Introduction

The cerebrospinal fluid (CSF) is a nourishing and protective layer surrounding the central nervous system (CNS). This protective cushion circulates within the ventricular system and the subarachnoid space around the brain and the spinal cord, which helps to provide the buoyancy to counteract various shears and stresses encountered during the movement of the skull and vertebral column.[1]

In various disorders that present with CSF leak, the loss of this protective nutrient-rich layer can injure the function of the brain and the spinal cord. Such conditions might be associated with fractures in the skull base, congenital bony defects, or raised intracranial pressure (ICP). CSF leak also predisposes the brain and spinal cord to the external environment, increasing the risk of meningitis, ventriculitis, and arachnoiditis.  

The traditional CSF formation, distribution, and absorption concept was previously based on the bulk flow model. However, based on recent literature, this model seems inadequate to explain the pathophysiological mechanisms of various CSF flow-related disorders. The currently accepted CSF flow system comprises pulsatile CSF flow, lymphatic system, capillary exchange, and the traditional ventricular-cisternal system. According to the current understanding, the production of CSF is from multiple sources, primarily from the choroid plexus of the lateral and fourth ventricles. The interstitial space, ependyma, and dural sleeves of the spinal nerve roots also contribute to the total CSF turnover.[2]

Similarly, CSF is absorbed in multiple sites, with dural venous sinuses being the major drainage site via arachnoid granulations, followed by choroid plexus and lymphatic system.[3]

Etiology

Cranial CSF leaks can manifest either in the form of rhinorrhea or otorrhea. The leaks often present as rhinorrhea unless the tympanic membrane is defective and will present as otorrhea. The communication site may exist at the anterior skull base, including frontal and ethmoidal air cells; the middle skull base, including sphenoid or mastoid air cells; and the posterior fossa, including the mastoid air cells and the middle ear. The most likely etiology underlying these abnormal defects is traumatic, out of which the most common mechanism is motor vehicle accidents (MVA), especially in moderate to high-velocity trauma. Following MVA, blunt trauma to the head can lead to skull base fractures, presenting as CSF rhinorrhoea.[4] 

Other common causes include iatrogenic defects following neurosurgical procedures like opening the sphenoid sinus in trans-sphenoidal surgeries or opening the mastoid air cells in posterior fossa surgeries. A small proportion of cases are caused by non-traumatic etiologies, which may be associated with raised ICP like hydrocephalus or intracranial space-occupying lesion or normal ICP like congenital defects, focal atrophy, or post-infection bony erosions. Similarly, spinal CSF leaks may follow traumatic or iatrogenic communication between the spinal subarachnoid space and the external environment.

Epidemiology

Approximately 90% of the CSF leaks are attributable to traumatic causes, with a vast majority exhibiting fractures of the skull base.[5] However, only 10% to 30% of skull base fractures are reported to present with a CSF leak. On the other hand, non-traumatic causes are less common. These primarily occur in adults older than 30 and are rare in children younger than 2.[6] Spontaneous CSF leaks are more common among obese middle-aged females.[7][8][9]

Pathophysiology

Among the traumatic causes of CSF leak, blunt trauma is more common than penetrating injuries, affecting the anterior skull base more frequently than the middle or posterior skull base.[10] Out of these, a frontal sinus fracture is the most common culprit causing CSF leaks. On the other hand, blunt head trauma involving the middle cranial fossa can cause rhinorrhea or otorrhea. In these middle cranial fossa cases, rupture of the tympanic membrane is an essential pathophysiologic intermediate for otorrhea to manifest. However, not all skull base fractures result in CSF leak, which depends on the interplay of several variables like raised ICP, arachnoidal disruption, dural injury, and the size of the bony defect. Penetrating injuries are associated with a higher rate of CSF leak and complications like meningitis and higher mortality.[4]

Among the non-traumatic causes of high-pressure CSF leaks, generally, thinning and resorption of the bone at the skull base occurs as thinning of the dural layer, which, over time, communicates with the subarachnoid space. One such condition is idiopathic intracranial hypertension, frequently in young to middle-aged obese women, and is associated with sellar floor erosions resulting in spontaneous CSF rhinorrhoea. Similarly, among the non-traumatic causes with normal ICP, a congenital bone and dura defect or one secondary to infective or inflammatory pathologies is usually seen.[11]

History and Physical

A clear, watery discharge from the nose or ears, usually in the setting of recent trauma or surgery, is the most common presentation of cranial CSF leaks. In some cases, headaches can be associated with a clear, watery discharge due to intracranial hypotension due to the loss of CSF. This headache is positional in most cases, increasing in an upright position and relieved on lying down. Anosmia in patients with CSF leak should point towards a traumatic cause, usually involving injury to the ethmoid bone.[12] 

Some patients might even present with conductive or sensorineural hearing loss, depending on the injury site. Spinal leaks are usually associated with postoperative wound complications, and they also present with symptoms attributable to intracranial hypotension similar to cranial CSF leaks.

Evaluation

The first step in evaluating a patient with a suspected CSF leak is to confirm that the fluid in question is CSF. Several tests can differentiate CSF from other fluids, and the most useful ones are listed below.

1. Beta-2-transferrin: The most specific test as β-2-transferrin is found only in the CSF (and the eye's vitreous fluid); therefore, its presence strongly suggests CSF.[13]
2. Glucose levels: Normal CSF glucose is 50 mg to 80 mg/100 mL (or greater than two-thirds of blood sugar level except in cases with hypoglycorrhachia like meningitis) compared to <5 mg/100 mL in other secretions like tears and mucus. Though not as sensitive and specific as β-2-transferrin levels, it still carries a good negative predictive value.
3. Halo sign: In traumatic cases of CSF leak, the fluid is blood-tinged and, thus, when allowed to drop on linen, gives a central disc of blood and a peripheral ring of clear fluid.
4. Reservoir sign: Copious fluid drainage in a particular head position, especially when the patient is upright after a long period spent lying down. It is a non-specific test but can still be suggestive of CSF.[14]

Once confirmed that the leaking fluid is only CSF, the next step is to localize the leak site. The following modalities can help:

1. Computed tomography (CT): Various signs to look for in a CT scan include skull base fractures and defects, tumors, hydrocephalus, and pneumocephalus.[15] A non-contrast high-resolution CT scan is usually sufficient to help detect fractures and defects in the skull base. A contrast-enhanced CT scan may help localize the leakage site because an abnormal enhancement of the adjacent brain parenchyma may sometimes be present due to inflammation in chronic CSF leak.
2. CT cisternography: This procedure localizes the leak site. It involves thin-slice computed tomography after 5 mL to 10 mL of iodinated non-ionic contrast material is administered via lumbar puncture. It is especially helpful in cases where a CT scan shows no bony defects or multiple bony defects (to determine which defect is actively leaking) or if a bony defect is not associated with changes in the adjacent brain parenchyma. The most common site of CSF rhinorrhea is the junction of the cribriform plate and ethmoid bone.[7][8][10]
3. MRI: The modality helps better identify posterior fossa space-occupying lesions and empty sella in cases of idiopathic intracranial hypertension. It is also helpful in cases with intracranial hypotension to demonstrate characteristic signs like brain sagging, pachymeningeal enhancement, engorgement of veins, pituitary hyperemia, subdural fluid collections, etc.[16][17][18][19]
4. MR cisternography: T1 fat suppression and T2 images before and after intrathecal gadolinium administration are more accurate than CT cisternography.

Treatment / Management

The management of CSF leaks should be tailored according to the underlying etiology. As many traumatic leaks cease spontaneously, waiting and watching for a short time is advisable. If the leakage persists, the first step involves conservative, non-invasive management by interventions that lower the ICP. These include recumbency, cerebral decongestants like acetazolamide, avoiding straining exercises, and not blowing the nose. Significant dural defects, bony spicules, comorbidities, and extremes of age reduce the chances of spontaneous healing of CSF leaks.[4]

For persistent leaks, drainage of CSF via repeated lumbar puncture or continuous lumbar drainage via percutaneous catheter can be done. However, for the non-traumatic causes or iatrogenic trauma during surgery, the likelihood of resolution with conservative management is lower. Nonetheless, an initial trial of conservative management followed by CSF diversion is instituted. Iatrogenic CSF leaks during posterior fossa surgeries can be prevented by meticulous watertight dural closure and obliteration of air cells with bone wax or by using a muscle patch with fibrin glue.

CSF Diversion Strategies

If conservative strategies fail, continuous or intermittent CSF drainage using a lumbar drain is performed. Continuous drainage is usually done at the rate of 5 ml/h to 10 ml/h (150 to 200 ml/day), while for intermittent drainage protocol, 20 ml to 30 ml of CSF is drained every 4 hours. Caution should be maintained to prevent over-drainage. A trial of CSF diversion is generally continued for 5 to 7 days—failure in control of the CSF leak warrants surgical management. In the scenario where conservative measures fail, surgical management is indicated irrespective of the leak's etiology. The surgical procedure and approach are tailored depending on the site of the leak. 

Timing of Surgery

The decision to proceed with definitive surgical management depends on the etiology and presentation concerning the initial insult. Early surgery without trial of conservative management or CSF diversion is indicated in patients suffering from penetrating injuries like gunshot wounds, meningitis, pneumocephalus, large identifiable bony defect, and external herniation of brain parenchyma through the wound. An initial trial of conservative management followed by CSF diversion is instituted in the remaining cases, and delayed definitive surgical management is planned if the above measures fail.

Non-Conservative Approach

Cranial CSF leaks

The traditional approach is a transcranial repair of skull base defects. For defects in the anterior cranial fossa, a bicoronal scalp flap is raised, and a pedicled pericranial flap is harvested. After a bifrontal craniotomy, the leak site is identified, and a combined intra and extradural repair is performed.[20] An autologous graft like temporal fascia or fascia lata is used intradural secured with fibrin glue and non-absorbable sutures along with a pedicled pericranial flap being placed extradural at the defect site to achieve a watertight dural seal. In cases where the autologous graft is unavailable, artificial dural substitutes can be used. A surgical repair is usually unnecessary for the leaks originating in the middle and posterior fossa as the spontaneous closure rate is higher. However, a subtemporal approach is preferred for a longitudinal petrous temporal fracture if needed. For a transverse fracture, a translabyrinthine or posterior fossa approach is taken depending on hearing status, which is preserved in the latter.[21]

Endoscopic repair of CSF leaks has gained popularity, especially for anterior and middle skull base repairs, owing to the panoramic view and better visualization of the defect site. Central leaks are managed using an endonasal trans-ethmoid or transseptal approach, while the transpterygoid approach is used for lateral leaks. After identifying the leak site, placing an appropriately sized graft completes the procedure.

Spinal CSF leaks

Wound re-exploration with identification of the leak site is made. The leak site can be repaired primarily or using a free graft reinforced with fibrin glue. A meticulous fascial closure in layers is paramount in achieving closure of the spinal CSF fistula.

Graft placement technique

A choice exists between the graft placement in the subdural and the extradural space. It is termed as underlay/inlay technique when placed subdurally, which can be achieved only during a transcranial repair. On the other hand, the overlay/onlay technique is defined as the placement of a graft over the dural defect from the extradural side, either transcranially or endoscopically. Current literature supports the results of either technique. Many surgeons prefer using a combination of both to achieve better results.

Graft materials

These can be classified as autologous and dural substitutes. The autologous grafts can be further classified as free grafts or pedicled grafts. Free grafts include fascia lata, free fat graft, free mucosal graft, free pericranial graft, and free temporalis fascia. Pedicled grafts include pedicled pericranial flap, pedicled muscle flap, and pedicled nasoseptal graft. The last decade has witnessed success rates using a pedicled nasoseptal graft called Hadad-Bassagasteguy flap based on a nasoseptal branch of the sphenopalatine artery during the endoscopic repair. Schwartz et al described the "gasket seal closure," which includes using autologous fascia lata with a bony buttress further reinforced with fibrin glue.[22]

Differential Diagnosis

The major differentials to cranial CSF leaks include other disorders that can result in watery nasal or ear discharge. These can be infectious etiologies like the common cold or allergic etiologies like allergic rhinitis. Ruling out such mimics is more pertinent among patients with no history of trauma or previous surgery. As highlighted in the evaluation section, it is important to confirm that the leaking fluid is CSF using clinical signs like reservoir or halo sign and laboratory tests like β-2 transferrin.

Prognosis

Many CSF leaks, especially traumatic causes, resolve spontaneously and are associated with a good prognosis. Among the remaining patients, more than 90% resolved with surgical repair. Meningitis may complicate the clinical course in a small proportion of cases, which may worsen the prognosis, especially among the late-onset CSF leaks. Prognosis is guarded among patients needing repeated surgical procedures due to the added surgical morbidity and the additional risk of meningitis.

Complications

Meningitis is the most common complication associated with CSF leak and is seen in 25% to 30% of patients. The risk is significantly higher among patients with a delayed leak onset in the 50% to 60% range compared to 5% to 10% in patients with early onset. It is also more common in patients with penetrating injuries. Antibiotics have no proven role in patients with no clinical evidence of meningitis.[23] In patients with evidence of meningitis, empirical antibiotics must be started, followed by culture-based antibiotics after the microbial culture and sensitivity are available. The most common pathogens include Streptococcus pneumoniae and Hemophilus influenzae.[24]

Polymicrobial and anaerobic infections can occur in cases with penetrating injuries. CSF over-drainage is a common complication following CSF diversion procedures like lumbar drain insertion. This leads to sagging of the brain parenchyma, which can lead to injury to bridging veins and result in a subdural hematoma. Hence, following any CSF diversion procedure, controlling CSF drainage, and preventing intracranial hypotension is very important.

Consultations

• Neurosurgery
• Neuroradiologist
• Otolaryngologist

Deterrence and Patient Education

A need for public health education exists regarding warning signs heralding meningitis, like fever, headache, neck rigidity, photophobia, etc. Further awareness must be raised on identifying true CSF leaks masquerading as innocuous pathologies like allergic rhinitis or the common cold. General awareness regarding the prevention of trauma and obesity may also help decrease the incidence of CSF leaks.

Pearls and Other Issues

1. Spontaneous closure of early post-traumatic CSF leak is seen in 60% to 70% of patients.
2. The most typical site of CSF rhinorrhea is the junction of the cribriform plate and ethmoid bone. 
3. Large dural defects, bony spicules, comorbidities, and extremes of age reduce the chances of spontaneous healing of CSF leaks. 
4. The most sensitive and specific investigation to detect CSF leaks is the β-2 transferrin assay.
5. In case of a dubious leak or suspected multiple defects, MR cisternography should be combined with a high-resolution CT scan to increase the detection accuracy of the leak site. 
6. Surgical management of cranial CSF leaks includes overlay or underlay techniques performed transcranially or endoscopically.
7. Prophylactic antibiotics have not been proven to prevent meningitis in CSF leaks.

Enhancing Healthcare Team Outcomes

CSF leak is a common condition due to traumatic and non-traumatic etiologies requiring an integrated multidisciplinary team consisting of a neurosurgeon, neuroradiologist, nurse practitioner, and laboratory technician. Many of these patients have associated trauma and require intensive care therapy and rehabilitative services. CSF leaks associated with specific underlying comorbidities like obesity need tailored specialty referrals like dieticians for dietary and lifestyle modifications.