Cerebrospinal Fluid (CSF) Leak

Last Literature Review: February 2021 Last Update:

Medical Experts



Julio Delgado, MD, MS
Executive Vice President, ARUP Laboratories
Professor, Vice Chairman, and Chief, Division of Clinical Pathology, University of Utah Department of Pathology

Cerebrospinal fluid (CSF) leaks (also known as CSF fistulas) result from dura mater defects or tears that enable CSF to escape containment. CSF leaks may be spinal or cranial. Tears in the dura mater primarily arise from craniofacial trauma or after procedures such as endoscopic sinus surgery and lumbar puncture.  CSF leaks can also occur spontaneously   or in relation to infection, hydrocephalus, congenital malformations, or neoplasms.  The most severe consequences of a CSF leak are brain abscess or bacterial meningitis due to the passage of bacteria into craniospinal spaces. Early diagnosis and intervention, particularly in the case of cranial CSF leaks, are critical to prevent these outcomes.   Diagnosis of cranial leaks can be challenging in outpatient and postsurgical contexts, in part because such leaks can be difficult to distinguish from chronic rhinitis. Beta (β)-2 transferrin testing is the preferred laboratory approach to assess patients for cranial CSF leaks because it is highly specific and sensitive for CSF secretions.    The β-2 transferrin in CSF is a desialylated form due to the presence of neuraminidase in the central nervous system. Neuroimaging is used to confirm the diagnosis of any CSF leak and to ascertain the location of the breach.    

Quick Answers for Clinicians

How do cerebrospinal fluid leaks present clinically?

Presenting signs of a cranial cerebrospinal fluid (CSF) leak include persistent headaches; discharge of clear, watery, and sometimes bloody fluid from the ear or nose, which is affected by bodily position; and postnasal drip with a salty taste.  Other possible signs include a sensation of ear fullness and difficulty hearing and the presence of a “halo” or “double ring” sign on bedsheets or on tissue used to collect fluid draining from the nose or ear.  However, the double ring sign is not specific for a CSF leak; this sign can appear when blood is mixed with fluids other than CSF.  Finally, because both cranial and spinal CSF leaks may result in a loss of CSF volume, persistent symptoms associated with intracranial hypotension such as positional headaches, nausea, light or sound sensitivity, and tinnitus  may suggest a potential leak, particularly in the absence of another apparent cause. 

Should glucose oxidase testing be used for the diagnosis of cerebrospinal fluid leaks?

Traditional assessment for cerebrospinal fluid (CSF) leaks involved testing nasal discharge with glucose oxidase strips (Glucostix). However, this testing is no longer recommended due to its inadequate sensitivity and specificity for CSF leak diagnosis.   Bacterial contamination can cause false-negative test results, and patients with diabetes may have false-positive results.  Glucose testing is also discouraged to confirm diagnosis. 

What is the connection between cerebrospinal fluid leaks and connective tissue disorders?

Spontaneous cerebrospinal fluid (CSF) leaks have been reported in association with heritable connective tissue disorders such as Marfan syndrome and Ehlers-Danlos syndrome. CSF leaks are thought to occur because of the fragility of connective tissue in these disorders.  Some investigators suggest that all patients with spontaneous CSF leaks be evaluated for connective tissue and vascular anomalies. 

How are cerebrospinal fluid leaks along the spine diagnosed?

Unlike cranial cerebrospinal fluid (CSF) leaks, which can often be confirmed with laboratory testing, spinal CSF leaks are diagnosed with imaging. In patients with chronic, unresolved symptoms suggestive of intracranial hypotension without another overt cause, magnetic resonance imaging (MRI) or digital subtraction myelography can be used to confirm the existence and location of a spinal CSF leak.   

Indications for Testing

Laboratory testing for a cranial CSF leak is appropriate in patients with otorrhea or rhinorrhea, particularly after trauma or surgery. 

Laboratory Testing

Beta-2 Transferrin

β-2 transferrin is a protein found in CSF, but not in serum, nasal secretions, or adjacent tissue.  Testing fluid from the ear or nose for β-2 transferrin is the recommended method to assess patients for a cranial CSF leak because this approach is noninvasive as well as highly sensitive and specific.    Immunofixation electrophoresis is the method typically used.  However, because β-2 transferrin is also a component of the vitreous humor, patients with eye ruptures can test positive for β-2 transferrin in the absence of a CSF leak.  Rare allelic variants of transferrin may also cause false-positive results in tests used to detect CSF leakage.  Patients with prolonged alcohol consumption can show increased concentrations of a carbohydrate-deficient transferrin isoform.  Simultaneous analysis of serum and CSF from the same individual is suggested to rule out these rare false-positive results. 

In patients with negative β-2 transferrin test results but high clinical suspicion for a CSF leak, imaging is recommended


Imaging, including high-resolution computed tomography, magnetic resonance cisternography, digital subtraction myelography, or magnetic resonance imaging (MRI) with or without intrathecal contrast, is used to detect the location of confirmed cranial CSF leaks and suspected or known spinal leaks and to guide intervention.    , 

Although radionucleotide cisternography may be helpful to assess patients with possible intermittent or low-volume CSF leaks, it is not recommended as a routine approach to diagnose or confirm cranial CSF leaks because of its higher cost, lower accuracy, and invasive nature compared with β-2 transferrin testing. 

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