Annual congress report
Published: 2021-05-14

Management of cerebrospinal fluid leak: the importance of multidisciplinary approach

Otorhinolaryngology, Head and Neck Surgery, “A. Gemelli” Hospital Foundation IRCCS, Catholic University of the Sacred Heart, Rome, Italy
Otorhinolaryngology, Head and Neck Surgery, “A. Gemelli” Hospital Foundation IRCCS, Catholic University of the Sacred Heart, Rome, Italy
Otorhinolaryngology, Head and Neck Surgery, “A. Gemelli” Hospital Foundation IRCCS, Catholic University of the Sacred Heart, Rome, Italy
Otorhinolaryngology, Head and Neck Surgery, “A. Gemelli” Hospital Foundation IRCCS, Catholic University of the Sacred Heart, Rome, Italy
CSF leak rhinoliquorrea endoscopic skull base surgery


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.


Cerebrospinal fluid fistula, also called CSF leak, is an uncommon but severe condition with potentially fatal outcome. CSF leaks can be essentially classified according to two criteria: etiology and location.

Considering etiology, O’Connell’s historical classification 1, subsequently revisited by Ommaya 2 and then by Har-El 3, considers two large groups:

  1. traumatic, with generally delayed clinical manifestation, divided into:
    1. iatrogenic, related to nasal (e.g. functional endoscopic sinus surgery [FESS], endoscopic sinus surgery [ESS]) (Fig.1), or cranial surgery (e.g. craniotomies), which are further divided into accidental and imperfect reconstruction. Patients with extensive pneumatization are most at risk 4.
    2. non iatrogenic, linked to blunt or penetrating trauma, which do not always result in an obvious liquor loss, but become evident, sometimes several years later, presenting a complicated clinical picture (e.g. meningitis, encephalocele). CSF leaks occur in 3% of closed head injuries, in 9% of open head injuries, and in 10-30% of skull base fractures 5. The frequency is higher in males between their thirties and fifties and are quite rare in childhood due to elasticity of cranial bones 6. In 80% of cases, early symptoms occur within the first two days of the event, and in 95% within the first three months of the traumatic event.
  2. non-traumatic, divided according to CSF pressure into high-pressure and low-pressure.

Diagnosis is difficult and depends mostly on disease etiology. Clinical diagnosis of a post-traumatic leak is immediate. Instead, spontaneous leaks are more complex to identify, because they are characterized by intermittent symptoms; therefore, absence of external abnormalities and infrequent symptoms cause often diagnostic delay. Spontaneous leaks comprise all leaks without recognized causal mechanisms 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 multidisciplinary team and different treatment options, not only limited 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.


The diagnostical algorithm is still a challenge and is of paramount importance for final therapeutical success. The diagnostic work up includes clinical ENT, neurosurgical and ophtalmological evaluation, in order to assess the potential etiological factors, the site and features of the CSF leak (i.e. flow, predisposing factors, etc.), laboratory findings of the collected nasal liquid and radiological evaluation. All these specialists contribute to the diagnosis and to the decision making process in the CSF leaks, but more extensively take part to the constitution of the Skull Base Team, that take care also of the problem of reconstruction of defect following surgical treatment of pathologies rising in this region 7.

The clinical evaluation of suspected CSF rhinorrea can be pointed out inviting patient to perform maneuvers that can increase intracranial pressure, to reveal any leak, nasal endoscopy can confirm the presence of bone defect or meningoceles or meningoencephaloceles. The collection of nasal secretions or liquid is used to test beta-2-transferrin and beta trace protein assays, the most sensitive and specific laboratory tests for CSF leak diagnosis, the former more commonly used because of availability 8. The opthalmogists can diagnose the presence of increased intracranial pressure evaluating the fundus oculi and eventual papilledema or using ultrasound to check optic nerve status 9.

When there is a clinical suspect or clear diagnosis of CSF leak the neuroradiological evaluation is essential, detecting leaks using computed tomography, magnetic resonance imaging, or nuclear imaging 10,11. The use of High Resolution Computed Tomography (HRTC) scan to assess any bony defect in the skull base, including also the petrous bone, followed by MRI that can show the presence of meningocele, meningoencephaloceles, inflammatory reaction of the nasal or middle ear mucosa, and obviously any meningeal or intracranial involvement (i.e. meningitis or meningoencephalitis, etc.). The MRI is also important in cases of spontaneous CSF leak to suggest long-standing Idiopathic Intracranial Hypertension (IIH), including empty sella, flattening of the posterior globes, optic nerve head protrusion, distention of the optic nerve sheaths, tortuosity of the optic nerve, cerebellar tonsillar herniation, meningoceles, CSF leaks, and transverse venous sinus stenosis 12. Other radiological examination such as CT cisternography, MR cisternography are still used in IIH diagnosis 13, both are nowadays disused due the introduction of intrathecal use of fluorescein that allows integration of diagnosis and treatment in one procedure reducing the morbility of such invasive radiological examination. The use of intrathecal fluorescein (ITF) is still not FDA approved and require a specific informed consent even if low-dose ITF is a safe and useful tool during endoscopic endonasal repair of CSF leaks with minimal complications and successful localization of the leak 14.


Treatment may include:

  1. conservative medical therapy, which is first choice in patients without immediate need for intervention or patients with spontaneous healing possibilities; however, surgery might be necessary in case conservative medical therapy is ineffective;
  2. surgical therapy, which is indicated in patients without spontaneous healing chances, as for example patients with cerebral herniations, iatrogenic dural leaks, spontaneous leaks – which are highly unlikely resolvable without surgery – or patients with underlying disease, such as tumours, requiring by default surgery including dural resection.

Both approaches have the goal of preventing complications, which are recurrent meningitis, intracranial abscesses, pneumoencephaloceles, and refractory epilepsy. The incidence of meningitis related to a posttraumatic CSF leak, either pre-operatively or during conservative management, ranges from 10% to 37% and is proportional to the duration of this condition 6.

The final decision of both therapeutical options is generally discussed in a multidisciplinary setting (Skull Base Team).

Conservative medical therapy includes bed rest with the head raised by 30° for 1-2 weeks. During this period, the patient must avoid activities, which may result in increased intracranial pressure. Some surgeons prescribe patients medications such as antiemetics, stool softeners and antitussives 15. Corticosteroids or diuretics can be additionally administered to reduce intracranial pressure, although their effectiveness is still debated in literature 16.

Lumbar drain might be recommended in an effort to minimize increased intracranial pressure, but drains are related to significant risks if used excessively, including drastic liquor pressure collaps and tension pneumocephalus 17.

Prophylactic antibiotics are often administered to decrease the risk of meningitis or local infection during conservative management of CSF leaks. However, this strategy carries the risk to create resistant bacteria; as a result, routine use of prophylactic antibiotics has been questioned 10-12. Nevertheless, prophylactic antibiotics are indispensable for high-risk patients like those with medical history of upper airways infection or meningitis 15.

Conservative treatment should be continued for at least two weeks; if conservative treatment fails, surgical therapy becomes imperative 20,21.

The risk of meningitis in cases of patients treated with conservative approach varies between 10 and 37% 20,21, therefore, 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 extremely variable with a duration of symptoms ranging from only few hours to two years before consulting a physician at the hospital. That delay is related to complexity of this pathology and lack of a multidisciplinary approach (i.e. collegial integration and sharing of the clinico-radiological informations).

The surgical strategy strongly depends on leak size, but also on the type, which can be classified in three categories:

  1. traumatic, non-iatrogenic skull base defect: in this leak type, the following risk factors should be considered: location, size, bone dislocations, and meningocele (Fig. 4), meningoencephalocele or cerebral hematoma. When the fracture is linear, less than 1 cm and not associated with intracranial complications, frontal sinus posterior wall or ethmoidal roof fractures, a wait-and-watch approach can be considered, because spontaneous healing due to fibrosis might be possible. Spontaneous healing occurs in 70-80% of patients within one week and in 20-30% of patients within few months, those leaks rarely recur. In all other patients, surgical strategy should be performed;
  2. traumatic, iatrogenic leaks: early surgical repair, if possible intraoperative, should be performed, because spontaneous healing is improbable, and the risk of recurrence is quite high. Moreover, infectious risk is directly proportional to the time in which the subarachnoid space and nasal cavities are interconnected. Indeed, it is necessary to operate as soon as possible in case of CSF rhinorrea after surgery to avoid meningitis or meningoencephalocele (Fig. 1);
  3. non-traumatic leaks (recurrent or intermittent rhinoliquorrea and/or meningoencephalitis): non-traumatic leaks can be divided depending on the intracranial pressure, into high-pressure leaks, which are linked to neoplasms, hydrocephalus, idiopathic intracranial hypertension (IIH), empty sella syndrome (Fig. 5), and low-pressure leaks, related to congenital anomalies. Surgery should be considered in all patients. If the patient experiences a single, spontaneously resolvable episode of rhinoliquorrea, leak identification can be difficult. The risk of complications is rare and an absolute indication for surgery does not exist.

Surgical approaches for CSF leaks

Surgical therapy involves two different approaches, which are intracranial and extracranial (endoscopic) surgery. The choice between these two surgical approaches is conditioned by:

  1. size and location of the leak;
  2. recurrences;
  3. meningocele or meningoencephalocele;
  4. patient’s general condition;
  5. surgeon’s preference.

Open intracranial approach

The repair of CSF leaks has rapidly evolved over the past 30 years. Open intracranial surgery, a typical neurosurgical approach, has historically been used for CSF leak repair, but in the recent two decades, the technique was largely replaced by endonasal endoscopic approaches, given to their high success, lower morbidity and complication rates, less invasiveness and shorter hospitalization time 20,22.

The type of intervention depends on the location and extension of the leak. Frontal craniotomy is performed in case of anterior leaks. Temporal or posterior craniotomy is indicated in case of middle or posterior cranial fossa leaks.

The visualization of dural lesions and the adjacent cerebral cortex are advantages of this approach, especially in case of increased intracranial pressure. Open intracranial surgery has a success rate ranging from 50 to 75%. Limited visualization of the leak at the sphenoidal level can cause hematoma, edema, convulsive seizures or permanent anosmia by damaging the nervous tissue, leading to increased morbidity and prolonged hospitalization. Complications are significantly higher in patients treated with an open intracranial approach compared with an endonasal endoscopic approach: meningitis, 3.9% versus 1.1%, respectively; abscesses, 6.8% versus 0.7%, respectively; and sepsis, 3.8% versus 0%, respectively 22.

Contraindications for an open intracranial approach are presence of intracranial hematomas, ethmoidal fractures extended to the orbit or frontal sinus posterior wall fractures. Instead, leak size and shape do not represent an absolute contraindication for open intracranial approach.

Extracranial approach

Extra-cranial non-endoscopic-endonasal surgery consisting in a bicoronal or eyebrow incision to create anterior osteoplastic flaps is nowadays rarely performed. Although the approach has a high success rates (86-100%), other concomitant abnormalities are not resectable and the approach causes visible scars compared with endoscopic approaches. Several techniques – external ethmoidectomy, trans-orbital ethmoidectomy (Lynch technique), trans-ethmoidal sphenoidotomy, trans-tectal sphenoidotomy and trans-antral –can be performed during extra-cranial non-endoscopic-endonasal surgery to implant autologous and/or heterologous materials.

Endonasal endoscopic treatment

In the last three decades, a complete revolution of surgical approach towards the endoscopic surgery occurred 23, which in the primary cases has almost completely replaced the open intracranial intervention 24,25, nowadays almost entirely reserved to complex cases. In 1981, Wigand et al. 23 described first an endoscopic approach to repair CSF leaks. Since then, several case series and reports described various endoscopic methods and materials for leak repair, with success rates varying between 60% and 100%, averaging around 90% 25 and nowadays the endonasal endoscopic approach is considered a gold standard 26,27. The endoscopic approach allows a wider view of the operating field, resulting in more precise and advanced interventions, which lead to a higher initial CSF leak repair success rate, and reduced complications and hospitalization time 22.

Furthermore, new endoscopic technologies led to further diagnostic characterization as well as treatment improvements 28,29. For example, ENTs, supported by neurosurgeons, perform nowadays endonasal endoscopy and have a predominant role to manage extensive intradural neoplasms where reconstruction of wide and complex CSF leaks is necessary. In particular, those leaks of the posterior cranial fossa require specific competences and simultaneous use of more tools during a four-handed endonasal endoscopic approach at the dural and intradural section of the skull.

The endonasal endoscopic approach can be described as follows:

  1. first, both imaging and endoscopic exploration should be employed to localize the exact site of the leak. Intrathecal fluorescein can be used to aid an exact diagnosis and localization of CSF leaks 30,31. It is necessary to observe carefully the spread of fluorescein at the terminal middle turbinate. If fluorescein spreads medial, at the level of the spheno-ethmoidal recess, the leak is probably at the sphenoidal level, posterior ethmoidal or close to the lamina cribrosa; instead, fluorescein in the middle meatus indicates that the leak is located at the level of the anterior ethmoid or frontal sinus;
  2. secondly, CSF leaks mucoperiostal edges should be accurately detached for at least 1 cm to regularize residual bone margins. It is crucial not to remove any residual lamellae to facilitate healing and closing of the CSF leak. The endoscopic procedure is based on a “four-hand” technique to act with multiple surgical instruments in both nostrils under endoscopic vision. Depending on leak location, size and type, surgeons choose one out of five possible access ways/techniques:
    1. direct paraseptal to the olfactory fissure - This technique is used in case the leak is localized at the level of the anterior third of the olfactory fissure and if the possible herniated mass has lateralized the lateral lamella of the middle turbinate. The approach avoids major damage to the ethmoidal structures. Initially, electrocoagulation of herniated sac pedicles is performed, which might require the additionally removal of the entire lesion in case of larger hernias. The second step involves intracranial skeletonization of the dural edge with subsequent mucosa removal of the surrounding defect area at the level of the olfactory fissure, corresponding portions of the nasal septum and lateral wall, to prepare the transplant area;
    2. direct paraseptal with sphenoidotomy - This access way allows reaching the sphenoidal sinus’ posterior wall, when the leak is located at the sellar floor or sinus roof; however, the sphenoid sinus is usually obliterated during intervention. The procedure involves the endoscopic identification and enlargement of the sphenoid sinus ostium to remove the intersphenoid septum and to create a single cavity. In the event that the natural ostium is unrecognizable, the sphenoid rostrum is opened in medial position to prevent internal carotid or iatrogenic optic nerve damage to gain access. The rostrum and posterior nasal septum end is additionally removed allowing the use of both nasal passages for a four-hand approach. Advantages is that the clivus region can be reached and a nasoseptal mucosa flap can be used;
    3. trans-ethmoidal with conservation of the basal lamina of the ethmoidal cornets - This approach is preferable when the defect is located at the ethmoidal level, particularly if laterally to the lamina of the cornets. The ethmoidal roof must be fully exposed to identify the precise lesion site. The technique involves the removal of the ethmoid labyrinth with exposure of the skull base and paranasal sinuses. The use of intrathecal fluorescein and endoscopic blue and yellow light filters allows identifying further leak locations, which might have remained unobserved during the diagnostic phase;
    4. trans-ethmoidal with removal of the basal lamina of the ethmoidal cornets - This approach is used in case the defect is located at the level of the middle and/or posterior third of the olfactory fissure, or at the level of the ethmoidal roof with medial involvement of the olfactory fissure. In case of smaller lesions, not entirely involving the olfactory fissure leaving the olfactory mucosa and olfactory filaments substantially intact, the middle turbinate and the entire basal lamina of the ethmoid cornets are obliterated to obtain a regular plane. On this regular plane a septal or turbinal mucoperiostial graft is implanted, which can only be achieved with overlay positioning. If the defect is localized at the ethmoidal roof level, the bone defect should be regularized by dissecting the epidural space even if this means enlarging the defect. After this step, the leak is closed with multilayer technique;
    5. transethmoidal-pterigoido-sphenoidal - This technique is performed to treat lateral wall sphenoid sinus leaks and other leaks requiring ethmoido-sphenoidotomy and a large middle meatal anthrostomy 32. The posterior fontanelle area is during the technique obliterated to expose the posterior wall of the maxillary sinus and the pterygoid base. The septal and nasal branches of the sphenopalatine artery are subsequently causticized. After, the anterior wall of the sphenoid sinus and the pterygoid base are milled to dominate the lateral wall of the sphenoid sinus and to access the lesion in order to perform the dural repair at the level of the middle cranial fossa.

Repair materials for CSF leaks

Studies comparing different graft types are still lacking in literature; in consequence, standardized criteria to choose adequate repair material are absent. The choice of CSF repair material depends much on location, size, bone dehiscence, surgeon’s preference as well as availability and quality of the materials 16,33.

The primary goal of a reconstruction is to separate intracranial and extracranial spaces to prevent complications such as pneumocephalus, leak and infection. Secondary aim is to promote rapid scarring, to protect neural and vascular tissues and to minimize morbidity.

Grafts should be at least 30% larger than the bone defect, because of post-operative retraction, and should perfectly fit in the implant site, to avoid tension 35.

Generally, graft types can be distinguished in autologous and heterologous.

Heterologous grafts (e.g. synthetics) have a greater rejection risk, which can cause infections. The effectiveness of the CSF leak repair, with different kind of heterologous materials, is related revascularization, which varies widely. Poor or insufficient revascularization of flaps depends on adjacent tissue transfer, and atrophic or previously irradiated nasal mucous membranes, which increases the risk of CSF leak recurrence.

Different heterologous grafts can be considered:

  1. absorbable collagen sponges (e.g. DuraGen®Secure, Dural Regeneration Matrix) - This type of graft is used to close smaller CSF leaks, after tumour removal such as pituitary adenoma, chordoma and Rathke cysts, using a trans-sphenoid endonasal access. Absorbable collagen sponge grafts have three major advantages: First, onlay positioning of the sponge on the dura mater allows a fast fibrinic adhesion of the collagen to the dura to promote, from the first day on, fibroblast penetration into the collagen matrix and proliferation. Second, the collagen sponge, created using a bovine flexor tendon, is inert and well tolerated, which means that it does not cause chronic inflammation nor rejection. Third, this technique does not require autologous grafts or fibrin glue;
  2. hydroxyapatite cement (HAC) - Less utilized.

Autologous grafts can be divided into nasal and extra-nasal. To repair CSF leaks abdominal fat, muscles, deep temporal, fascia lata (Fig. 1), and pericranial flap, or middle turbinate mucoperiostal and septal mucopericondral flaps (Fig. 5) can be used. Septum mucopericondrals flaps are most commonly used for leaks smaller than 20 mm, because of their availability on the surgical site; they are easy to prepare and adapt to bony surfaces; their capillarity and the reduced postoperative traction minimize potential CSF leak recurrence. Additionally, muscle, temporal and abdominal fat grafts can be considered CSF leak larger than 20 mm, which can be subsequently covered by septal mucosa flaps.

A composed tissue graft might be considered, if associated with cartilage or bones. In 2003, Schick et al. 34 demonstrated that compound tissue grafts are most suitable for dura mater graft surgery, as they facilitate cell migration (fibroblasts and epithelial cells) to the center of the dural perforation. This is contrary to synthetic materials or cartilage, which limit or even inhibit this process. But the real revolution is in the use of pedicled vascularized different mucoperiosteal and mucopericondrals flaps that strongly improved the success rate of reconstruction of skull base defect.

Autologous grafts can be placed with different techniques:

  1. underlay technique - During underlay technique, the dura mater is separated from the skull base dehiscence edges to obtain an adequate support plan. This support plan has the aim to stabilize the autologous graft, which must be prepared or shaped accordingly to fit between the bone and dura mater on all dehiscence sides;
  2. overlay technique - The overlay technique foresees to remove the mucosa and in a second step, the autologous graft is placed above the dural lesion and the exposed bone margins. Mucopericondral and mucoperiostial flaps are most frequently used, which are placed with the connective side towards the defect;
  3. obliterative technique - This technique is mainly used in case of a poorly pneumatized sphenoid (Fig. 3) and frontal sinus. In a first step, complete removal of sinus mucosa should be achieved to avoid mucoceles; secondly, sinus cavities should be filled with autologous abdominal fat used preferably in a monobloc; after, the anterior sinus wall should be coated with a free autologous graft of mucopericondrium or muco-periosteum 35.

The choice between these techniques depends on different variables. Regarding the leak diameter, usually the bigger the diameter, the easier and safer an underlay graft can be implanted. Concerning leak location, in case the leak is placed at level of lamina cribrosa, dura is very difficult to detach from the intracranial bone at the level of olfactory fissure, because of tenacious adhesion between dura and olfactory holes. Therefore, overlay technique should be performed. Furthermore, the space to move surgical instruments should be considered; overlay technique is more preferable in smaller spaces.

Regarding large ventral skull leaks (over 2 cm), comprising bone and dura, but even smaller leaks associated with high intracranial pressure, multilayer technique is recommended. This multilayer technique should consist of an intradural collagen graft between dura and brain, a second onlay graft in contact with the dura and bone and as a third layer a vascularized or mucosa flap 36,37. In a further step, some defects might be supplemented with adipose tissue. Numerous variations of these techniques are successfully used today 38,39.

Generally, rigid reconstruction with bone or allograft material is less recommended because this type of graft is related to a higher migration and infection risk.

Reconstructions based on the location of the leak

Snyderman et al. 17 tried to standardize various reconstructions 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 tumours 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. It is positioned between the cerebral and dural surface with incisions on the grafts edges to allow anterior adaptation to both sides of the cerebral falx.

As a second or middle graft layer, non-porous materials need to be used. The autologous fascia lata graft is generally preferred among the various options of several autologous materials, such as cadaveric tissues, as it is easy 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. Importantly, complete demucosization should be achieved to avoid mucoceles and to allow adherence.

Finally, for the third layer a nasoseptal flap is usually used, which can be raised from the antero-superior portion of the nasal septum, and might be additionally enlarged to the lateral wall rather than to the floor of the sphenoid sinus. If additional material is required to reach the required length, the clival recess can be obliterated with fat grafting. However, it is not necessary to cover entirely the fascia lata with the nasoseptal flap, because vascularization of the central part of the fascia lata graft initiates early. If for surgical or oncological reasons a nasoseptal flap cannot be used, an extracranial flap of pericranium can be alternatively raised by a bicoronal incision and implanted through a bone window measuring 1.5 x 2.5 cm at the root of the nose from one orbit to the other. The flap pedicles can be attached unilaterally or bilaterally to the supraorbital arteries. If unilaterally attached, an obstruction of the frontal sinuses is less likely, because the rotation arch is greater; instead, if bilaterally attached the blood support will be more robust, but the rotation arch is inferior and increased compression on the vascular pedicles from the bone window can cause postoperative edema. Endoscopic graft positioning allows keeping the proximal frontal sinus in contact with the posterior bone table; laterally the flap can be pushed between orbital content and orbital roof or can be used to reconstruct the periorbita, if previously resected to verify tumour margins. Both types of flaps should be stabilized with nasal packing to keep them in place for 5-7 days 17.

Posterior cranial fossa: the typical defect requiring reconstruction – often associated with the treatment of tumours such as nasopharyngeal cancer, chordomas and chondrosarcomas – extends from the dorsum sella floor above the inferior foramen magnum in the sagittal plane and is limited by the carotids. Clival defects are located in an area with intense liquor flow and therefore most difficult to reconstruct. Reconstruction with vascularized flaps is essential, especially in case of irradiated tissue and exposed carotid arteries 40. Clival bone coverage helps to prevent from osteoradionecrosis and consequent osteomyelitis.

Instead, at the posterior cranial fossa level, a multilayer reconstruction is mandatory with inlay and onlay grafts similar to previous used materials, which cover the entire defect with a vascularized flap. Unlike the anterior skull base, the clival defect should be filled with body fat above the lata fascia onlay graft to allow easier positioning of the vascularized flap and contact with the underlying surface, which reduces the risk of pontine herniation of the paraclival carotids. Nasoseptal flaps extending at the floor and lower meatus of the nasal fossa, are widely used to reconstruct the posterior cranial fossa and to obtain a greater mucous surface; they can be horizontally oriented when transferred. If unavailable, 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 stabilized. A fixer called fibrin glue is mainly used for autologous free grafts such as mucosa, fat, muscle and mucoperiostal flaps. Another type of “fixer” are nasal swabs. Merocel and surgicel are most widely used and in alternatives avitene, gelfoam and lyfoam can be utilized.

Drainage types after reconstruction

Lumbar or spino-peritoneal drainage can be placed during the intervention, which can remain in place for about three days. The advantage of spino-peritoneal drainage is that during this period, liquor pressure can be directly measured to monitor and regulate the eventual recurrence of liquorrea. Additionally, fluorescein can be intrathecally injected 31. Once the intervention is completed, presence of fluorescein in liquor allows a quick and immediate intraoperative control if the CSF leak repair was successfull. The place of the pre-existing leak is displayed with a blue light filter: a negative finding confirms leak closure. Operation’s success can also be verified through Valsalva maneuver, realized with anesthesiologists help.

Instead, placement of a permanent drainage (ventricle-peritoneal or spino-peritoneal) is reserved to selected cases and should be discussed in a multidisciplinary team.

Intraoperative navigation systems for skull base reconstructions and CSF leak

Real-time intraoperative navigation systems are a new technology, which process pre-operatively acquired CT and MR images (Fig. 4), to establish the position of surgeon’s instruments on a monitor during the surgery 28. This system allows visualization of deeper portions of the skull to avoid lesions of vascular and nervous structures. Additionally, surgical navigation systems can be useful to diagnose neoplastic forms, allowing targeted biopsies. Through imaging fusion tools, it is possible to map any areas removed to verify radicality of surgical treatment. On the monitor, various CT and MR images are simultaneously reported and the location of surgical instruments and video endoscopes are indicated in real-time.

This imaging technique is especially helpful if the surgeon faces the following several difficulties during surgery: anatomical variants, excessive bleeding reducing visibility; absence of reference points due to previous surgeries or invasive diseases, and loss of depth perception related to endoscopy. Mainly two categories of navigation systems exist: those using electromagnetic signals and those using optical signals. Recently, hybrid systems have been developed, which allow using both technologies, depending on the intervention type. New technologies are in constant evolution and can be used for an increasing number of nasosinusal diseases like neoplastic pathologies, severe polyposis, invasive mycotic sinusitis, traumas, orbital decompression, drainage of orbital abscesses, closure of rhinoliquoral fistulas, trans-sphenoidal access to pituitary, coanal atresia, and skull base mucocele (cordomas, chondrosarcoma). Further technological progress concerns the add-on of new generation surgical instruments like 3D, 4K endoscopic systems in addition to the neuronavigation 4,42,43.

Post-operative management

Time of hospitalization and post-operative therapeutic measures vary according to patients’ general condition and leak features. Life parameters and diuresis should be constantly monitored. The most important element is bed rest. As previously described, patients must remain in supine position for 48 hours, with the head 30° inclined. The nasal package is usually removed during the fifth post-operative day. It is necessary to perform daily nasal hygiene 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 seventh post-operative day, with the indication to avoid physical 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 debridements and residues of the reabsorbable material are removed. Fibrin and the intranasal clots should be aspirated to examine clearly patency of the senotomies, graft tightness and vitality. A normal or uneventful post-operative course foresees follow-up visits every three months for one year with MRI scheduled at least every 6 months. After that semi-annual checks including MRI visits are planned for two years. Finally, annual checks including MRI for two more years should be performed.


CSF leaks are historically difficult to diagnose and treat because of their wide variability 14. Recent years’ technical innovations, increasingly combined by multidisciplinary collaborations, have changed the diagnostic and therapeutic paradigm, which is mostly related to a better comprehension of CSF leaks anatomical and physiological aspects 19,41.

The main objective of the diagnostics has been to improve the anatomical localization of the leak. It is essential to assess precisely leak dimensions and localization to create adequate therapeutic planning. Nowadays, the combination of multiple CT and RMN fusion imaging strategies allow obtaining a 91% accurate identification pre-operatively. The interaction and role of expert neuroradiologist is of paramount importance. Moreover the development of new and detailed RMN sequences has helped to outline complex CSF leaks. In addition, the possibility to obtain a more sophisticated image navigation systems allows comparing various types of defects and helps to understand differences between CSF leaks and their presentation.

Several critical issues require close collaboration of neurosurgeons and all other professional figures involved in the Skull Base Team, who contribute to manage this complex pathology from an anatomic-functional point of view.

Collaboration with neurosurgeon starts during non-invasive preoperative functional diagnostic and allows clarifying the diagnostic field and gives the possibility to acquire preoperative information on liquor dynamics, intracranial pressure development and differentiation between high and low flow leaks to create a targeted surgical setting. Whenever possible a dedicated radiologist assesses, in collaboration with ENT and neurosurgeon, MRI and CT scans to identify likely idiopathic intracranial hypertension. Posterior Sclera flattening, widening of optic nerve subarachnoid space widening, optic nerve head protrusion, arachnoid pits (bony scalloping) skull base foramina enlargement, bilateral transverse sinus stenosis, total/partial empty sella are amongst the most common signs of this hypertension type 4 .

Body mass index (BMI), especially in female gender, has a linear relationship with intracranial hypertension, which is closely related to leak’s complexity 42. This population need a strict diagnostic follow-up and a preventive treatment of intracranial hypertension in order to prevent leak’s onset. In this population, even after repair intervention, permanence of underlying risk factors involves a chronic increase of intracranial pressure itself with a remodeling and a thinning of basicranium at the level of the thinnest bone limiting. That process favors meninges’ bulging through orifices 36-38. Careful monitoring methods allow early recognition of complications and make it possible to make a second surgical exploration. This kind of multidisciplinary collaboration, could finally allow to deeper and better understand etiology of pathologies still poorly clarified (as in the case of spontaneous CSF leaks).

In recent years, technological advances overcome many of the obstacles associated with endonasal cranial base surgery. The most recent visualization technologies (e.g. 3D and 4K cameras), angled instruments 49 and their different applications aided also by navigation systems contributed to the fact that the endoscopic endonasal approach become the best surgical approach to treat CSF leaks by offering the best surgical outcomes.

This approach allows achieving success rates of almost 95%, and reduces significantly patient morbidity if performed by highly skilled surgeons 22. Although ENT surgeons are directly involved in the surgical procedure, neurosurgeons are necessarily involved to manage and choose complex dural and intracranial reconstruction and to treat eventual complications. Therefore, surgeons need intensive training to acquire surgical skills and experience 50,51. To date, no adequate risk stratification to outline reconstructive algorithms still exist. The development of a treatment algorithm based on leaks localization (regardless from causes), dimension and presentation methods is therefore most desirable.

Moreover the predictive criteria to support decision-making on lumbar drain in patients with spontaneous leaks and intracranial hypertension are still absent. It remains unclear how different factors like time of placement (before during or after surgery), intensity of adjustment (more or less than 10 cc/h), and time of removal (correlated to infection risk) influence outcomes 17,44. Neurosurgeons’ experience is essential to answer these unsolved questions and to decide on lumbar drain placement during the multidisciplinary assessment in preoperative setting. Increased risks for infections and pneumocephalus causing higher morbidity, mortality, longer hospitalization and cost are well known and need to be considered. Until now the placement of lumbar drain can be generally considered in cases of spontaneous CSF leak due to intracranial hypertension, in case of large dural defects, and high flow fistulas in the anterior and posterior cranial fossa and it is generally not indicated in the reconstruction of sellar or suprasellar defects. Lumbar drain can reduce fistula recurrence from 41% to 5% after transsphenoidal surgery 52,53.


CSF leaks remain a challenging issue requiring new and innovative techniques for early diagnosis and treatment. Dynamic multidisciplinary teams, who apply various imaging techniques represented by newer diagnostic and endoscopic technologies to diagnose, treat and rigorously follow up patients, are the future for CSF leak management. Additionally, neurosurgeon’s experience will contribute significantly to develop new biomaterials with increased durability, which may replace autologous grafts in the future. New biomaterials might facilitate multilayer repairs and standardize heterogeneity of repair methods, which is related to variability of materials used today and still conditioned largely only by surgeon’s preferences.

Conclusively, the correct diagnosis and best treatment can only be determined in a dedicated Skull Base Team composed by neurosurgeons, otolaryngologists, neuroradiologists, ophthalmologists, endocrinologists, in order to completely evaluate a patient with CSF leak from the first visit, during treatment and follow-up.

Figures and tables

Figure 1.A CT scan in coronal (A) sagittal (B) and 3D reconstruction (C) of posttraumatic (jatrogenic) CSF leak at the level of the left ethmoid sinus occurred during Functional Endoscopic Sinus Surgery (FESS) surgery for nasal polyposis. A massive pneumocephalus occurred due to delayed diagnosis of 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* underlay layer and second** overlay layer + rotation of middle turbinate (MT).

Figure 2.A case of spontaneous right nostril rhinoliquorrea (A) in a patient with a meningoencephalocele in the right sphenoid sinus as showed in T2 weighted MRI (B arrow) through a bony defect (C arrow) in the lateral recess of sphenoid (Sternberg’s canal) (C arrow) and how it appears (*) with 45° angled endoscopic examination of the sphenoid sinus.

Figure 3.Coronal CT scan (A) and sagittal (B) T2 weighted MRI showed the presence of sphenoiditis and erosion of the clivus in a 54-year-old male patient with rinoliquorrea 2 years after chemoradiotherapy for a nasopharyngeal cancer. The precise site of leakage was uncertain at the imaging so we used intrathecal fluorescein for a precise localization. The endoscopic pictures shows fluorescein coming out from the sphenoid ostium (a) and after sphenodotomy the trasudation of the liquor (b, c) throught the clivus and below the sella (S). 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 sphenoidotomy, and fibrin glue (*).

Figure 4.Coronal CT scan (A) and T2 weighted MRI of a case of spontaneous CSF leak due to meningocele of the right olfactory groove. The endoscopic view (C) after precise localization using Navigation System (D) yellow cross-air in the 3 planes and endoscopic view of the tip of the instrument.

Figure 5.CT scan in sagittal (A) and axial view (B) in a case of meningoencefalitis (showed in the Sagittal post Contrast Enhancement MRI (D) and 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 flap was used (dotted line in F) as it appear 2 months after surgery.


  1. O’Connell JEA. Primary spontaneous cerebrospinal fluid rhinorrhea. J Neurol Neurosurg Psychiat. 1964; 27:241-246. DOI
  2. Ommaya AK, Di Chiro G, Baldwin M. Non-traumatic cerebrospinal fluid rhinorrhoea. J Neurol Neurosurg Psychiatry. 1968; 31:214-2125. DOI
  3. Har-El G. What is “spontaneous” cerebrospinal fluid rhinorrhea? Classification of cerebrospinal fluid leaks. Ann Otol Rhinol Laryngol. 1999; 108:323-326. DOI
  4. Gray ST, Wu AW. Comprehensive techniques in CSF leak repair and skull base reconstruction. Karger: Basel; 2013. DOI
  5. Memduh K, Bayram C, Ahmet D. Management of skull base fractures. Oper Tech Otolaryngol - Head Neck Surg. 2008; 19:214-223. DOI
  6. Hegazy HM, Carrau RL, Snyderman CH. Transnasal endoscopic repair of cerebrospinal fluid rhinorrhea: a meta-analysis. Laryngoscope. 2000; 110:1166-172. DOI
  7. Snyderman CH, Wang EW, Fernandez-Miranda JC. The making of a skull base team and the value of multidisciplinary approach in the management of sinonasal and ventral skull base malignancies. Otolaryngol Clin North Am. 2017; 50:457-465. DOI
  8. Lipschitz N, Hazenfield JM, Breen JT. Laboratory testing and imaging in the evaluation of cranial cerebrospinal fluid leaks and encephaloceles. Curr Opin Otolaryngol Head Neck Surg. 2019; 27:339-343. DOI
  9. Kohli AA, Pistilli M, Alfaro C. Role of ocular ultrasonography to distinguish papilledema from pseudopapilledema. J Neuroophthalmol. 2020. DOI
  10. Freesmeyer M, Schwab M, Besteher B. High-resolution PET cisternography with 64Cu-DOTA for CSF leak detection. Clin Nucl Med. 2019; 44:735-737. DOI
  11. Eljazzar R, Loewenstern J, Dai JB. Detection of cerebrospinal fluid leaks: is there a radiologic standard of care? A systematic review. World Neurosurg. 2019; 127:307-315. DOI
  12. Bidot S, Saindane AM, Peragallo JH. Brain imaging in idiopathic intracranial hypertension. J Neuroophthalmol. 2015; 35:400-411. DOI
  13. Martineau P, Chakraborty S, Faiz K. Imaging of the spontaneous low cerebrospinal fluid pressure headache: a review. Can Assoc Radiol J. 2020; 71:174-185. DOI
  14. Banu MA, Kim JH, Shin BJ. Low-dose intrathecal fluorescein and etiology-based graft choice in endoscopic endonasal closure of CSF leaks. Clin Neurol Neurosurg. 2014; 116:28-34. DOI
  15. Bernal-Sprekelsen M, Alobid I, Mullol J. Closure of cerebrospinal fluid leaks prevents ascending bacterial meningitis. Rhinology. 2005; 43:277-281.
  16. Oakley GM, Orlandi RR, Woodworth BA. Management of cerebrospinal fluid rhinorrhea: an evidence-based review with recommendations. Int Forum Allergy Rhinol. 2016; 6:17-24. DOI
  17. Snyderman CH, Wang EW, Zenonos GA. Reconstruction after endoscopic surgery for skull base malignancies. J Neurooncol. 2020; 150:463-468. DOI
  18. Lee DH, Lim SC, Joo YE. Treatment outcomes of endoscopic repairs of sinonasal cerebrospinal fluid leaks. J Craniofac Surg. 2011; 22:1266-1270. DOI
  19. Reddy M, Baugnon K. Imaging of cerebrospinal fluid rhinorrhea and otorrhea. Radiol Clin North Am. 2017; 55:167-187. DOI
  20. Eftekhar B, Ghodsi M, Nejat F. Prophylactic administration of ceftriaxone for the prevention of meningitis after traumatic pneumocephalus: results of a clinical trial. J Neurosurg. 2004; 101:757-761. DOI
  21. Friedman JA, Ebersold MJ, Quast LM. Post-traumatic cerebrospinal fluid leakage. World J Surg. 2001; 25:1062-1066. DOI
  22. Dai JB, Del Signore AG, Govindaraj S. Investigation of skull-based cerebrospinal fluid leak repair: a single-institution comprehensive study of 116 cases over 10 years. World Neurosurg. 2020; 135:e1-11. DOI
  23. Wigand ME. Transnasal ethmoidectomy under endoscopical control. Rhinology. 1981; 19:7-15.
  24. Gilat H, Rappaport Z, Yaniv E. Endoscopic transnasal cerebrospinal fluid leak repair: a 10 year experience. Isr Med Assoc J. 2011; 13:597-600.
  25. Psaltis AJ, Schlosser RJ, Banks CA. A systematic review of the endoscopic repair of cerebrospinal fluid leaks. Otolaryngol Head Neck Surg. 2012; 147:196-203. DOI
  26. Locatelli D, Rampa F, Acchiardi I. Endoscopic endonasal approaches for repair of cerebrospinal fluid leaks: nine-year experience. Neurosurgery. 2006; 58:246-257. DOI
  27. Presutti L, Mattioli F, Villari D. Transnasal endoscopic treatment of cerebrospinal fluid leak: 17 years’ experience. Acta Otorhinolaryngol Ital. 2009; 29:191-196.
  28. Paludetti G, Sergi B, Rigante M. New techniques and technology to repair cerebrospinal fluid rhinorrhea. Acta Otorhinolaryngol Ital. 2004; 24:130-136.
  29. Prickett KK, Wise SK. Grafting materials in skull base reconstruction. Adv Otorhinolaryngol. 2013; 74:24-32. DOI
  30. Sharma SD, Kumar G, Bal J. Endoscopic repair of cerebrospinal fluid rhinorrhoea. Eur Ann Otorhinolaryngol Head Neck Dis. 2016; 133:187-190. DOI
  31. S Raza SM, Banu MA, Donaldson A. Sensitivity and specificity of intrathecal fluorescein and white light excitation for detecting intraoperative cerebrospinal fluid leak in endoscopic skull base surgery: a prospective study. J Neurosurg. 2016; 124:621-626. DOI
  32. Pasquini E, Sciarretta V, Farneti G. Endoscopic treatment of encephaloceles of the lateral wall of the sphenoid sinus. Minim Invasive Neurosurg. 2004; 47:209-213. DOI
  33. Soudry E, Turner JH, Nayak JV. Endoscopic reconstruction of surgically created skull base defects: a systematic review. Otolaryngol - Head Neck Surg. 2014; 150:730-738. DOI
  34. Schick B, Wolf G, Romeike BFM. Dural cell culture: a new approach to study duraplasty. Cells Tissues Organs. 2003; 173:129-37. DOI
  35. Castelnuovo PG, Delú G, Locatelli D. Endonasal endoscopic duraplasty: our experience. Skull Base. 2006; 16:19-23. DOI
  36. Harvey RJ, Parmar P, Sacks R. Endoscopic skull base reconstruction of large dural defects: a systematic review of published evidence. Laryngoscope. 2012; 122:452-459. DOI
  37. Bolzoni Villaret A, Bosio R, Tomenzoli D. Endoscopic duraplasty for cerebrospinal fluid (CSF) leak. Otolaryngol Neck Surg. 2010; 143:P278. DOI
  38. Eloy JA, Marchiano E, Vázquez A. Management of skull base defects after surgical resection of sinonasal and ventral skull base malignancies. Otolaryngol Clin North Am. 2017; 50:397-417. DOI
  39. Hachem RA, Elkhatib A, Beer-Furlan A. Reconstructive techniques in skull base surgery after resection of malignant lesions: a wide array of choices. Curr Opin Otolaryngol Head Neck Surg. 2016; 24:91-97. DOI
  40. Pagella F, Pusateri A, Matti E. Endoscopic management of spontaneous clival cerebrospinal fluid leaks: case series and literature review. World Neurosurg. 2016; 86:470-477. DOI
  41. Lloyd KM, DelGaudio JM, Hudgins PA. Imaging of skull base cerebrospinal fluid leaks in adults. Radiology. 2008; 248:725-736. DOI
  42. Riley CA, Soneru CP, Tabaee A. Technological and ideological innovations in endoscopic skull base surgery. World Neurosurg. 2019;S1878-8750(19)30220-7. DOI
  43. Lauretti L, D’Alessandris QG, Rigante M. O-arm in endonasal endoscopic cranial base surgery: technical note on initial feasibility. World Neurosurg. 2018; 117:103-108. DOI
  44. Uozumi Y, Taniguchi M, Nakai Comparative evaluation of 3-dimensional high definition and 2-dimensional 4-k ultra-high definition endoscopy systems in endonasal skull base surgery. Oper Neurosurg. 2020; 19:281-287. DOI
  45. Dallan I, Cambi C, Emanuelli E. Multiple spontaneous skull base cerebrospinal fluid leaks: some insights from an international retrospective collaborative study. Eur Arch Otorhinolaryngol. 2020; 277:3357-63. DOI
  46. Pérez MA, Bialer OY, Bruce BB. Primary spontaneous cerebrospinal fluid leaks and idiopathic intracranial hypertension. J Neuro-Ophthalmology. 2013; 33:327-334. DOI
  47. Hornby C, Botfield H, O’Reilly MW. Evaluating the fat distribution in idiopathic intracranial hypertension using dual-energy X-ray absorptiometry scanning. Neuroophthalmology. 2018; 42:99-104. DOI
  48. Gafoor V, Smita B, Jose J. Long-term response of cerebrospinal fluid pressure in patients with idiopathic intracranial hypertension - A prospective observational study. Ann Indian Acad Neurol. 2017; 20:220-224. DOI
  49. Rigante M, La Rocca G, Lauretti L. Preliminary experience with 4K ultra-high definition endoscope: analysis of pros and cons in skull base surgery. Acta Otorhinolaryngol Ital. 2017; 37:237-241. DOI
  50. Lavigne P, Faden D, Gardner PA. Validation of training levels in endoscopic endonasal surgery of the skull base. Laryngoscope. 2019; 129:2253-2257. DOI
  51. Mattavelli D, Ferrari M, Rampinelli V. Development and validation of a preclinical model for training and assessment of cerebrospinal fluid leak repair in endoscopic skull base surgery. Int Forum Allergy Rhinol. 2020; 10:89-96. DOI
  52. Lopatin AS, Kapitanov DN, Potapov AA. Endonasal endoscopic repair of spontaneous cerebrospinal fluid leaks. Arch Otolaryngol Head Neck Surg. 2003; 129:859-863. DOI
  53. Senior BA, Jafri K, Benninger M. Safety and efficacy of endoscopic repair of csf leaks and encephaloceles: a survey of the members of the American Rhinologic Society. Am J Rhinol. 2001; 15:21-25. DOI


Jacopo Galli

Otorhinolaryngology, Head and Neck Surgery, “A. Gemelli” Hospital Foundation IRCCS, Catholic University of the Sacred Heart, Rome, Italy

Francesco Morelli

Otorhinolaryngology, Head and Neck Surgery, “A. Gemelli” Hospital Foundation IRCCS, Catholic University of the Sacred Heart, Rome, Italy

Mario Rigante

Otorhinolaryngology, Head and Neck Surgery, “A. Gemelli” Hospital Foundation IRCCS, Catholic University of the Sacred Heart, Rome, Italy

Gaetano Paludetti

Otorhinolaryngology, Head and Neck Surgery, “A. Gemelli” Hospital Foundation IRCCS, Catholic University of the Sacred Heart, Rome, Italy


© Società Italiana di Otorinolaringoiatria e chirurgia cervico facciale , 2021

  • Abstract viewed - 325 times
  • PDF downloaded - 229 times
  • xml downloaded - 0 times