaerobic infection was suspect-                     (74.0%) were younger than 3 years (Fig. 1). Twenty-five
ed. Since 2014, both aerobic and anaerobic cultures have                      (50%) were male.
been routinely performed in children with AM. For patients                    Symptoms and signs of available data in 42 cases are pre-
with sterile cultures who undergo surgical intervention, a                    sented in Table I. Redness and swelling of the mastoid were
broad-range 16S rRNA polymerase chain reaction (PCR)                          reported in 78.6% and 76.2% of cases, respectively. Dis-
and sequencing panel are performed to identify the caus-                      charge from the ear was reported in 20 cases (47.6%) and bi-
ative pathogen. Fn-SVT and non-Fn SVT characteristics                         lateral otitis in 9 cases (21.4%). When comparing Fusobac-
were only compared for patients treated since 2014 to avoid                   terium and non-Fusobacterium cases diagnosed since 2014,
the inclusion of patients who might have previously been                      we found no significant difference in symptoms and signs.
misdiagnosed as non-Fn SVT.                                                   The incidence of thrombosis propagation to other sinuses
                                                                              and epidural space abscess is presented in Figure 2. In all,
Antibiotics treatment protocol                                                40% of children had transverse sinus involvement, and the
In our institute, children hospitalised with AM are generally                 same number had internal jugular vein involvement.
                                                                              All children were treated with broad-spectrum antibiotics
treated with a second-generation cephalosporin (cefuroxime).
                                                                              (mainly ceftriaxone, and either metronidazole or clinda-
In a severe clinical presentation with high fever and high in-
                                                                              mycin). Forty-seven children (94%) underwent ventilation
flammatory markers, empiric coverage is wider and includes a                  tube insertion and cortical mastoidectomy with the removal
third-generation cephalosporin (ceftriaxone) and an antibiotic                of the bony plate over the sigmoid sinus and epidural space,
covering anaerobic bacteria (clindamycin or metronidazole).

Statistical analysis
Continuous variables are presented as medians with range,
and compared between groups using the Mann-Whitney
test. Categorical variables were compared between groups
using the Fisher exact test. Time to recanalisation was eval-
uated from the initiation of anticoagulation treatment to the
date of the MRI showing recanalisation and compared us-
ing Kaplan-Meier survival curves. IBM SPSS Statistics for
Windows, version 25.0 (IBM Corp. Armonk, NY) was used                         Figure 1. Age distribution at the presentation of 50 children with sinus ve-
for all analyses.                                                             nous thrombosis.


Table I. Symptoms and signs of 42 children with mastoiditis with sinus venous thrombosis, and comparison between Fusobacterium and non-Fusobacterium
cases diagnosed since 2014.
 P-value                   Non-Fusobacterium                      Fusobacterium                 Number of children (%)           Symptom/Sign
                                (n = 6)                              (n = 15)                           (n = 42)
 p = 0.69                        3(50%)                           7 (46.7%)                            18 (42.9%)                          Pain
 p = 0.64                       2(33.3%)                           8(53.3%)                            20 (47.6%)                       Discharge
 p = 0.61                       1(16.7%)                            6(40%)                              9 (21.4%)                     Bilateral otitis
 p = 0.6                        4 (66.7%)                          12(80%)                             33 (78.6%)               Retro auricular erythema
 p=1                            4 (66.7%)                         11(73.3%)                            32 (76.2%)               Retro auricular swelling
 p = 0.44                       1 (16.7%)                         5 (33.3%)                            12 (28.6%)                    Retro auricular
                                                                                                                                       fluctuation
 p=1                            4 (66.7%)                         10 (66.7%)                           31 (73.8%)                 Protrusion of auricle
                                    0                                  0                                2 (4.8%)                        Headache
 p=1                                0                              1(6.7%)                              3 (7.1%)                  Cranial nerve palsy




390
                                                                                                                              Paediatric otogenic sinus venous thrombosis




                                                                                          to third imaging was 165 days (range 39-371 days). No sig-
                                                                                          nificant difference was observed between children who had
                                                                                          documented imaging at follow-up and those who did not,
                                                                                          considering age at diagnosis, mean body temperature, maxi-
                                                                                          mal white blood cell count (WBC), C-reactive protein (CRP),
                                                                                          sinus involvement on primary CT imaging during hospital-
                                                                                          isation and microbiologic profile. In 26 patients, imaging fol-
                                                                                          low-up was performed with MRV; in 10 patients, all treated
                                                                                          before 2010, the imaging was by CTV. Recanalisation was
                                                                                          demonstrated in 33 patients (91.6%) (complete recanalisation
                                                                                          in 58.3% and partial recanalisation in 33.3%). For 3 patients,
Figure 2. Site involvement among 50 children with sinus venous thrombosis                 the haematologist decided to stop anticoagulant treatment
based on radiological and surgical findings.
                                                                                          due mainly to clinical and laboratory exams, even though re-
                                                                                          canalisation was not demonstrated on follow-up imaging.
without sinus aspiration, thrombectomy, or sinus ligation.                                No long-term neurologic or haematologic sequelae were
Two other children underwent ventilation tube insertion                                   observed in any children during a mean haematologic fol-
only because the SVT was detected by CT after AM had                                      low-up of 9.8 months.
responded clinically to conservative treatment.                                           Of 46 children who underwent haematologic thrombophil-
Forty-six children (92%) received LMWH for a medi-                                        ic work-up (Tab. II), 38 (83%) had at least one positive
an time of 4 months (range: 2-12 months). The few cases                                   pro-thrombotic factor. Three patients had 3 pro-thrombot-
that were not treated with LMWH were from earlier years                                   ic factors (6.5%), 9 had 2 factors (19.6%) and 26 had one
when the standardised treatment approach that includes an-                                factor (56.5%, positive LAC and APLA was considered 1
ti-coagulant treatment and imaging follow-up was not yet                                  factor). In total, 28 children (62% of those examined) were
completely embedded in our institute. Out of these four                                   positive for LAC, 12 of them were also APLA positive (of
cases, only one had documented follow-up imaging which                                    41 examined, 29%) while 5 patients were APLA positive
demonstrated complete recanalisation.                                                     without LAC (12.2%).
Follow-up imaging was documented in 36 children, and all
received LMWH. The median time from hospitalisation to                                    Fn mastoiditis with SVT versus non-Fn mastoiditis with SVT
first follow-up imaging was 99 days (range 39-227 days). A                                Since 2014, when anaerobic cultures were routinely taken,
second follow-up imaging was performed in 10 cases, (all                                  21 children were diagnosed with AM and SVT. Of these,
without recanalisation at the first imaging) with a median                                15 (71.4%) had Fn infections. Of those negative to Fn, four
time from first to second imaging of 117.5 days (range 63-                                (19%) were positive to group A streptococcus; one had
222 days). Four patients without recanalisation had a third                               co-infection of group A streptococcus with Pseudomonas
follow-up imaging performed. The median time from second                                  aeruginosa, and another co-infection of group A strepto-


Table II. Hypercoagulability factors among children with otogenic sinus venous thrombosis during 2000-2019.
  Hypercoagulability factor          Non-Fn SVT (%) since 2014            Fn SVT (%) since 2014                                  All cases                 P-value
                                               (n = 6)                           (n = 15)                                        (n = 46)
 LAC                                               2/6 (33%)                            10/15 (67%)                            28/45 (62%)                p = 0.038
 APLA                                              3/5 (60%)                            8/15 (53%)                             17/41 (41%)                 p = 0.77
 APCR                                              1/5 (20%)                            2/15 (13%)                              4/36 (11%)                 p = 0.43
 Lipoprotein a                                     1/4 (25%)                            3/15 (20%)                             14/39 (36%)                   p=1
 Factor V Leiden (Heterozygote)                       0/1                                2/4 (50%)                             5/23 (22%)
 Protein C                                            0/6                                  0/13                                    0/39
 Protein S                                            0/6                                  0/15                                    0/39
 Homocysteine (homozygote)                            0/3                                  0/13                                1/40 (2.5%)
 Factor II                                            0/4                                  0/14                                1/41 (2.4%)
 Factor VIII                                          0/6                                  0/13                                    0/46
 Anti Thrombin III                                    0/6                                  0/13                                    0/39
Fn: Fusobacterium necrophorum; LAC: Lupus antianticoagulant; APLA: antiphospholipid antibodies; APCR: Activated protein C resistance.




                                                                                                                                                                     391
E. Yosefof et al.




Table III. Clinical characteristics of 21 children with sinus venous thrombosis diagnosed from 2014 according to the presence of Fusobacterium necrophorum
infection.
 Clinical characteristic                           Non-Fusobacterium                        Fusobacterium                            P-value
                                                          (n = 6)                              (n = 15)
 Age (months)                                                   30.3                                  29.1                                     p = 0.9
 Male                                                           67%                                   60%                                     p = 0.79
 Bacteraemia                                                     0                                    6.7%                                      p=1
 Max. WBC (K)                                           18.32 (16.39-29.28)                    19.14 (9.91-36.66)                             p = 0.88
 Max. CRP                                                 14.2(6.8-27.5)                         19.5 (7.2-32.3)                              p = 0.38
 Hospitalisation (days)                                      15.5 (13-31)                           19 (11-35)                                p = 0.57
 IV Ab (days)                                                 25 (17-45)                            26(11-51)                                 p = 0.85
 Anticoagulation (months)                                      4 (3-6.5)                            4.5 (3-12)                                p = 0.47
WBC: white blood cells count; CRP: C-reactive protein; IV Ab: intravenous antibiotic.



coccus with Staphylococcus aureus. Two children had ster-
ile cultures with negative PCR for Fn.
Among children with SVT, the mean ages of those with
and without Fn were similar (29.1 and 30.3 months, re-
spectively, p = 0.9), as was the male to female ratio (60%
males in the Fn mastoiditis sub-group vs 67% in the non-
Fn mastoiditis sub-group, p = 0.79). Significant differences
were not found between children with Fn SVT and non-Fn
SVT in median hospitalisation time (19 days vs 15.5 days,
p = 0.57), median maximal WBC count (19,140 vs 18,320,
p = 0.88), mean maximal CRP level (19.5 vs 14.2, p = 0.38)
and mean duration of intravenous antibiotic treatment (26
vs 25 days) (Tab. III).
The mean time to recanalisation was 120 days (78 to 187)
for patients with Fn and 88 days (86 to 90) for patients with-                          Figure 3. Kaplan-Meier survival curves comparing mean time to recanalisa-
                                                                                        tion in children with sinus venous thrombosis and with and without Fn infection.
out Fn (Kaplan-Meier analysis, log rank test, p = 0.027)
(Fig. 3). Children with Fn infection were treated with LM-
WH for a median of 4.5 months (range 3-12) compared to
4 (range 3-6.5) months among those without Fn infection;
this difference was not significant (p = 0.42).
Table II compares haematologic factors among the 21 pa-
tients diagnosed since Fn infection was routinely tested. Of
the 15 children with Fn infection, 10 (67%) were positive
for LAC; this compares to 2 (33%) of the 6 children with-
out Fn infection (p = 0.038). APLA antibody positivity was
similar in the two groups. Positivity for APLA was detected
in 8/15 (53%) of the children with Fn infection and 3/5
(60%) of the children tested without Fn (p = 0.77). No cor-
relation was found between the number of pro-thrombotic
factors and Fn (p = 0.69).
We analysed the effect of LAC on the time to recanalisation
regarding the 21 children diagnosed since 2014. Children
positive for LAC (12 cases, with data regarding time for re-
canalisation for 11 of them) had a significantly longer time
                                                                                        Figure 4. Kaplan-Meier survival curves comparing mean time to recanali-
to recanalisation compared to those negative for LAC (9                                 sation in children with sinus venous thrombosis and positive and negative for
cases) with a log rank p-value of 0.041 (Fig. 4).                                       Lupus anticoagulant.



392
                                                                                              Paediatric otogenic sinus venous thrombosis




Discussion                                                          (60%). No significant association was found between the
                                                                    other thrombophilic factors and Fn infection.
The current study highlights the thrombogenic role of Fn            Fn infection is well known for its possible severe inflam-
infection in the pathogenesis of SVT in AM. We herein               matory and thrombogenic potential, especially in Lemierre
confirmed the very good short- and long-term outcomes               syndrome, in which tonsillitis results in thrombophlebitis
presented in our earlier study 13. These outcomes followed          of the internal jugular vein. Holm et al. 16 showed that Fn
conservative surgical treatment with ventilation tube inser-        activates an inflammatory response that results in bradyki-
tion, cortical mastoidectomy and unroofing of the sigmoid           nin release and activation of the intrinsic coagulation path-
sinus and epidural space (as performed in 94% of the pa-            way by binding to factor XI.
tients) combined with broad spectrum antibiotics and anti-          Our finding of at least one pro-thrombotic factor in 83% of
coagulation treatment. No long-term neurologic or haema-            our cohort concurs with the report of at least one pro-throm-
tologic sequelae were recorded for children.                        botic factor in 24 (96%) of 25 children with otogenic SVT
A significantly longer time to recanalisation was demon-            in a study by Scorpecci et al. 17. Only 64% of the children in
strated among patients with Fn infection compared to non-           that study were treated surgically. All patients were treated
Fn patients. However, we found no differences between               with LMWH and the recanalisation rate was slightly lower
these groups in other clinical and laboratory factors as-           than observed in the present cohort: with 68% recanalisation
sessed. These included WBC count, CRP level, hospital-              after 6 months and 80% after 12 months of MRI follow-up.
isation time and duration of intravenous antibiotics.               Our study demonstrates a strong tendency for thrombophil-
In contrast to our findings, a multicentre study of children        ia among children with SVT, especially LAC/APLA. These
with AM and SVT reported longer mean hospitalisation                hypercoagulability factors are often transient in children
time among 28 children with Fn infection than among the 24          and associated with infectious processes. In the absence of
without (19.8 vs 13.7 days, p = 0.02) 12. Similar to our results,   follow-up data on the perseverance of the LAC/APLA, we
they showed no difference in the duration of antibiotic ther-       cannot unequivocally determine whether this thrombogen-
apy (31.3 vs 31.5 days, p = 0.97). The protocols of the two         ic tendency is the result of the infection, or whether these
studies were similar. They performed a first MRI follow-up          children are at continued risk for thrombogenic events due
after a mean of 2.2 months and a second MRI after an aver-          to inherited conditions. To answer these questions, further
age of 5.1 months. We performed a first MRI 3 months after          long-term follow-up studies are needed in larger cohorts.
hospitalisation and a second after 6 months if recanalisation       Our thrombogenic work-up included inherent factors such
was not demonstrated. In their study, a difference in the rate      as factor V Leiden and homocysteine levels. Zangari et al. 18
of complete recanalisation was demonstrated by the end of           published a study of 5 children who had otogenic SVT, all
the radiologic follow-up in favour of non-Fn cases; however,        of whom were heterozygote for the MTHFR mutation. One
this difference was not statistically significant (61.5% in Fn      of the children was also Factor V Leiden heterozygote, sim-
vs 84.2% in non-Fn, p = 0.18). In contrast, our study demon-        ilar to the rate of 22% positive cases for Factor V Leiden
strated a significantly longer time to recanalisation among         in our cohort. All 5 children were treated with LMWH and
children with Fn infection (120 vs 88 days, p = 0.027).             showed full or partial recanalisation in follow-up MRI, also
We observed haematological abnormalities at diagnosis in            in agreement with our high rate of recanalisation of 91.6%.
83% of children with SVT. Overall, 33/46 (72%) of patients          Schneider et al. 19 attempted to examine the prevalence of
had positive LAC and/or APLA; this compares with an es-             thrombophilia in a long-term follow-up of children with
timated prevalence of positive LAC and APLA in 1-5% of              otogenic SVT. A total of 7 patients were recalled for work-
the general population 14,15. Outstandingly, we found that          up after an average of 13 years after the SVT episode. Three
the prevalence of LAC was 67% in children with Fn SVT               patients (43%) were positive for at least one pro-thrombot-
compared to 33% in the non-Fn SVT group. This differ-               ic factor, including elevated factor IX, decreased protein C
ence was significant (p = 0.038). Based on this finding, we         and S and elevated ACL. Two patients had long-term se-
can cautiously presume that the strong thrombogenic ef-             quelae including hearing loss and headache.
fect of Fn infection is associated with LAC elevation. Fur-         Even in patients with Fn infection and positive hypercoagu-
thermore, we were able to demonstrate by Kaplan-Meier               lability work-up, no long-term haematologic or neurologic
curves that children who were LAC positive had a signifi-           sequelae were recorded in our series.
cantly longer time to recanalisation, suggesting a key role         Limitations of this study include its retrospective nature and
for LAC as a thrombogenic factor in these cases. Our study          the absence of data on the possible long-term thrombogenic
demonstrated a high prevalence of APLA antibodies both              effect of Fn infection, in the context of positive LAC and
among children with Fn SVT (53%) and with non-Fn SVT                APLA antibodies. Hence, we cannot reach any conclusions



                                                                                                                                   393
E. Yosefof et al.




regarding the long-term relation between Fn infection and                       4
                                                                                     Zanoletti E, Cazzador D, Faccioli C, et al. Intracranial venous sinus
the prothrombotic state. Furthermore, due to the dominance                           thrombosis as a complication of otitis media in children: critical re-
                                                                                     view of diagnosis and management. Int J Pediatr Otorhinolaryngol
of Fn as the pathogen among AM with SVT cases, our con-
                                                                                     2015;79:2398-2403. https://doi.org/10.1016/j.ijporl.2015.10.059
trol group of non-Fn was relatively small.                                      5
                                                                                     Ropposch T, Nemetz U, Braun EM, et al. Management of otogenic
                                                                                     sigmoid sinus thrombosis. Otol Neurotol 2011;32:1120-1123. https://
Conclusions                                                                          doi.org/10.1097/MAO.0b013e31822a1ec0
                                                                                6
                                                                                     Steven A, Raghavan P, Altmeyer W, et al. Venous thrombosis: causes
A combination of broad-spectrum antibiotics, anticoagula-                            and imaging appearance. Hematol Oncol Clin North Am 2016;30:867-
tion, and a conservative surgical intervention with ventila-                         885. https://doi.org/10.1016/j.hoc.2016.03.008
tion tube insertion, cortical mastoidectomy and unroofing                       7
                                                                                     Young G. How I treat pediatric venous thromboembolism. Blood
of the bony plate over the sinus yields good outcomes in                             2017;130:1402-1408. https://doi.org/10.1182/blood-2017-04-742320
children with both Fn and non-Fn otogenic SVT.                                  8
                                                                                     Stern Shavit S, Raveh E, Levi L, et al. Surgical intervention for acute
Most children in our cohort had haematological abnormali-                            mastoiditis: 10 years experience in a tertiary children hospital. Eur
ties. The availability of anaerobic cultures and PCR exams in                        Arch Otorhinolaryngol 2019;276:3051-3056. https://doi.org/10.1007/
the past few years demonstrated that Fn infection is a major                         s00405-019-05606-2
pathogen in SVT, followed by group A Streptococcus. SVT                         9
                                                                                     Yarden-Bilavsky H, Raveh E, Livni G, et al. Fusobacterium necropho-
with Fn infection demonstrated a longer time to recanalisa-                          rum mastoiditis in children – emerging pathogen in an old disease. Int
                                                                                     J Pediatr Otorhinolaryngol 2013;77:92-96. https://doi.org/10.1016/j.
tion and a higher rate of LAC. The role of Fn infection in the
                                                                                     ijporl.2012.10.003
induction of LAC, and the consequent influence of LAC on                        10
                                                                                     Stergiopoulou T, Walsh TJ. Fusobacterium necrophorum otitis
SVT secondary to AM, is an interesting field for further study.
                                                                                     and mastoiditis in infants and young toddlers. Eur J Clin Mi-
                                                                                     crobiol Infect Dis 2016;35:735-740. https://doi.org/10.1007/
Conflict of interest statement                                                       s10096-016-2612-1
The authors declare no conflict of interest.                                    11
                                                                                     Gelbart M, Bilavsky E, Chodick G, et al. Fusobacterium necrophorum
                                                                                     as an emerging pathogen of acute mastoiditis. Pediatr Infect Dis J
Funding                                                                              2019;38:12-15. https://doi.org/10.1097/INF.0000000000002021
This research did not receive any specific grant from funding                   12
                                                                                     Coudert A, Fanchette J, Regnier G, et al. Fusobacterium necrophorum,
agencies in the public, commercial, or not-for-profit sectors.                       a major provider of sinus thrombosis in acute mastoiditis: a retrospec-
                                                                                     tive multicentre paediatric study. Clin Otolaryngol 2020;45:182-189.
                                                                                     https://doi.org/10.1111/coa.13478
Author contributions
Conceptualisation: EY, OH, DU. Data and material acqui-
                                                                                13
                                                                                     Ulanovski D, Yacobovich J, Kornreich L, et al. Pediatric oto-
                                                                                     genic sigmoid sinus thrombosis: 12-Year experience. Int J Pedi-
sition: EY, MS, ER. Data Analysis: JY, ER. Writing and                               atr Otorhinolaryngol 2014;28:930-933. https://doi.org/10.1016/j.
editing: EY, OH, DU. Reviewing: MS, ER, JY.                                          ijporl.2014.03.016
                                                                                14
                                                                                     Gómez-Puerta J, Cervera R. Diagnosis and classification of the an-
Ethical consideration                                                                tiphospholipid syndrome. J Autoimmun 2014;48-49:20-25. https://
The study was approved by the local institutional review                             doi.org/10.1016/j.jaut.2014.01.006
board with waiver of informed consent (approval number/                         15
                                                                                     Sridevi C, Krishnam Raju P. Antiphospholipid antibody syndrome –
protocol number(IRB-0242-17-RMC).                                                    an overview. J Indian Coll Cardiol 2011;1:79-97.
The research was conducted ethically, with all study proce-                     16
                                                                                     Holm K, Frick IM, Björck L, et al. Activation of the contact system
dures being performed in accordance with the requirements                            at the surface of Fusobacterium necrophorum represents a possi-
of the World Medical Association’s Declaration of Helsinki.                          ble virulence mechanism in Lemièrre’s syndrome. Infect Immun
                                                                                     2011;79:3284-3290. https://doi.org/10.1128/IAI.05264-11
                                                                                17
                                                                                     Scorpecci A, Massoud M, Giannantonio S, et al. Lateral sinus throm-
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