INTRODUCTION — Examination of the cerebrospinal fluid (CSF) may provide critically important diagnostic information in a number of infectious and noninfectious medical conditions. Knowledge of the normal physiology and pathophysiology of CSF production and flow is useful in interpreting such test results.
This topic will review the normal physiology and composition of CSF. The technique for obtaining CSF via lumbar puncture and the complications and contraindications to this test are discussed separately. (See "Lumbar puncture: Technique, contraindications, and complications in adults".)
CSF analysis in children is presented elsewhere. (See "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Interpretation'.)
PHYSIOLOGY OF CSF FORMATION AND FLOW — Cerebrospinal fluid (CSF) is produced by the choroid plexus in the lateral, third, and fourth ventricles and circulates through the subarachnoid space between the arachnoid mater and the pia mater . The choroid plexus consists of projections of vessels and pia mater that protrude into the ventricular cavities as frond-like villi containing capillaries in loose connective stroma. A specialized layer of ependymal cells called the choroidal epithelium overlies these villi (figure 1).
CSF is formed in the choroid plexus by both filtration and active transport. In normal adults, the CSF volume is 90 to 200 mL ; approximately 20 percent of the CSF is contained in the ventricles; the rest is contained in the subarachnoid space in the cranium and spinal cord. The normal rate of CSF production is approximately 20 mL per hour.
CSF circulates from the lateral ventricles though the interventricular foramina of Monro into the third ventricle and then the fourth ventricle via the cerebral aqueduct. Thereafter, CSF passes through median (foramen of Magendie) and lateral (foramina of Luschka) apertures in the fourth ventricle into the subarachnoid space at the base of the brain and then flows over the convexities of the brain and down the length of the spinal cord. The CSF is propelled along the neuroaxis by a cranio-caudal pulsatile wave induced by flow in the cerebral arteries and by the associated expansions of the vascular compartment in the cranial vault.
CSF is reabsorbed in the arachnoid villi, located along the superior sagittal and intracranial venous sinuses and around the spinal nerve roots. Each arachnoid villus functions as a one-way valve permitting unidirectional flow of CSF into the blood. Arachnoid villi and venous sinuses are separated by endothelial cells connected by tight junctions (figure 1). Arachnoid villi normally allow the passage of particles less than 7.5 micron in diameter from the CSF into the blood.
Movement of CSF and cellular components across arachnoid villi occurs via transport within giant vesicles. These vesicles may become obstructed by bacteria or cells as a result of an inflammatory process or by red blood cells during subarachnoid hemorrhage.
Lipid-soluble molecules or drugs readily diffuse across the vascular endothelium and epithelium of the choroid plexus into the interstitial fluid and CSF. In contrast, ionically charged molecules generally require active transport for entry into the CSF. Drug entry also may be altered in patients with meningitis by the accompanying inflammation, and this may subsequently rapidly change with regression of this inflammation with therapy. (See 'CSF in CNS infection' below.)
In addition to these well-described transport mechanisms, newer studies have documented the existence of other pathways involved in the movement of CSF and solutes throughout the central nervous system (CNS) . These include perivascular pathways within the CNS parenchyma that support the clearance of solutes from the brain to the CSF and extra-axial meningeal lymphatic vessels associated with the dural sinuses that facilitate the movement of solutes in the CSF into the systemic vascular system. The finding of dura-associated lymphatic vessels is contrary to long-held beliefs about the absence of meningeal lymphatics. The role of these lymphatic pathways, however, in the clearance of interstitial and CSF solutes has not yet been elucidated.
CSF PRESSURE — Cerebrospinal fluid (CSF) secretion and reabsorption remain in balance in most healthy individuals to maintain a CSF pressure less than 15 cmH2O. The normal CSF pressure as measured with a manometer in a patient lying flat in the lateral decubitus position with the legs extended is between 6 and 25 cmH2O ; however, some experts consider the upper limit of normal CSF pressure to be 20 cmH2O (figure 2) . A variety of factors, such as the patient's position, the skill of the person performing the lumbar puncture, and the patient’s degree of relaxation, can affect the measurement of the opening pressure.
Patients with obesity tend to have higher opening pressures; however, the correlation between opening pressure and body mass index was weak in a study involving 242 outpatients with a variety of neurologic complaints and/or conditions that are not associated with elevated CSF pressure . In a subsequent analysis of a community-based population, increasing body mass index was moderately associated with higher opening pressure . In this study, increasing age was moderately associated with a lower opening pressure.
The differential diagnosis of an increase in CSF pressure relates to disruptions in the normal physiology of CSF secretion and absorption and whether or not compensatory mechanisms develop. Processes, such as infection, bleeding, or a tumor, can alter the balance between CSF secretion and reabsorption and have potential to cause intracranial hypertension. Slow-growing masses, such as abscesses or tumors, may allow time for compensation between CSF secretion and absorption to occur; thus, a rise in CSF pressure may not occur until the normal compliance of the intracranial structures is overcome. In contrast, acute infections, such as meningitis, typically lead to rapid increases in CSF pressure due to alterations in either production or reabsorption of CSF, or as a result of cerebral edema. (See "Neurologic complications of bacterial meningitis in adults", section on 'Increased intracranial pressure'.)
Intracranial hypertension may cause downward and backward shifting of the cerebrum and brainstem, as well as herniation of the cingulate gyrus, the uncus of the temporal lobe, or the cerebellar tonsils; these may result in respiratory depression or death. (See "Evaluation and management of elevated intracranial pressure in adults".)
THE BLOOD-BRAIN BARRIER — The term "blood-brain barrier" is used to describe barrier systems that separate the brain and the cerebrospinal fluid (CSF) from the blood and prevent entry by simple diffusion of fluids, electrolytes, and other substances from blood into the CSF or brain . There are actually two barriers: a blood-brain barrier and a blood-CSF barrier. Both barriers separate the central nervous system (CNS) from systemic immune responses and affect the composition of the brain interstitial fluid and CSF. The blood-brain and the blood-CSF barriers are not precisely equivalent .
Blood-brain barrier — The blood-brain barrier controls the content of brain interstitial fluid. It has a 5000-fold greater surface area than the blood-CSF barrier . The anatomic basis for the blood-brain barrier is a series of high-resistance, tight junctions between endothelial cells as well as astrocytes with processes that terminate in overlapping fashion on capillary walls.
Lipid-soluble small molecules with a molecular mass less than 400 to 600 Da are transported readily through the blood-brain barrier. In contrast, many drugs and other small molecules cannot cross this barrier system .
Blood-CSF barrier — The blood-CSF barrier controls the composition of the CSF, which, as noted above, is primarily dependent upon secretion in the choroid plexus. The blood-CSF barrier is formed by tight junctions between choroid epithelial cells.
Both barrier systems are dynamic. Endothelial cells and astrocytes that compose the blood-brain barrier and cells forming the blood-CSF barrier are capable of producing cytokines such as tumor necrosis factor and interleukins. In addition, astrocytes can act as antigen-presenting cells that modulate the immunologic response to CNS infections. Release of cytokines from endothelial cells and astrocytes probably mediate or generate much of the CNS inflammatory response in infectious and noninfectious conditions.
A brain-CSF barrier also exists in the pia mater. A continuous layer of astrocytes overlies the basement membrane of cells in the pia mater. These astrocytes are separated by gap junctions that affect the movement of constituents from the CSF into the brain.
Microbe entry in meningitis — The mechanism by which bacteria or other microbes traverse the blood-brain barrier and enter the CNS remains poorly understood. A number of theories have been advanced [9-14]. As examples:
●Microbes in the blood could traverse the blood-brain barrier via attachment of specific bacterial surface constituents to endothelial cells. Such surface constituents include the capsular polysaccharide present on many of the encapsulated bacteria that cause acute bacterial meningitis. As an example, the phosphorylcholine moiety of the pneumococcal cell wall lipoteichoic acid appears to utilize endogenous receptors for platelet activating factor to facilitate attachment and transcellular migration across endothelium .
●Pili on gram-negative rods may facilitate bacterial entry into the brain or CSF. Such interactions have been hypothesized to occur in children with Escherichia coli meningitis  and in patients with meningitis due to certain strains of Neisseria meningitidis .
●Microbes can theoretically transverse the blood-brain barrier inside circulating cells such as monocytes. This phenomenon has been described as a "Trojan horse mechanism."
A more detailed discussion of the pathogenesis of bacterial meningitis is presented in a separate topic review. (See "Pathogenesis and pathophysiology of bacterial meningitis".)
COMPOSITION OF THE CSF
Xanthochromia — Normal cerebrospinal fluid (CSF) is clear and colorless. Both infectious and noninfectious processes can alter the appearance of the CSF. As few as 200 white blood cells (WBCs)/microL or 400 red blood cells (RBCs)/microL will cause CSF to appear turbid. CSF will appear grossly bloody if ≥6000 RBCs/microL are present .
Red blood cells rapidly lyse after entry into CSF. The breakdown of hemoglobin first to oxyhemoglobin (pink) and later to bilirubin (yellow) leads to a yellow or pink discoloration of the CSF known as xanthochromia. Spectrophotometry can be used to analyze blood breakdown products as they progress from oxyhemoglobin to methemoglobin and finally to bilirubin, thereby ruling out traumatic blood [15-17]. Although xanthochromia is generally confirmed visually , laboratory confirmation with spectrophotometry may be more sensitive and, if available, is recommended by some experts [15,19,20].
Xanthochromia can be detected as soon as two to four hours after RBCs have entered the subarachnoid space, and therefore this is often used in the diagnosis of subarachnoid hemorrhage (SAH). Xanthochromia is present in over 90 percent of patients with a subarachnoid hemorrhage within 12 hours of the onset of bleeding, and it may persist thereafter for two to four weeks [15,21-23]. The use of xanthochromia and RBC count to distinguish SAH from traumatic tap is discussed separately. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Lumbar puncture'.)
Xanthochromia can also occur with increased CSF concentrations of protein (≥150 mg/dL) or systemic hyperbilirubinemia (serum bilirubin >10 to 15 mg/dL) .
Normal findings — The CSF is normally acellular. However, up to 5 WBCs and 5 RBCs are considered normal in adults when the CSF is sampled by lumbar puncture (LP). More than 3 polymorphonuclear leukocytes (PMNs)/microL are abnormal in adults. The CSF cell profiles in neonates and children are discussed separately. (See "Bacterial meningitis in the neonate: Clinical features and diagnosis", section on 'Cell count' and "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Interpretation'.)
The CSF cell count determination should be performed promptly since the count may be falsely low if measured more than 60 minutes after the LP is performed. This spuriously low cell count may be due to settling of the cells in the CSF over time and/or adherence of RBCs or PMNs to plastic tubes.
Pleocytosis — An elevated CSF WBC concentration does not diagnose an infection, since increases in the CSF WBC concentration can occur in infectious and noninfectious inflammatory states. The following truisms about the interpretation of CSF cell counts may be useful:
●The CSF cell count must always be correlated with clinical findings. PMNs, for example, predominate in the CSF of as many as two-thirds of patients with meningitis due to enteroviruses; a shift to lymphocytic predominance usually occurs within 12 to 24 hours [24,25]. On the other hand, lymphocytes rarely predominate in the early phases of bacterial meningitis. (See "Aseptic meningitis in adults" and 'CSF in CNS infection' below.)
●The presence of eosinophils in the CSF has limited diagnostic utility. CSF eosinophilia may occur in parasitic infestations but also in infections due to other microorganisms, including Mycobacterium tuberculosis, Mycoplasma pneumoniae, Rickettsia rickettsii, some fungi, and in noninfectious conditions, such as lymphomas, leukemias of various types, subarachnoid hemorrhage, and obstructive hydrocephalus.
Predicted WBC count after traumatic tap — Accidental trauma to a capillary or venule may occur during performance of an LP, increasing the number of both RBCs and WBCs in the CSF. If a traumatic lumbar puncture is suspected and the peripheral WBC count is not abnormally low or high, a good rule of thumb for estimating the adjusted WBC count is to subtract 1 WBC for every 500 to 1500 RBCs measured in the CSF. The formula in the following Calculator can also be used to determine the adjusted WBC count in the presence of CSF RBCs (calculator 1) [26,27]. The interpretation of CSF pleocytosis in the setting of bacterial meningitis is discussed in detail separately.
The presence or absence of otherwise unexplained xanthochromia also may help distinguish a traumatic tap from subarachnoid hemorrhage as long as the LP is performed at least six hours after the onset of headache. (See 'Xanthochromia' above.)
Interpretation of traumatic LPs in children is discussed separately. (See "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Interpretation'.)
Chemical composition — Determination of CSF protein and glucose concentrations are routinely done and may reveal useful clinical information.
Protein — Proteins are largely excluded from the CSF by the blood-CSF barrier. Proteins gaining access to the CSF primarily reach the CSF by transport within pinocytotic vesicles traversing capillary endothelial cells. The normal CSF protein concentration ranges from 23 to 38 mg/dL (0.23 to 0.38 g/L) in adults ; in one report, the extreme upper and lower CSF protein concentrations in normal individuals were 58 and 9 mg/dL (0.58 and 0.09 g/L), respectively . CSF protein concentrations in premature and term neonates normally range between 20 and 170 mg/dL (0.2 and 1.7 g/L) . The CSF protein concentration may be mildly elevated in patients with diabetes mellitus.
CSF protein can also be elevated by a subarachnoid hemorrhage or a traumatic LP. The presence of CSF bleeding results in approximately 1 mg of protein/dL per 1000 RBCs/microL. When assessing the potential effect of CSF bleeding on an elevated CSF protein concentration, the CSF protein concentration and RBC count should be performed on the same tube of CSF.
Elevations in the CSF protein concentration can occur in both infectious and noninfectious conditions, including conditions associated with obstruction of CSF flow.
CSF protein elevations may persist for weeks or months following recovery from meningitis and have little utility in assessing cure or the response to therapy . (See 'CSF in CNS infection' below.)
Immunoglobulins and oligoclonal bands — Immunoglobulins are almost totally excluded from the CSF in healthy individuals. The blood to CSF ratio of IgG is normally 500:1 or more. Elevations in oligoclonally expanded immunoglobulin concentrations in the CSF, termed oligoclonal bands, may occur in any disorder that disrupts the blood-brain barrier. Oligoclonal bands may also be caused by intrathecal production of IgG, and the presence of such bands is a diagnostic criterion for multiple sclerosis . Examples of other diseases that can cause oligoclonal bands in the CSF include infections (eg, nervous system Lyme disease), autoimmune diseases, brain tumors, and lymphoproliferative diseases. Given how many diseases can result in oligoclonal bands in the CSF, the diagnostic utility of this finding is limited. (See "Nervous system Lyme disease", section on 'Cerebrospinal fluid analysis' and "Evaluation and diagnosis of multiple sclerosis in adults", section on 'CSF analysis and oligoclonal bands'.)
Glucose — Low CSF glucose concentration (hypoglycorrhachia) may occur in a variety of infectious and noninfectious pathologic conditions. Elevated CSF glucose concentrations only occur in the setting of hyperglycemia.
●CSF glucose concentrations less than 18 mg/dL (1.0 mmol/L) are strongly predictive of bacterial meningitis . Abnormally low CSF glucose concentrations can also occur in mycobacterial, mycoplasmal (M. pneumoniae), treponemal, and fungal CNS infections (table 1). During recovery from meningitis, CSF glucose concentration tends to normalize more rapidly than the CSF cell count and protein concentration. (See 'CSF in CNS infection' below.)
In contrast, the CSF glucose concentration is typically normal during most viral CNS infections, although low concentrations have been reported in patients with meningoencephalitis due to mumps, enteroviruses, lymphocytic choriomeningitis (LCM), herpes simplex, and herpes zoster viruses.
●Low CSF glucose concentrations can also occur in noninfectious conditions; patients with leptomeningeal carcinomatosis, leukemia, CNS lymphoma, severe subarachnoid hemorrhages, or neurosarcoidosis may have hypoglycorrhachia because of cellular or inflammatory infiltrates that disrupt the active transport of glucose into the CSF (table 1) . Salicylate poisoning has been reported to cause low CSF glucose concentration, but this has not been well-documented, and this association is speculative [32-34].
Also, hypoglycemic patients who present with CNS symptoms may have low CSF glucose concentrations. (See "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, causes, and diagnosis".)
In the setting of hyperglycemia, a low CSF glucose may not be recognized if only the absolute CSF glucose concentration is considered. The normal CSF-to-serum glucose ratio ranges from 0.5 to 0.8 [35-37], and shows large hourly diurnal variations related to timing of food intake . Attempts to "correct" the CSF glucose concentration for hyperglycemia should take into account the fact that it takes several hours for the serum glucose to equilibrate with the CSF glucose; thus the timing of the last meal and/or administration of insulin or oral hypoglycemic may be relevant . Other considerations include that CSF-to-serum glucose ratios in neonates are highly variable and also that ventricular CSF glucose concentration is 6 to 18 mg/dL (0.33 to 1.0 mmol/L) higher than in the lumbar CSF . In addition, CSF glucose levels rarely exceed 300 mg/dL (16.7 mmol/L) even in patients with severe hyperglycemia.
Lactate — Determination of the CSF lactate concentration has been suggested as a useful test to differentiate bacterial from viral meningitis. Two meta-analyses that included 25 studies (1692 patients) and 31 studies (1885 patients) concluded that the diagnostic accuracy of CSF lactate was superior to that of CSF white blood cell count, glucose, and protein concentration in differentiating bacterial from aseptic meningitis [40,41], although sensitivity was lower in patients who received antimicrobial treatment prior to lumbar puncture , and CSF lactate may be elevated in patients with other CNS diseases [42-45].
Cytology — Cytology is occasionally useful for the diagnosis of malignancy involving the CNS . In such instances, at least 10 to 15 mL of fluid should be sent to the pathology laboratory for prompt examination. Cytology should be performed within one hour of collection in specialized laboratories with experienced staff .
CSF IN CNS INFECTION — Chemical analysis and Gram stain of the cerebrospinal fluid (CSF) are an integral part of the evaluation of patients with suspected meningitis or encephalitis. Although there is overlap, there are broad general differences between the findings in bacterial and viral infections (table 2). (See "Clinical features and diagnosis of acute bacterial meningitis in adults" and "Viral encephalitis in adults" and "Aseptic meningitis in adults".)
Among patients with viral meningitis, the typical findings include:
●The CSF white blood cell (WBC) count is usually less than 250/microL and almost always less than 2000/microL . The differential typically shows a predominance of lymphocytes, although early infection may reveal a predominance of neutrophils that, within the next 24 hours, generally shows a shift from neutrophils to lymphocytes .
●The CSF protein concentration is typically less than 150 mg/dL; it has been estimated that CSF protein concentrations greater than 220 mg/dL reduce the probability of viral infection to 1 percent or less .
●The CSF glucose concentration is usually more than 50 percent of serum concentration, but moderately reduced values are occasionally seen with herpes simplex virus (HSV), mumps, some enteroviruses, and lymphocytic choriomeningitis virus.
Among patients with bacterial meningitis, the classic findings are (table 2):
●A CSF WBC count above 1000/microL, usually with a neutrophilic predominance
●A CSF protein concentration above 250 mg/dL
●A CSF glucose concentration below 45 mg/dL (2.5 mmol/L)
However, the spectrum of CSF values in bacterial meningitis is so wide that there is substantial overlap with the findings in viral infection (table 2). This was illustrated in a review of 296 episodes of community-acquired bacterial meningitis: 50 percent had a CSF glucose above 40 mg/dL (2.2 mmol/L), 44 percent had a CSF protein below 200 mg/dL, and 13 percent had a CSF white cell count below 100/microL . (See "Clinical features and diagnosis of acute bacterial meningitis in adults", section on 'Cerebrospinal fluid analysis'.)
●Cerebrospinal fluid pressure – The normal cerebrospinal fluid (CSF) pressure is 6 to 20 cmH2O; patients with obesity may have CSF pressures up to 25 cmH2O. (See 'Physiology of CSF formation and flow' above.)
Infection, bleeding, or a tumor can alter the balance between CSF secretion and reabsorption, resulting in intracranial hypertension. The normal CSF pressure as measured with a manometer in a patient lying flat in the lateral decubitus position with the legs extended is between 6 and 25 cmH2O; however, some experts consider the upper limit of normal CSF pressure to be 20 cmH2O. (See 'Physiology of CSF formation and flow' above and 'CSF pressure' above.)
●Cerebrospinal fluid color – Normal CSF is clear and colorless. Xanthochromia, a yellow or pink discoloration of the CSF, most often indicates the presence of hemoglobin degradation products due to recent hemorrhage.
Other causes of xanthochromia include increased CSF concentrations of protein (≥150 mg/dL) and systemic hyperbilirubinemia (serum bilirubin >10 to 15 mg/dL). (See 'Xanthochromia' above.)
●Cells in the cerebrospinal fluid – The CSF is normally acellular, although up to 5 white blood cells (WBCs) and 5 red blood cells (RBCs) are considered normal in adults when the CSF is sampled by lumbar puncture (LP). Newborns may have up to 20 WBCs/microL in the CSF. (See 'Normal findings' above.)
An elevated CSF WBC concentration does not diagnose an infection; increases in the CSF WBC concentration can occur in a variety of both infectious and noninfectious inflammatory states. (See 'Pleocytosis' above.)
●Cerebrospinal fluid chemistry – The two major tests performed in the chemistry laboratory on CSF are determination of protein and glucose concentrations. (See 'Chemical composition' above.)
●Central nervous system infection – Cell count and differential, chemical analysis, and Gram stain of the CSF are essential to evaluate patients with suspected meningitis or encephalitis. Although there is overlap, there are broad general differences between the findings in bacterial and viral infections (table 2). (See 'CSF in CNS infection' above.)
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