10.14639/0392-100X-suppl.1-41-2021-02
Cerebrospinal fluid (CSF) leak remains a rare condition, characterized by serious complications and potentially fatal. According to different etiologies, CSF leaks may be classified into two main categories: traumatic and spontaneous. Spontaneous fistulas seem to be mainly related to obesity and idiopathic intracranial hypertension. Diagnosis is both clinical and radiological. During the last three decades, surgical treatment has mostly shifted to endonasal endoscopic approach, which widely demonstrated to be more effective than invasive intracranial ones. Post-operative complications, long-term sequelae and hospital stay are strongly reduced thanks to endoscopic approach. The diagnosis and treatment of CSF leaks represent a difficult and challenge task. The main effort seems to be related to the precise localization of the leak. An accurate assessment of both predisposing factors and comorbidities is mandatory in case of spontaneous leaks. However, a clinical multidisciplinary evaluation as well as treatment, is essential to decrease the rate of failure of surgery. The presence of a dedicated instruments, the Skull Base Team, the knowledge of reconstructive materials and techniques represents a decisive result in therapeutical management even if for each patient an effective therapeutic algorithm can be obtained considering the correct leak detection and characteristics. In conclusion the strict teamwork with neurosurgeons, neuroradiologists, ophtalmologists will enable the development also of innovative biomaterials, which could spread and standardize multi-layer techniques, nowadays still related to surgeon preferences.
text/xml
1827-675X
1683
en
Gaetano Paludetti
https://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
endoscopic skull base surgery
Management of cerebrospinal fluid leak: the importance of multidisciplinary approach
Text.Serial.Journal
https://www.actaitalica.it/
41
Annual congress report
2021-05-14
2021-05-10
2021-05-14
2021-05-14
18-29
1
Gaetano Paludetti
2021/05/14
10.14639/0392-100X-suppl.1-41-2021-02
18
Otorhinolaryngology, Head and Neck Surgery, “A. Gemelli” Hospital Foundation IRCCS, Catholic University of the Sacred Heart, Rome, Italy
1827-675X
endoscopic skull base surgery
29
Management of cerebrospinal fluid leak: the importance of multidisciplinary approach
https://www.actaitalica.it/article/download/1683/556
41
ACTA OTORHINOLARYNGOLOGICA ITALICA 2021;41(SUPPL.1):S18-S29; doi: 10.14639/0392-100X-suppl.1-41-2021-02




Management of cerebrospinal fluid leak:
the importance of multidisciplinary approach
Trattamento delle fistole rinoliquorali: quando è richiesto un approccio chirurgico
multidisciplinare al basicranio?
Jacopo Galli, Francesco Morelli, Mario Rigante, Gaetano Paludetti
Otorhinolaryngology, Head and Neck Surgery, “A. Gemelli” Hospital Foundation IRCCS, Catholic University of the Sacred Heart,
Rome, Italy


SUMMARY
Cerebrospinal fluid (CSF) leak remains a rare condition, characterized by serious compli-
cations and potentially fatal. According to different etiologies, CSF leaks may be classi-
fied into two main categories: traumatic and spontaneous. Spontaneous fistulas seem to be
mainly related to obesity and idiopathic intracranial hypertension. Diagnosis is both clini-
cal and radiological. During the last three decades, surgical treatment has mostly shifted
to endonasal endoscopic approach, which widely demonstrated to be more effective than
invasive intracranial ones. Post-operative complications, long-term sequelae and hospital
stay are strongly reduced thanks to endoscopic approach. The diagnosis and treatment of
CSF leaks represent a difficult and challenge task. The main effort seems to be related to
the precise localization of the leak. An accurate assessment of both predisposing factors and
comorbidities is mandatory in case of spontaneous leaks. However, a clinical multidiscipli-       Received: September 29, 2020
nary evaluation as well as treatment, is essential to decrease the rate of failure of surgery.    Accepted: January 8, 2021
The presence of a dedicated instruments, the Skull Base Team, the knowledge of recon-
structive materials and techniques represents a decisive result in therapeutical management       Correspondence:
even if for each patient an effective therapeutic algorithm can be obtained considering the       Mario Rigante
correct leak detection and characteristics. In conclusion the strict teamwork with neurosur-      Otorhinolaryngology, Head and Neck Surgery,
geons, neuroradiologists, ophtalmologists will enable the development also of innovative          Foundation IRCCS “A. Gemelli” University
biomaterials, which could spread and standardize multi-layer techniques, nowadays still           Hospital, Catholic University of the Sacred Heart,
related to surgeon preferences.                                                                   Rome, Italy
                                                                                                  Email: mario.rigante@policlinicogemelli.it
KEY WORDS: CSF leak, rhinoliquorrea, endoscopic skull base surgery
                                                                                                  Funding
                                                                                                  None.
RIASSUNTO
Le fistole rinoliquorali sono una patologia poco comune ma, a causa delle temibili compli-
canze, potenzialmente fatale. A seconda dell’eziologia, possono essere classificate in trau-      Conflict of interest
                                                                                                  The Authors declare no conflict of interest.
matiche e spontanee. La diagnosi è sia clinica che radiologica. Negli ultimi tre decenni, il
trattamento chirurgico si è molto evoluto, passando da un approccio invasivo intracranico
ad un approccio endoscopico endonasale, il quale si è dimostrato maggiormente efficace a            How to cite this article: Galli J, Morelli F,
fronte di un minore numero di complicanze post-operatorie a breve e lungo termine e della           Rigante M, et al. Management of cerebrospi-
riduzione dei tempi operatori e di ospedalizzazione. La diagnosi ed il trattamento delle            nal fluid leak: the importance of multidisci-
fistole rinoliquorali sono da sempre stati alquanto complessi. Le principali problematiche          plinary approach. Acta Otorhinolaryngol Ital
dipendono dalle difficoltà di localizzazione della sede della fistola e, nel caso delle forme       2021;41(SUPPL.1):S18-S29.          https://doi.
                                                                                                    org/10.14639/0392-100X-suppl.1-41-2021-02
spontanee, anche dal corretto inquadramento di eventuali fattori predisponenti e comorbi-
lità. Al fine di ridurre al minimo i rischi di insuccesso del trattamento chirurgico è necessa-
                                                                                                  © Società Italiana di Otorinolaringoiatria
rio un approccio gestionale di tipo multidisciplinare. In conclusione, la possibilità di assu-    e Chirurgia Cervico-Facciale
mere le decisioni terapeutiche nell’ambito di un équipe multidisciplinare dedicata – Skull
Base Team –, che si avvalga della presenza di otorinolaringoiatra e neurochirurgo, così                          OPEN ACCESS
come del neuroradiologo e dell’oculista, è fondamentale per localizzare con precisione la
sede e delineare le caratteristiche della fistola in modo da ottenere il successo terapeutico.    This is an open access article distributed in accordance with
                                                                                                  the CC-BY-NC-ND (Creative Commons Attribution-Non-
La stretta collaborazione multidisciplinare potrà inoltre permettere lo sviluppo in futuro di     Commercial-NoDerivatives 4.0 International) license. The
nuovi biomateriali in grado di facilitare e standardizzare le tecniche di riparazione multi-      article can be used by giving appropriate credit and mentio-
strato, oggi in gran parte condizionate dalle preferenze del chirurgo.                            ning the license, but only for non-commercial purposes and
                                                                                                  only in the original version. For further information: https://
PAROLE CHIAVE: fistole rinoliquorali, rinoliquorrea, chirurgia endoscopica, basicranio            creativecommons.org/licenses/by-nc-nd/4.0/deed.en




S18
                                                                                                                       Multidisciplinary management of CSF leak




Introduction
Cerebrospinal fluid fistula, also called CSF leak, is an un-
common but severe condition with potentially fatal out-
come. CSF leaks can be essentially classified according to
two criteria: etiology and location.
Considering etiology, O’Connell’s historical classifica-
tion 1, subsequently revisited by Ommaya 2 and then by
Har-El 3, considers two large groups:
• traumatic, with generally delayed clinical manifesta-
   tion, divided into:
   – iatrogenic, related to nasal (e.g. functional endoscop-
      ic sinus surgery [FESS], endoscopic sinus surgery
      [ESS]) (Fig.1), or cranial surgery (e.g. craniotomies),
      which are further divided into accidental and imper-
      fect reconstruction. Patients with extensive pneumati-
      zation are most at risk 4.
   – non iatrogenic, linked to blunt or penetrating trauma,
                                                                                     Figure 2. A case of spontaneous right nostril rhinoliquorrea (A) in a patient
      which do not always result in an obvious liquor loss,                          with a meningoencephalocele in the right sphenoid sinus as showed in T2
      but become evident, sometimes several years later,                             weighted MRI (B arrow) through a bony defect (C arrow) in the lateral recess of
      presenting a complicated clinical picture (e.g. men-                           sphenoid (Sternberg’s canal) (C arrow) and how it appears (*) with 45° angled
      ingitis, encephalocele). CSF leaks occur in 3% of                              endoscopic examination of the sphenoid sinus.
      closed head injuries, in 9% of open head injuries, and
      in 10-30% of skull base fractures 5. The frequency is
                                                                                     Diagnosis is difficult and depends mostly on disease etiolo-
      higher in males between their thirties and fifties and
                                                                                     gy. Clinical diagnosis of a post-traumatic leak is immediate.
      are quite rare in childhood due to elasticity of cranial
                                                                                     Instead, spontaneous leaks are more complex to identify,
      bones 6. In 80% of cases, early symptoms occur with-
                                                                                     because they are characterized by intermittent symptoms;
      in the first two days of the event, and in 95% within
                                                                                     therefore, absence of external abnormalities and infrequent
      the first three months of the traumatic event.
                                                                                     symptoms cause often diagnostic delay. Spontaneous leaks
• non-traumatic, divided according to CSF pressure into
                                                                                     comprise all leaks without recognized causal mechanisms
   high-pressure and low-pressure.
                                                                                     and are more often associated with meningeal herniations
                                                                                     (Fig. 2), multiple localizations and higher recurrence rates.
                                                                                     The treatment of CSF leaks, posttraumatic as well as
                                                                                     spontaneous, was until the recent past nearly exclusively
                                                                                     referred to the neurosurgeon. Nowadays, the successful
                                                                                     management of CSF leaks has changed almost exclusively
                                                                                     into endonasal endoscopic approach, even if a multidisci-
                                                                                     plinary team and different treatment options, not only lim-
                                                                                     ited to surgery, are still necessary. Aim of this review is to
                                                                                     provide an update on CSF leak management by discussing
                                                                                     when and how a multisciplinary approach could improve
                                                                                     outcomes.

                                                                                     Diagnosis
Figure 1. A CT scan in coronal (A) sagittal (B) and 3D reconstruction (C) of         The diagnostical algorithm is still a challenge and is of par-
posttraumatic (jatrogenic) CSF leak at the level of the left ethmoid sinus oc-       amount importance for final therapeutical success. The di-
curred during Functional Endoscopic Sinus Surgery (FESS) surgery for nasal           agnostic work up includes clinical ENT, neurosurgical and
polyposis. A massive pneumocephalus occurred due to delayed diagnosis of
                                                                                     ophtalmological evaluation, in order to assess the potential
intraoperative leak. The patient underwent to endoscopic repair of the wide
defect (D arrow) using fascia lata graft in a multilayer fashion (E and F): first*   etiological factors, the site and features of the CSF leak (i.e.
underlay layer and second** overlay layer + rotation of middle turbinate (MT).       flow, predisposing factors, etc.), laboratory findings of the



                                                                                                                                                              S19
J. Galli et al.




collected nasal liquid and radiological evaluation. All these        tients with spontaneous healing possibilities; however,
specialists contribute to the diagnosis and to the decision          surgery might be necessary in case conservative medical
making process in the CSF leaks, but more extensively take           therapy is ineffective;
part to the constitution of the Skull Base Team, that take        • surgical therapy, which is indicated in patients without
care also of the problem of reconstruction of defect follow-         spontaneous healing chances, as for example patients
ing surgical treatment of pathologies rising in this region 7.       with cerebral herniations, iatrogenic dural leaks, sponta-
The clinical evaluation of suspected CSF rhinorrea can be            neous leaks – which are highly unlikely resolvable with-
pointed out inviting patient to perform maneuvers that can           out surgery – or patients with underlying disease, such
increase intracranial pressure, to reveal any leak, nasal en-        as tumours, requiring by default surgery including dural
doscopy can confirm the presence of bone defect or menin-            resection.
goceles or meningoencephaloceles. The collection of nasal         Both approaches have the goal of preventing complica-
secretions or liquid is used to test beta-2-transferrin and be-   tions, which are recurrent meningitis, intracranial abscess-
ta trace protein assays, the most sensitive and specific labo-    es, pneumoencephaloceles, and refractory epilepsy. The in-
ratory tests for CSF leak diagnosis, the former more com-         cidence of meningitis related to a posttraumatic CSF leak,
monly used because of availability 8. The opthalmogists           either pre-operatively or during conservative management,
can diagnose the presence of increased intracranial pres-         ranges from 10% to 37% and is proportional to the duration
sure evaluating the fundus oculi and eventual papilledema         of this condition 6.
or using ultrasound to check optic nerve status 9.                The final decision of both therapeutical options is generally
When there is a clinical suspect or clear diagnosis of CSF        discussed in a multidisciplinary setting (Skull Base Team).
leak the neuroradiological evaluation is essential, detecting     Conservative medical therapy includes bed rest with the
leaks using computed tomography, magnetic resonance im-           head raised by 30° for 1-2 weeks. During this period, the
aging, or nuclear imaging 10,11. The use of High Resolution       patient must avoid activities, which may result in increased
Computed Tomography (HRTC) scan to assess any bony                intracranial pressure. Some surgeons prescribe patients
defect in the skull base, including also the petrous bone, fol-   medications such as antiemetics, stool softeners and anti-
lowed by MRI that can show the presence of meningocele,           tussives 15. Corticosteroids or diuretics can be additionally
meningoencephaloceles, inflammatory reaction of the nasal         administered to reduce intracranial pressure, although their
or middle ear mucosa, and obviously any meningeal or in-          effectiveness is still debated in literature 16.
tracranial involvement (i.e. meningitis or meningoencepha-        Lumbar drain might be recommended in an effort to mini-
litis, etc.). The MRI is also important in cases of spontaneous   mize increased intracranial pressure, but drains are related
CSF leak to suggest long-standing Idiopathic Intracranial         to significant risks if used excessively, including drastic liq-
Hypertension (IIH), including empty sella, flattening of the      uor pressure collaps and tension pneumocephalus 17.
posterior globes, optic nerve head protrusion, distention of      Prophylactic antibiotics are often administered to decrease
the optic nerve sheaths, tortuosity of the optic nerve, cer-      the risk of meningitis or local infection during conservative
ebellar tonsillar herniation, meningoceles, CSF leaks, and        management of CSF leaks. However, this strategy carries
transverse venous sinus stenosis 12. Other radiological ex-       the risk to create resistant bacteria; as a result, routine use
amination such as CT cisternography, MR cisternography            of prophylactic antibiotics has been questioned 10-12. Nev-
are still used in IIH diagnosis 13, both are nowadays disused     ertheless, prophylactic antibiotics are indispensable for
due the introduction of intrathecal use of fluorescein that       high-risk patients like those with medical history of upper
allows integration of diagnosis and treatment in one pro-         airways infection or meningitis 15.
cedure reducing the morbility of such invasive radiological       Conservative treatment should be continued for at least two
examination. The use of intrathecal fluorescein (ITF) is still    weeks; if conservative treatment fails, surgical therapy be-
not FDA approved and require a specific informed consent          comes imperative 20,21.
even if low-dose ITF is a safe and useful tool during endo-       The risk of meningitis in cases of patients treated with con-
scopic endonasal repair of CSF leaks with minimal compli-         servative approach varies between 10 and 37% 20,21, there-
cations and successful localization of the leak 14.               fore, recent literature suggests performing surgery as early
                                                                  as possible (Fig. 5). The time interval between onset of the
                                                                  pathology and diagnosis with subsequent hospitalization is
Treatment                                                         extremely variable with a duration of symptoms ranging
Treatment may include:                                            from only few hours to two years before consulting a physi-
• conservative medical therapy, which is first choice in          cian at the hospital. That delay is related to complexity of
  patients without immediate need for intervention or pa-         this pathology and lack of a multidisciplinary approach (i.e.



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                                                                                              Multidisciplinary management of CSF leak




collegial integration and sharing of the clinico-radiological       30 years. Open intracranial surgery, a typical neurosurgical
informations).                                                      approach, has historically been used for CSF leak repair,
The surgical strategy strongly depends on leak size, but            but in the recent two decades, the technique was largely re-
also on the type, which can be classified in three categories:      placed by endonasal endoscopic approaches, given to their
• traumatic, non-iatrogenic skull base defect: in this leak         high success, lower morbidity and complication rates, less
   type, the following risk factors should be considered: lo-       invasiveness and shorter hospitalization time 20,22.
   cation, size, bone dislocations, and meningocele (Fig. 4),       The type of intervention depends on the location and exten-
   meningoencephalocele or cerebral hematoma. When the              sion of the leak. Frontal craniotomy is performed in case
   fracture is linear, less than 1 cm and not associated with       of anterior leaks. Temporal or posterior craniotomy is in-
   intracranial complications, frontal sinus posterior wall         dicated in case of middle or posterior cranial fossa leaks.
   or ethmoidal roof fractures, a wait-and-watch approach           The visualization of dural lesions and the adjacent cerebral
   can be considered, because spontaneous healing due to            cortex are advantages of this approach, especially in case of
   fibrosis might be possible. Spontaneous healing occurs in        increased intracranial pressure. Open intracranial surgery
   70-80% of patients within one week and in 20-30% of              has a success rate ranging from 50 to 75%. Limited visu-
   patients within few months, those leaks rarely recur. In         alization of the leak at the sphenoidal level can cause he-
   all other patients, surgical strategy should be performed;       matoma, edema, convulsive seizures or permanent anosmia
• traumatic, iatrogenic leaks: early surgical repair, if possible   by damaging the nervous tissue, leading to increased mor-
   intraoperative, should be performed, because spontaneous         bidity and prolonged hospitalization. Complications are
   healing is improbable, and the risk of recurrence is quite       significantly higher in patients treated with an open intrac-
   high. Moreover, infectious risk is directly proportional to      ranial approach compared with an endonasal endoscopic
   the time in which the subarachnoid space and nasal cavi-         approach: meningitis, 3.9% versus 1.1%, respectively; ab-
   ties are interconnected. Indeed, it is necessary to operate as   scesses, 6.8% versus 0.7%, respectively; and sepsis, 3.8%
   soon as possible in case of CSF rhinorrea after surgery to       versus 0%, respectively 22.
   avoid meningitis or meningoencephalocele (Fig. 1);               Contraindications for an open intracranial approach are
• non-traumatic leaks (recurrent or intermittent rhi-               presence of intracranial hematomas, ethmoidal fractures
   noliquorrea and/or meningoencephalitis): non-traumat-            extended to the orbit or frontal sinus posterior wall frac-
   ic leaks can be divided depending on the intracranial            tures. Instead, leak size and shape do not represent an abso-
   pressure, into high-pressure leaks, which are linked             lute contraindication for open intracranial approach.
   to neoplasms, hydrocephalus, idiopathic intracranial
   hypertension (IIH), empty sella syndrome (Fig. 5), and           Extracranial approach
   low-pressure leaks, related to congenital anomalies.             Extra-cranial non-endoscopic-endonasal surgery consist-
   Surgery should be considered in all patients. If the pa-         ing in a bicoronal or eyebrow incision to create anterior os-
   tient experiences a single, spontaneously resolvable             teoplastic flaps is nowadays rarely performed. Although the
   episode of rhinoliquorrea, leak identification can be dif-       approach has a high success rates (86-100%), other con-
   ficult. The risk of complications is rare and an absolute        comitant abnormalities are not resectable and the approach
   indication for surgery does not exist.                           causes visible scars compared with endoscopic approaches.
                                                                    Several techniques – external ethmoidectomy, trans-orbital
                                                                    ethmoidectomy (Lynch technique), trans-ethmoidal sphe-
Surgical approaches for CSF leaks                                   noidotomy, trans-tectal sphenoidotomy and trans-antral –
Surgical therapy involves two different approaches, which           can be performed during extra-cranial non-endoscopic-en-
are intracranial and extracranial (endoscopic) surgery. The         donasal surgery to implant autologous and/or heterologous
choice between these two surgical approaches is condi-              materials.
tioned by:
• size and location of the leak;                                    Endonasal endoscopic treatment
• recurrences;                                                      In the last three decades, a complete revolution of surgi-
• meningocele or meningoencephalocele;                              cal approach towards the endoscopic surgery occurred 23,
• patient’s general condition;                                      which in the primary cases has almost completely replaced
• surgeon’s preference.                                             the open intracranial intervention 24,25, nowadays almost en-
                                                                    tirely reserved to complex cases. In 1981, Wigand et al. 23
Open intracranial approach                                          described first an endoscopic approach to repair CSF leaks.
The repair of CSF leaks has rapidly evolved over the past           Since then, several case series and reports described vari-



                                                                                                                                S21
J. Galli et al.




ous endoscopic methods and materials for leak repair, with            surrounding defect area at the level of the olfactory
success rates varying between 60% and 100%, averaging                 fissure, corresponding portions of the nasal septum
around 90% 25 and nowadays the endonasal endoscopic ap-               and lateral wall, to prepare the transplant area;
proach is considered a gold standard 26,27. The endoscopic        –   direct paraseptal with sphenoidotomy - This access
approach allows a wider view of the operating field, result-          way allows reaching the sphenoidal sinus’ posterior
ing in more precise and advanced interventions, which lead            wall, when the leak is located at the sellar floor or si-
to a higher initial CSF leak repair success rate, and reduced         nus roof; however, the sphenoid sinus is usually oblit-
complications and hospitalization time 22.                            erated during intervention. The procedure involves
Furthermore, new endoscopic technologies led to further               the endoscopic identification and enlargement of the
diagnostic characterization as well as treatment improve-             sphenoid sinus ostium to remove the intersphenoid
ments 28,29. For example, ENTs, supported by neurosur-                septum and to create a single cavity. In the event that
geons, perform nowadays endonasal endoscopy and have a                the natural ostium is unrecognizable, the sphenoid
predominant role to manage extensive intradural neoplasms             rostrum is opened in medial position to prevent inter-
where reconstruction of wide and complex CSF leaks is                 nal carotid or iatrogenic optic nerve damage to gain
necessary. In particular, those leaks of the posterior cranial        access. The rostrum and posterior nasal septum end is
fossa require specific competences and simultaneous use               additionally removed allowing the use of both nasal
of more tools during a four-handed endonasal endoscopic               passages for a four-hand approach. Advantages is that
approach at the dural and intradural section of the skull.            the clivus region can be reached and a nasoseptal mu-
The endonasal endoscopic approach can be described as                 cosa flap can be used;
follows:                                                          –   trans-ethmoidal with conservation of the basal lami-
• first, both imaging and endoscopic exploration should be            na of the ethmoidal cornets - This approach is prefer-
   employed to localize the exact site of the leak. Intrathe-         able when the defect is located at the ethmoidal level,
   cal fluorescein can be used to aid an exact diagnosis and          particularly if laterally to the lamina of the cornets.
   localization of CSF leaks 30,31. It is necessary to observe        The ethmoidal roof must be fully exposed to identify
   carefully the spread of fluorescein at the terminal mid-           the precise lesion site. The technique involves the re-
   dle turbinate. If fluorescein spreads medial, at the level         moval of the ethmoid labyrinth with exposure of the
   of the spheno-ethmoidal recess, the leak is probably at            skull base and paranasal sinuses. The use of intrathe-
   the sphenoidal level, posterior ethmoidal or close to the          cal fluorescein and endoscopic blue and yellow light
   lamina cribrosa; instead, fluorescein in the middle mea-           filters allows identifying further leak locations, which
   tus indicates that the leak is located at the level of the         might have remained unobserved during the diagnos-
   anterior ethmoid or frontal sinus;                                 tic phase;
• secondly, CSF leaks mucoperiostal edges should be ac-           –   trans-ethmoidal with removal of the basal lamina of
   curately detached for at least 1 cm to regularize residual         the ethmoidal cornets - This approach is used in case
   bone margins. It is crucial not to remove any residual la-         the defect is located at the level of the middle and/or
   mellae to facilitate healing and closing of the CSF leak.          posterior third of the olfactory fissure, or at the level
   The endoscopic procedure is based on a “four-hand”                 of the ethmoidal roof with medial involvement of the
   technique to act with multiple surgical instruments in             olfactory fissure. In case of smaller lesions, not en-
   both nostrils under endoscopic vision. Depending on                tirely involving the olfactory fissure leaving the ol-
   leak location, size and type, surgeons choose one out of           factory mucosa and olfactory filaments substantially
   five possible access ways/techniques:                              intact, the middle turbinate and the entire basal lam-
   – direct paraseptal to the olfactory fissure - This tech-          ina of the ethmoid cornets are obliterated to obtain a
      nique is used in case the leak is localized at the level        regular plane. On this regular plane a septal or turbi-
      of the anterior third of the olfactory fissure and if the       nal mucoperiostial graft is implanted, which can only
      possible herniated mass has lateralized the lateral la-         be achieved with overlay positioning. If the defect is
      mella of the middle turbinate. The approach avoids              localized at the ethmoidal roof level, the bone defect
      major damage to the ethmoidal structures. Initially,            should be regularized by dissecting the epidural space
      electrocoagulation of herniated sac pedicles is per-            even if this means enlarging the defect. After this step,
      formed, which might require the additionally removal            the leak is closed with multilayer technique;
      of the entire lesion in case of larger hernias. The sec-    –   transethmoidal-pterigoido-sphenoidal - This tech-
      ond step involves intracranial skeletonization of the           nique is performed to treat lateral wall sphenoid si-
      dural edge with subsequent mucosa removal of the                nus leaks and other leaks requiring ethmoido-sphe-



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                                                                                            Multidisciplinary management of CSF leak




     noidotomy and a large middle meatal anthrostomy 32.            chronic inflammation nor rejection. Third, this technique
     The posterior fontanelle area is during the technique          does not require autologous grafts or fibrin glue;
     obliterated to expose the posterior wall of the maxil-      • hydroxyapatite cement (HAC) - Less utilized.
     lary sinus and the pterygoid base. The septal and nasal     Autologous grafts can be divided into nasal and extra-nasal.
     branches of the sphenopalatine artery are subsequent-       To repair CSF leaks abdominal fat, muscles, deep temporal,
     ly causticized. After, the anterior wall of the sphenoid    fascia lata (Fig. 1), and pericranial flap, or middle turbinate
     sinus and the pterygoid base are milled to dominate         mucoperiostal and septal mucopericondral flaps (Fig. 5)
     the lateral wall of the sphenoid sinus and to access the    can be used. Septum mucopericondrals flaps are most com-
     lesion in order to perform the dural repair at the level    monly used for leaks smaller than 20 mm, because of their
     of the middle cranial fossa.                                availability on the surgical site; they are easy to prepare
                                                                 and adapt to bony surfaces; their capillarity and the re-
Repair materials for CSF leaks                                   duced postoperative traction minimize potential CSF leak
                                                                 recurrence. Additionally, muscle, temporal and abdominal
Studies comparing different graft types are still lacking in     fat grafts can be considered CSF leak larger than 20 mm,
literature; in consequence, standardized criteria to choose      which can be subsequently covered by septal mucosa flaps.
adequate repair material are absent. The choice of CSF           A composed tissue graft might be considered, if associated
repair material depends much on location, size, bone de-         with cartilage or bones. In 2003, Schick et al. 34 demon-
hiscence, surgeon’s preference as well as availability and       strated that compound tissue grafts are most suitable for
quality of the materials 16,33.                                  dura mater graft surgery, as they facilitate cell migration
The primary goal of a reconstruction is to separate intracra-    (fibroblasts and epithelial cells) to the center of the dural
nial and extracranial spaces to prevent complications such       perforation. This is contrary to synthetic materials or carti-
as pneumocephalus, leak and infection. Secondary aim is          lage, which limit or even inhibit this process. But the real
to promote rapid scarring, to protect neural and vascular        revolution is in the use of pedicled vascularized different
tissues and to minimize morbidity.                               mucoperiosteal and mucopericondrals flaps that strongly
Grafts should be at least 30% larger than the bone defect,       improved the success rate of reconstruction of skull base
because of post-operative retraction, and should perfectly       defect.
fit in the implant site, to avoid tension 35.
Generally, graft types can be distinguished in autologous        Autologous grafts can be placed with different techniques:
and heterologous.                                                • underlay technique - During underlay technique, the
                                                                    dura mater is separated from the skull base dehiscence
Heterologous grafts (e.g. synthetics) have a greater rejec-         edges to obtain an adequate support plan. This support
tion risk, which can cause infections. The effectiveness of         plan has the aim to stabilize the autologous graft, which
the CSF leak repair, with different kind of heterologous            must be prepared or shaped accordingly to fit between
materials, is related revascularization, which varies widely.       the bone and dura mater on all dehiscence sides;
Poor or insufficient revascularization of flaps depends on       • overlay technique - The overlay technique foresees to
adjacent tissue transfer, and atrophic or previously irradi-        remove the mucosa and in a second step, the autologous
ated nasal mucous membranes, which increases the risk of            graft is placed above the dural lesion and the exposed
CSF leak recurrence.                                                bone margins. Mucopericondral and mucoperiostial
Different heterologous grafts can be considered:                    flaps are most frequently used, which are placed with
• absorbable collagen sponges (e.g. DuraGen®Secure,                 the connective side towards the defect;
   Dural Regeneration Matrix) - This type of graft is used       • obliterative technique - This technique is mainly used in
   to close smaller CSF leaks, after tumour removal such            case of a poorly pneumatized sphenoid (Fig. 3) and fron-
   as pituitary adenoma, chordoma and Rathke cysts, using           tal sinus. In a first step, complete removal of sinus mu-
   a trans-sphenoid endonasal access. Absorbable collagen           cosa should be achieved to avoid mucoceles; secondly,
   sponge grafts have three major advantages: First, onlay          sinus cavities should be filled with autologous abdomi-
   positioning of the sponge on the dura mater allows a fast        nal fat used preferably in a monobloc; after, the anterior
   fibrinic adhesion of the collagen to the dura to promote,        sinus wall should be coated with a free autologous graft
   from the first day on, fibroblast penetration into the col-      of mucopericondrium or muco-periosteum 35.
   lagen matrix and proliferation. Second, the collagen          The choice between these techniques depends on different
   sponge, created using a bovine flexor tendon, is inert        variables. Regarding the leak diameter, usually the bigger
   and well tolerated, which means that it does not cause        the diameter, the easier and safer an underlay graft can



                                                                                                                              S23
J. Galli et al.




                                                                                    Reconstructions based on the location
                                                                                    of the leak
                                                                                    Snyderman et al. 17 tried to standardize various reconstruc-
                                                                                    tions types based on the leak location. Particularly, authors
                                                                                    described intervention types more suitable for anterior,
                                                                                    middle and posterior cranial fossa reconstruction.
                                                                                    Anterior cranial fossa: lesions in the anterior cranial fossa,
                                                                                    necessitating surgery, are typically caused by sinonasal tu-
                                                                                    mours and less commonly by cranio-facial traumas. If they
                                                                                    originated from large sized anterior cranial base defect,
                                                                                    they usually extend frontal from one orbit to the other and
                                                                                    sagittal from the planum sphenoidale to the posterior wall
                                                                                    of the frontal sinus. Generally, a three-layer reconstruction
                                                                                    is performed. Circumferential dissection of the epidural
                                                                                    plane facilitates to implant the graft in the epidural space.
                                                                                    The three layers are represented by a first internally placed
                                                                                    layer that prevents liquor flow, without totally sealing off
                                                                                    the leak. This layer can be autologous or heterologous, and
                                                                                    has to be shaped that it exceeds for 1 cm the dural edges.
Figure 3. Coronal CT scan (A) and sagittal (B) T2 weighted MRI showed the           It is positioned between the cerebral and dural surface with
presence of sphenoiditis and erosion of the clivus in a 54-year-old male patient    incisions on the grafts edges to allow anterior adaptation to
with rinoliquorrea 2 years after chemoradiotherapy for a nasopharyngeal can-        both sides of the cerebral falx.
cer. The precise site of leakage was uncertain at the imaging so we used in-
trathecal fluorescein for a precise localization. The endoscopic pictures shows     As a second or middle graft layer, non-porous materials
fluorescein coming out from the sphenoid ostium (a) and after sphenodotomy          need to be used. The autologous fascia lata graft is gen-
the trasudation of the liquor (b, c) throught the clivus and below the sella (S).   erally preferred among the various options of several au-
An obliterative technique (d) was preferred using an autologous fat graft (fg),
a cartilage graft of the nasal septum (e) in a gasket seal way on the sphenoi-
                                                                                    tologous materials, such as cadaveric tissues, as it is easy
dotomy, and fibrin glue (*).                                                        to implant and obtain, and well tolerated, because it heals
                                                                                    fast. An adequate size needs always to be considered, as the
                                                                                    graft must generously overlap the edges of the leak. Im-
be implanted. Concerning leak location, in case the leak                            portantly, complete demucosization should be achieved to
is placed at level of lamina cribrosa, dura is very difficult                       avoid mucoceles and to allow adherence.
to detach from the intracranial bone at the level of olfac-                         Finally, for the third layer a nasoseptal flap is usually used,
tory fissure, because of tenacious adhesion between dura                            which can be raised from the antero-superior portion of the
and olfactory holes. Therefore, overlay technique should                            nasal septum, and might be additionally enlarged to the lat-
be performed. Furthermore, the space to move surgical in-                           eral wall rather than to the floor of the sphenoid sinus. If
struments should be considered; overlay technique is more                           additional material is required to reach the required length,
preferable in smaller spaces.                                                       the clival recess can be obliterated with fat grafting. How-
Regarding large ventral skull leaks (over 2 cm), comprising                         ever, it is not necessary to cover entirely the fascia lata with
                                                                                    the nasoseptal flap, because vascularization of the central
bone and dura, but even smaller leaks associated with high
                                                                                    part of the fascia lata graft initiates early. If for surgical or
intracranial pressure, multilayer technique is recommended.
                                                                                    oncological reasons a nasoseptal flap cannot be used, an
This multilayer technique should consist of an intradural col-
                                                                                    extracranial flap of pericranium can be alternatively raised
lagen graft between dura and brain, a second onlay graft in                         by a bicoronal incision and implanted through a bone win-
contact with the dura and bone and as a third layer a vascular-                     dow measuring 1.5 x 2.5 cm at the root of the nose from
ized or mucosa flap 36,37. In a further step, some defects might                    one orbit to the other. The flap pedicles can be attached
be supplemented with adipose tissue. Numerous variations of                         unilaterally or bilaterally to the supraorbital arteries. If uni-
these techniques are successfully used today 38,39.                                 laterally attached, an obstruction of the frontal sinuses is
Generally, rigid reconstruction with bone or allograft mate-                        less likely, because the rotation arch is greater; instead, if
rial is less recommended because this type of graft is re-                          bilaterally attached the blood support will be more robust,
lated to a higher migration and infection risk.                                     but the rotation arch is inferior and increased compression



S24
                                                                                                      Multidisciplinary management of CSF leak




on the vascular pedicles from the bone window can cause            Drainage types after reconstruction
postoperative edema. Endoscopic graft positioning allows
                                                                   Lumbar or spino-peritoneal drainage can be placed dur-
keeping the proximal frontal sinus in contact with the pos-
                                                                   ing the intervention, which can remain in place for about
terior bone table; laterally the flap can be pushed between
                                                                   three days. The advantage of spino-peritoneal drainage
orbital content and orbital roof or can be used to recon-
                                                                   is that during this period, liquor pressure can be directly
struct the periorbita, if previously resected to verify tumour
                                                                   measured to monitor and regulate the eventual recurrence
margins. Both types of flaps should be stabilized with nasal
                                                                   of liquorrea. Additionally, fluorescein can be intrathecally
packing to keep them in place for 5-7 days 17.
                                                                   injected 31. Once the intervention is completed, presence of
Posterior cranial fossa: the typical defect requiring recon-
                                                                   fluorescein in liquor allows a quick and immediate intraop-
struction – often associated with the treatment of tumours
                                                                   erative control if the CSF leak repair was successfull. The
such as nasopharyngeal cancer, chordomas and chondro-
                                                                   place of the pre-existing leak is displayed with a blue light
sarcomas – extends from the dorsum sella floor above the
                                                                   filter: a negative finding confirms leak closure. Operation’s
inferior foramen magnum in the sagittal plane and is limit-
                                                                   success can also be verified through Valsalva maneuver, re-
ed by the carotids. Clival defects are located in an area with
                                                                   alized with anesthesiologists help.
intense liquor flow and therefore most difficult to recon-
                                                                   Instead, placement of a permanent drainage (ventricle-peri-
struct. Reconstruction with vascularized flaps is essential,
                                                                   toneal or spino-peritoneal) is reserved to selected cases and
especially in case of irradiated tissue and exposed carotid
                                                                   should be discussed in a multidisciplinary team.
arteries 40. Clival bone coverage helps to prevent from os-
teoradionecrosis and consequent osteomyelitis.
Instead, at the posterior cranial fossa level, a multilayer re-    Intraoperative navigation systems for skull
construction is mandatory with inlay and onlay grafts simi-        base reconstructions and CSF leak
lar to previous used materials, which cover the entire defect
                                                                   Real-time intraoperative navigation systems are a new tech-
with a vascularized flap. Unlike the anterior skull base, the
                                                                   nology, which process pre-operatively acquired CT and
clival defect should be filled with body fat above the lata
                                                                   MR images (Fig. 4), to establish the position of surgeon’s
fascia onlay graft to allow easier positioning of the vascular-
                                                                   instruments on a monitor during the surgery 28. This system
ized flap and contact with the underlying surface, which re-
                                                                   allows visualization of deeper portions of the skull to avoid
duces the risk of pontine herniation of the paraclival carotids.
                                                                   lesions of vascular and nervous structures. Additionally,
Nasoseptal flaps extending at the floor and lower meatus of
                                                                   surgical navigation systems can be useful to diagnose neo-
the nasal fossa, are widely used to reconstruct the posterior
                                                                   plastic forms, allowing targeted biopsies. Through imaging
cranial fossa and to obtain a greater mucous surface; they
                                                                   fusion tools, it is possible to map any areas removed to ver-
can be horizontally oriented when transferred. If unavailable,
                                                                   ify radicality of surgical treatment. On the monitor, various
temporoparietal, pericranial fascia or lateral nasal wall flaps
can be used. However, the lateral nasal wall is more difficult
to prepare and has a limited rotation arc 17.
Middle cranial fossa: defects are located in the Meckel’s
cave and limited by the inferior and medial internal carotid
arteries, the upper orbital fissure and the orbit above. They
are less common, smaller and necessitate generally a two-
layer reconstruction; an inlay and a vascularized layer might
be sufficient even though a classic three-layer approach can
be performed using nasoseptal flaps, which require generally
a transpterigoid approach from the affected side 17.

Stabilization of the graft with “fixers”
Once reconstruction is completed, grafts should be stabi-
lized. A fixer called fibrin glue is mainly used for autologous
free grafts such as mucosa, fat, muscle and mucoperiostal
                                                                   Figure 4 Coronal CT scan (A) and T2 weighted MRI of a case of spontane-
flaps. Another type of “fixer” are nasal swabs. Merocel and
                                                                   ous CSF leak due to meningocele of the right olfactory groove. The endoscopic
surgicel are most widely used and in alternatives avitene,         view (C) after precise localization using Navigation System (D) yellow cross-air
gelfoam and lyfoam can be utilized.                                in the 3 planes and endoscopic view of the tip of the instrument.



                                                                                                                                             S25
J. Galli et al.




                                                                                  with physiological solution. Antibiotics should be taken for
                                                                                  at least ten days after surgery to prevent form infections.
                                                                                  Patients are usually discharged between the fifth and sev-
                                                                                  enth post-operative day, with the indication to avoid physi-
                                                                                  cal stress, sneezing or other activities causing increasing
                                                                                  of intracranial pressure for about 30 days. Air travel is not
                                                                                  recommended. At discharge, a first follow-up visit after
                                                                                  10-15 days from surgery is scheduled in which nasal de-
                                                                                  bridements and residues of the reabsorbable material are
                                                                                  removed. Fibrin and the intranasal clots should be aspirated
                                                                                  to examine clearly patency of the senotomies, graft tight-
                                                                                  ness and vitality. A normal or uneventful post-operative
Figure 5. CT scan in sagittal (A) and axial view (B) in a case of menin-          course foresees follow-up visits every three months for one
goencefalitis (showed in the Sagittal post Contrast Enhancement MRI (D) and
                                                                                  year with MRI scheduled at least every 6 months. After that
T2 weighted MRI (E) The bony erosion on the clivus as it appear endoscopically
(arrow) The lesion was treated with multilayer technique and finally nasoseptal   semi-annual checks including MRI visits are planned for
flap was used (dotted line in F) as it appear 2 months after surgery.             two years. Finally, annual checks including MRI for two
                                                                                  more years should be performed.

CT and MR images are simultaneously reported and the
location of surgical instruments and video endoscopes are
                                                                                  Discussion
indicated in real-time.                                                           CSF leaks are historically difficult to diagnose and treat
This imaging technique is especially helpful if the surgeon                       because of their wide variability 14. Recent years’ techni-
faces the following several difficulties during surgery: ana-                     cal innovations, increasingly combined by multidisci-
tomical variants, excessive bleeding reducing visibility;                         plinary collaborations, have changed the diagnostic and
absence of reference points due to previous surgeries or in-                      therapeutic paradigm, which is mostly related to a better
vasive diseases, and loss of depth perception related to en-                      comprehension of CSF leaks anatomical and physiological
doscopy. Mainly two categories of navigation systems exist:                       aspects 19,41.
those using electromagnetic signals and those using optical                       The main objective of the diagnostics has been to improve
signals. Recently, hybrid systems have been developed,                            the anatomical localization of the leak. It is essential to as-
which allow using both technologies, depending on the in-                         sess precisely leak dimensions and localization to create
tervention type. New technologies are in constant evolution                       adequate therapeutic planning. Nowadays, the combination
and can be used for an increasing number of nasosinusal                           of multiple CT and RMN fusion imaging strategies allow
diseases like neoplastic pathologies, severe polyposis, in-                       obtaining a 91% accurate identification pre-operatively.
vasive mycotic sinusitis, traumas, orbital decompression,                         The interaction and role of expert neuroradiologist is of
drainage of orbital abscesses, closure of rhinoliquoral fistu-                    paramount importance. Moreover the development of new
las, trans-sphenoidal access to pituitary, coanal atresia, and                    and detailed RMN sequences has helped to outline com-
skull base mucocele (cordomas, chondrosarcoma). Further                           plex CSF leaks. In addition, the possibility to obtain a more
technological progress concerns the add-on of new genera-                         sophisticated image navigation systems allows comparing
tion surgical instruments like 3D, 4K endoscopic systems                          various types of defects and helps to understand differences
in addition to the neuronavigation 4,42,43.                                       between CSF leaks and their presentation.
                                                                                  Several critical issues require close collaboration of neuro-
                                                                                  surgeons and all other professional figures involved in the
Post-operative management                                                         Skull Base Team, who contribute to manage this complex
Time of hospitalization and post-operative therapeutic                            pathology from an anatomic-functional point of view.
measures vary according to patients’ general condition                            Collaboration with neurosurgeon starts during non-invasive
and leak features. Life parameters and diuresis should be                         preoperative functional diagnostic and allows clarifying the
constantly monitored. The most important element is bed                           diagnostic field and gives the possibility to acquire preop-
rest. As previously described, patients must remain in su-                        erative information on liquor dynamics, intracranial pres-
pine position for 48 hours, with the head 30° inclined. The                       sure development and differentiation between high and low
nasal package is usually removed during the fifth post-op-                        flow leaks to create a targeted surgical setting. Whenever
erative day. It is necessary to perform daily nasal hygiene                       possible a dedicated radiologist assesses, in collaboration



S26
                                                                                                  Multidisciplinary management of CSF leak




with ENT and neurosurgeon, MRI and CT scans to iden-              risk) influence outcomes 17,44. Neurosurgeons’ experience
tify likely idiopathic intracranial hypertension. Posterior       is essential to answer these unsolved questions and to de-
Sclera flattening, widening of optic nerve subarachnoid           cide on lumbar drain placement during the multidiscipli-
space widening, optic nerve head protrusion, arachnoid            nary assessment in preoperative setting. Increased risks for
pits (bony scalloping) skull base foramina enlargement,           infections and pneumocephalus causing higher morbidity,
bilateral transverse sinus stenosis, total/partial empty sella    mortality, longer hospitalization and cost are well known
are amongst the most common signs of this hypertension            and need to be considered. Until now the placement of lum-
type 4 .                                                          bar drain can be generally considered in cases of spontane-
Body mass index (BMI), especially in female gender, has           ous CSF leak due to intracranial hypertension, in case of
a linear relationship with intracranial hypertension, which       large dural defects, and high flow fistulas in the anterior and
is closely related to leak’s complexity 42. This population       posterior cranial fossa and it is generally not indicated in
need a strict diagnostic follow-up and a preventive treat-
                                                                  the reconstruction of sellar or suprasellar defects. Lumbar
ment of intracranial hypertension in order to prevent leak’s
                                                                  drain can reduce fistula recurrence from 41% to 5% after
onset. In this population, even after repair intervention, per-
                                                                  transsphenoidal surgery 52,53.
manence of underlying risk factors involves a chronic in-
crease of intracranial pressure itself with a remodeling and
a thinning of basicranium at the level of the thinnest bone       Conclusions
limiting. That process favors meninges’ bulging through           CSF leaks remain a challenging issue requiring new and
orifices 36‑38. Careful monitoring methods allow early rec-       innovative techniques for early diagnosis and treatment.
ognition of complications and make it possible to make a
                                                                  Dynamic multidisciplinary teams, who apply various im-
second surgical exploration. This kind of multidisciplinary
                                                                  aging techniques represented by newer diagnostic and en-
collaboration, could finally allow to deeper and better un-
                                                                  doscopic technologies to diagnose, treat and rigorously fol-
derstand etiology of pathologies still poorly clarified (as in
                                                                  low up patients, are the future for CSF leak management.
the case of spontaneous CSF leaks).
In recent years, technological advances overcome many of          Additionally, neurosurgeon’s experience will contribute
the obstacles associated with endonasal cranial base sur-         significantly to develop new biomaterials with increased
gery. The most recent visualization technologies (e.g. 3D         durability, which may replace autologous grafts in the fu-
and 4K cameras), angled instruments 49 and their different        ture. New biomaterials might facilitate multilayer repairs
applications aided also by navigation systems contributed         and standardize heterogeneity of repair methods, which is
to the fact that the endoscopic endonasal approach become         related to variability of materials used today and still con-
the best surgical approach to treat CSF leaks by offering the     ditioned largely only by surgeon’s preferences.
best surgical outcomes.                                           Conclusively, the correct diagnosis and best treatment can
This approach allows achieving success rates of almost            only be determined in a dedicated Skull Base Team com-
95%, and reduces significantly patient morbidity if per-          posed by neurosurgeons, otolaryngologists, neuroradiolo-
formed by highly skilled surgeons 22. Although ENT sur-           gists, ophthalmologists, endocrinologists, in order to com-
geons are directly involved in the surgical procedure, neu-       pletely evaluate a patient with CSF leak from the first visit,
rosurgeons are necessarily involved to manage and choose          during treatment and follow-up.
complex dural and intracranial reconstruction and to treat
eventual complications. Therefore, surgeons need intensive
                                                                  References
training to acquire surgical skills and experience 50,51. To
date, no adequate risk stratification to outline reconstruc-
                                                                  1
                                                                      O’Connell JEA. Primary spontaneous cerebrospinal fluid rhinor-
                                                                      rhea. J Neurol Neurosurg Psychiat 1964;27:241-246. https://doi.
tive algorithms still exist. The development of a treatment           org/10.1177/019459989110400402
algorithm based on leaks localization (regardless from            2
                                                                      Ommaya AK, Di Chiro G, Baldwin M, et al. Non-traumatic cerebro-
causes), dimension and presentation methods is therefore              spinal fluid rhinorrhoea. J Neurol Neurosurg Psychiatry 1968;31:214-
most desirable.                                                       2125. https://doi.org/10.1136/jnnp.31.3.214
Moreover the predictive criteria to support decision-mak-         3
                                                                      Har-El G. What is “spontaneous” cerebrospinal fluid rhinorrhea?
ing on lumbar drain in patients with spontaneous leaks and            Classification of cerebrospinal fluid leaks. Ann Otol Rhinol Laryngol
                                                                      1999;108:323-326. https://doi.org/10.1177/000348949910800401.
intracranial hypertension are still absent. It remains unclear    4
                                                                      Gray ST, Wu AW. Pathophysiology of iatrogenic and traumatic skull
how different factors like time of placement (before dur-             base injury. In: Bleier BS, editor. Comprehensive techniques in CSF
ing or after surgery), intensity of adjustment (more or less          leak repair and skull base reconstruction. Basel: Karger 2013. vol 74,
than 10 cc/h), and time of removal (correlated to infection           pp. 12-23. https://doi.org/10.1159/000342264




                                                                                                                                      S27
J. Galli et al.




5
     Memduh K, Bayram C, Ahmet D. Management of skull base frac-                       sive study of 116 cases over 10 years. World Neurosurg 2020;135:e1-
     tures. Oper Tech Otolaryngol - Head Neck Surg 2008;19:214-223.                    11. https://doi.org/10.1016/j.wneu.2019.09.133
     https://doi.org/10.1016/j.otot.2008.09.001                                   23
                                                                                       Wigand ME. Transnasal ethmoidectomy under endoscopical control.
6
     Hegazy HM, Carrau RL, Snyderman CH, et al. Transna-                               Rhinology 1981;19:7-15.
     sal endoscopic repair of cerebrospinal fluid rhinorrhea: a me-               24
                                                                                       Gilat H, Rappaport Z, Yaniv E. Endoscopic transnasal cerebro-
     ta-analysis.     Laryngoscope       2000;110:1166-172.        https://doi.        spinal fluid leak repair: a 10 year experience. Isr Med Assoc
     org/10.1097/00005537-200007000-00019                                              J 2011;13:597-600.
7
     Snyderman CH, Wang EW, Fernandez-Miranda JC, et al. The making               25
                                                                                       Psaltis AJ, Schlosser RJ, Banks CA, et al. A systematic review of the
     of a skull base team and the value of multidisciplinary approach in the           endoscopic repair of cerebrospinal fluid leaks. Otolaryngol Head Neck
     management of sinonasal and ventral skull base malignancies. Oto-                 Surg 2012;147:196-203. https://doi.org/10.1177/0194599812451090
     laryngol Clin North Am. 2017;50:457-465. https://doi.org/10.1016/j.
     otc.2016.12.017
                                                                                  26
                                                                                       Locatelli D, Rampa F, Acchiardi I, et al. Endoscopic endonasal ap-
                                                                                       proaches for repair of cerebrospinal fluid leaks: nine-year experi-
8
     Lipschitz N, Hazenfield JM, Breen JT, et al. Laboratory testing and               ence. Neurosurgery 2006;58:246-257. https://doi.org/10.1227/01.
     imaging in the evaluation of cranial cerebrospinal fluid leaks and en-
                                                                                       NEU.0000193924.65297.3F
     cephaloceles. Curr Opin Otolaryngol Head Neck Surg 2019;27:339-
     343. https://doi.org/10.1097/MOO.000000000000057
                                                                                  27
                                                                                       Presutti L, Mattioli F, Villari D, et al. Transnasal endoscopic treatment
                                                                                       of cerebrospinal fluid leak: 17 years’ experience. Acta Otorhinolaryn-
9
     Kohli AA, Pistilli M, Alfaro C, et al. Role of ocular ultrasonography to
                                                                                       gol Ital 2009;29:191-196.
     distinguish papilledema from pseudopapilledema. J Neuroophthalmol
     2020 June 19. https://doi.org/10.1097/WNO.0000000000000984.
                                                                                  28
                                                                                       Paludetti G, Sergi B, Rigante M, et al. New techniques and technol-
     Online ahead of print                                                             ogy to repair cerebrospinal fluid rhinorrhea. Acta Otorhinolaryngol
                                                                                       Ital 2004;24:130-136.
10
     Freesmeyer M, Schwab M, Besteher B, et al. High-resolution PET cis-
     ternography with 64Cu-DOTA for CSF leak detection. Clin Nucl Med             29
                                                                                       Prickett KK, Wise SK. Grafting materials in skull base recon-
     2019;44:735-737. https://doi.org/10.1097/RLU.0000000000002695                     struction. Adv Otorhinolaryngol 2013;74:24-32. https://doi.
                                                                                       org/10.1159/000342265
11
     Eljazzar R, Loewenstern J, Dai JB, et al. Detection of cerebrospinal
     fluid leaks: is there a radiologic standard of care? A systematic re-        30
                                                                                       Sharma SD, Kumar G, Bal J, et al. Endoscopic repair of cerebro-
     view. World Neurosurg 2019; 127:307-315. https://doi.org/10.1016/j.               spinal fluid rhinorrhoea. Eur Ann Otorhinolaryngol Head Neck Dis
     wneu.2019.01.299                                                                  2016;133:187-190. https://doi.org/10.1016/j.anorl.2015.05.010
12
     Bidot S, Saindane AM, Peragallo JH, et al. Brain imaging in idiopath-        31
                                                                                       S Raza SM, Banu MA, Donaldson A, et al. Sensitivity and specific-
     ic intracranial hypertension, J Neuroophthalmol 2015;35:400-411                   ity of intrathecal fluorescein and white light excitation for detecting
     https://doi.org/10.1097/WNO.0000000000000303                                      intraoperative cerebrospinal fluid leak in endoscopic skull base sur-
13
     Martineau P, Chakraborty S, Faiz K, et al. Imaging of the spontaneous             gery: a prospective study. J Neurosurg 2016;124:621-626. https://doi.
     low cerebrospinal fluid pressure headache: a review. Can Assoc Ra-                org/10.3171/2014.12.JNS14995
     diol J 2020;71:174-185. https://doi.org/10.1177/0846537119888395             32
                                                                                       Pasquini E, Sciarretta V, Farneti G, et al. Endoscopic treatment of en-
14
     Banu MA, Kim JH, Shin BJ, et al. Low-dose intrathecal fluoresce-                  cephaloceles of the lateral wall of the sphenoid sinus. Minim Invasive
     in and etiology-based graft choice in endoscopic endonasal closure                Neurosurg 2004;47:209-213. https://doi.org/10.1055/s-2004-818522
     of CSF leaks. Clin Neurol Neurosurg 2014;116:28-34. https://doi.             33
                                                                                       Soudry E, Turner JH, Nayak JV, et al. Endoscopic reconstruc-
     org/10.1016/j.clineuro.2013.11.006                                                tion of surgically created skull base defects: a systematic review.
15
     Bernal-Sprekelsen M, Alobid I, Mullol J, et al. Closure of cerebro-               Otolaryngol - Head Neck Surg 2014;150:730-738. https://doi.
     spinal fluid leaks prevents ascending bacterial meningitis. Rhinology             org/10.1177/0194599814520685.
     2005;43:277-281.                                                             34
                                                                                       Schick B, Wolf G, Romeike BFM, et al. Dural cell culture: a new ap-
16
     Oakley GM, Orlandi RR, Woodworth BA, et al. Management of                         proach to study duraplasty. Cells Tissues Organs 2003;173:129–37.
     cerebrospinal fluid rhinorrhea: an evidence-based review with rec-                https://doi.org/10.1159/000069469
     ommendations. Int Forum Allergy Rhinol 2016;6:17-24. https://doi.            35
                                                                                       Castelnuovo PG, Delú G, Locatelli D, et al. Endonasal endoscopic
     org/10.1002/alr.21627                                                             duraplasty: our experience. Skull Base 2006;16:19-23. https://doi.
17
     Snyderman CH, Wang EW, Zenonos GA, et al. Reconstruction af-                      org/10.1055/s-2005-922096
     ter endoscopic surgery for skull base malignancies. J Neurooncol             36
                                                                                       Harvey RJ, Parmar P, Sacks R, et al. Endoscopic skull base recon-
     2020;150:463-468. https://doi.org/10.1007/s11060-020-03465-0                      struction of large dural defects: a systematic review of published
18
     Lee DH, Lim SC, Joo YE. Treatment outcomes of endoscopic repairs                  evidence. Laryngoscope 2012;122:452-459. https://doi.org/10.1002/
     of sinonasal cerebrospinal fluid leaks. J Craniofac Surg 2011;22:1266-            lary.22475
     1270. https://doi.org/10.1097/SCS.0b013e31821c6ad3                           37
                                                                                       Bolzoni Villaret A, Bosio R, Tomenzoli D, et al. Endoscopic dura-
19
     Reddy M, Baugnon K. Imaging of cerebrospinal fluid rhinorrhea                     plasty for cerebrospinal fluid (CSF) leak. Otolaryngol Neck Surg
     and otorrhea. Radiol Clin North Am 2017;55:167-187. https://doi.                  2010;143:P278. https://doi.org/10.1016/j.otohns.2010.06.598
     org/10.1016/j.rcl.2016.08.005                                                38
                                                                                       Eloy JA, Marchiano E, Vázquez A, et al. Management of skull base
20
     Eftekhar B, Ghodsi M, Nejat F, et al. Prophylactic administration of              defects after surgical resection of sinonasal and ventral skull base ma-
     ceftriaxone for the prevention of meningitis after traumatic pneumo-              lignancies. Otolaryngol Clin North Am 2017;50:397-417. https://doi.
     cephalus: results of a clinical trial. J Neurosurg 2004;101:757-761.              org/10.1016/j.otc.2016.12.013
     https://doi.org/10.3171/jns.2004.101.5.0757                                  39
                                                                                       Hachem RA, Elkhatib A, Beer-Furlan A, et al. Reconstructive tech-
21
     Friedman JA, Ebersold MJ, Quast LM. Post-traumatic cerebrospi-                    niques in skull base surgery after resection of malignant lesions: a
     nal fluid leakage. World J Surg 2001;25:1062-1066. https://doi.                   wide array of choices. Curr Opin Otolaryngol Head Neck Surg
     org/10.1007/s00268-001-0059-7                                                     2016;24:91-97. https://doi.org/10.1097/MOO.0000000000000233
22
     Dai JB, Del Signore AG, Govindaraj S, et al. Investigation of skull-         40
                                                                                       Pagella F, Pusateri A, Matti E, et al. Endoscopic management of
     based cerebrospinal fluid leak repair: a single-institution comprehen-            spontaneous clival cerebrospinal fluid leaks: case series and literature




S28
                                                                                                                Multidisciplinary management of CSF leak




     review. World Neurosurg 2016;86:470-477. https://doi.org/10.1016/j.      47
                                                                                   Hornby C, Botfield H, O’Reilly MW, et al. Evaluating the fat distri-
     wneu.2015.11.026                                                              bution in idiopathic intracranial hypertension using dual-energy X-
                                                                                   ray absorptiometry scanning. Neuroophthalmology 2018;42:99-104.
41
     Lloyd KM, DelGaudio JM, Hudgins PA. Imaging of skull base cer-
                                                                                   https://doi.org/10.1080/01658107.2017.1334218
     ebrospinal fluid leaks in adults. Radiology 2008;248:725-736. https://
     doi.org/10.1148/radiol.2483070362
                                                                              48
                                                                                   Gafoor V, Smita B, Jose J. Long-term response of cerebrospinal fluid
                                                                                   pressure in patients with idiopathic intracranial hypertension - A pro-
42
     Riley CA, Soneru CP, Tabaee A, et al. Technological and ideologi-             spective observational study. Ann Indian Acad Neurol 2017;20:220-
     cal innovations in endoscopic skull base surgery. World Neurosurg             224. https://doi.org/10.4103/aian.AIAN_32_17
     2019 Jan 29:S1878-8750(19)30220-7. https://doi.org/10.1016/j.            49
                                                                                   Rigante M, La Rocca G, Lauretti L, et al. Preliminary experience with
     wneu.2019.01.120. Online ahead of print.                                      4K ultra-high definition endoscope: analysis of pros and cons in skull
43
     Lauretti L, D’Alessandris QG, Rigante M, et al. O-arm in endonasal            base surgery. Acta Otorhinolaryngol Ital 2017;37:237-241. https://
     endoscopic cranial base surgery: technical note on initial feasibil-          doi.org/10.14639/0392-100X-1684
     ity. World Neurosurg 2018;117:103-108. https://doi.org/10.1016/j.        50
                                                                                   Lavigne P, Faden D, Gardner PA, et al. Validation of training levels
     wneu.2018.06.015                                                              in endoscopic endonasal surgery of the skull base. Laryngoscope
44
     Uozumi Y, Taniguchi M, Nakai, et al. Comparative evaluation of 3-di-          2019;129:2253-2257. https://doi.org/10.1002/lary.27895
     mensional high definition and 2-dimensional 4-k ultra-high definition    51
                                                                                   Mattavelli D, Ferrari M, Rampinelli V, et al. Development and valida-
     endoscopy systems in endonasal skull base surgery. Oper Neurosurg             tion of a preclinical model for training and assessment of cerebro-
     2020;19:281-287. https://doi.org/10.1093/ons/opz426                           spinal fluid leak repair in endoscopic skull base surgery. Int Forum
                                                                                   Allergy Rhinol 2020;10:89-96. https://doi.org/10.1002/alr.22451
45
     Dallan I, Cambi C, Emanuelli E, et al. Multiple spontaneous skull        52
                                                                                   Lopatin AS, Kapitanov DN, Potapov AA. Endonasal endoscopic
     base cerebrospinal fluid leaks: some insights from an internation-
                                                                                   repair of spontaneous cerebrospinal fluid leaks. Arch Otolaryn-
     al retrospective collaborative study. Eur Arch Otorhinolaryngol               gol Head Neck Surg 2003;129:859-863. https://doi.org/10.1001/
     2020;277:3357-63. https://doi.org/10.1007/s00405-020-06227-w                  archotol.129.8.859
46
     Pérez MA, Bialer OY, Bruce BB, et al. Primary spontaneous cer-           53
                                                                                   Senior BA, Jafri K, Benninger M. Safety and efficacy of endoscopic
     ebrospinal fluid leaks and idiopathic intracranial hypertension. J            repair of csf leaks and encephaloceles: a survey of the members of the
     Neuro-Ophthalmology 2013;33:327-334. https://doi.org/10.1097/                 American Rhinologic Society. Am J Rhinol 2001;15:21-25. https://
     WNO.0b013e318299c292                                                          doi.org/10.2500/105065801781329356




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