Version August 2024
INTRODUCTION — Examination of the cerebrospinal fluid (CSF) provides important diagnostic information in many infectious and noninfectious medical conditions of the nervous system. Understanding the physiology of CSF production and flow and the composition of CSF aids in both evaluation and diagnosis and can guide therapy.
This topic will review the physiology and composition of CSF in normal and common disease states. The technique for obtaining CSF via lumbar puncture, including the contraindications and complications to this test, are discussed separately. (See "Lumbar puncture: Technique, contraindications, and complications in adults".)
CSF PHYSIOLOGY
Circulation — CSF is produced continuously within the choroid plexus and circulates throughout the intracranial ventricular system as well as the cranial and spinal subarachnoid spaces before being resorbed into venous system via the arachnoid villi (figure 1) [1].
●Production at the choroid plexus — CSF is produced by the choroid plexus in the lateral, third, and fourth ventricles; it is formed by both filtration and active transport. 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.
●CSF flow — 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.
●Resorption
•Arachnoid villi – CSF is absorbed in the arachnoid villi, located along the superior sagittal and intracranial venous sinuses and around the spinal nerve roots. Arachnoid villi and venous sinuses are separated by endothelial cells connected by tight junctions (figure 1). Each arachnoid villus functions as a one-way valve permitting unidirectional flow of CSF into the blood via transport within giant vesicles. Arachnoid villi normally allow the passage of particles less than 7.5 microns in diameter from the CSF into the blood. These vesicles may become obstructed by bacteria or cells as a result of an inflammatory process or by red blood cells during subarachnoid hemorrhage.
Molecules or drugs that are lipid soluble readily diffuse across the vascular endothelium and epithelium of the choroid plexus into the interstitial fluid and CSF. By contrast, ionically charged molecules generally require active transport for entry into the CSF. Drug entry may be altered in patients with meningitis by the accompanying inflammation, and this may subsequently rapidly change with regression of inflammation with therapy. (See 'Central nervous system infection' below.)
•Glymphatic and other perivascular pathways – In addition to well-described transport mechanisms in the arachnoid villi, newer studies have documented the existence of dural and other pathways involved in the movement of CSF and solutes throughout the central nervous system (CNS) [2]. The finding of dura-associated lymphatic vessels is contrary to long-held beliefs about the absence of meningeal lymphatics. CSF outflow also occurs along these dural blood vessels as well as via spinal and cranial nerves into the skull bone marrow. These perivascular pathways support the clearance of solutes from the brain to both the CSF and extra-axial meningeal lymphatic vessels [3]. CSF outflow into bone marrow also stimulates hematopoiesis in the cranial bone marrow that secondarily leads to ingress of leukocytes into the meninges [4]. The precise role of these perivascular pathways, however, in the clearance of interstitial and CSF solutes has not yet been fully elucidated.
CSF volume and pressure — In normal adults, the CSF volume is 90 to 200 mL [5]. 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 [6].
CSF secretion and reabsorption remain in balance in most healthy individuals to maintain a CSF pressure less than 15 cm H2O. 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 cm H2O [7]; however, some experts consider the upper limit of normal CSF pressure to be 20 cm H2O [8]. Patients with obesity tend to have higher opening pressures, but studies assessing the correlation between opening pressure and body mass index report conflicting results [7,9]. A variety of factors, such as the patient’s age, body position, the presence of positive pressure ventilation, the skill of the person performing the lumbar puncture, and the patient’s degree of relaxation can affect the measurement of the opening pressure. (See "Lumbar puncture: Technique, contraindications, and complications in adults", section on 'Technique'.)
Pathologic processes, such as infection, bleeding, or neoplasm, can alter CSF flow dynamics or the balance between CSF production and reabsorption and may cause hydrocephalus and/or 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 or CSF flow is completely obstructed. By 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 from cerebral edema. (See 'Intracranial hypertension or hypotension' below.)
Blood-brain barrier — The term "blood-brain barrier" is a term used to describe cellular structural systems that separate the brain and the CSF from the blood. These systems help to maintain homeostasis and avoid infection within the CNS by preventing simple diffusion of fluids, electrolytes, and other substances from blood into the CSF or brain [10]. There are actually two barriers: a blood-brain barrier and a blood-CSF barrier, which are not equivalent [10]. Both barriers separate the CNS from systemic immune responses and affect the composition of the brain interstitial fluid and CSF (figure 2).
●Blood-brain barrier — The blood-brain barrier is situated between cerebral blood vessels and neuronal and glial tissue. 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. It regulates the content of brain interstitial fluid and has a 5000-fold greater surface area than the blood-CSF barrier [10].
Lipid-soluble small molecules with a molecular mass less than 400 to 600 daltons are transported readily through the blood-brain barrier. By contrast, many drugs and other larger molecules cannot cross this barrier system [11].
●Blood-CSF barrier — The blood-CSF barrier is located between cerebral blood vessels and ventricular or other CSF spaces. The blood-CSF barrier is formed by tight junctions between choroid epithelial cells. It helps to regulate the composition of the CSF, which is primarily dependent upon secretion in the choroid plexus [12].
Both barrier systems are dynamic. Endothelial cells and astrocytes that compose the blood-brain barrier and cells forming the blood-CSF barrier produce cytokines such as tumor necrosis factor and interleukins [13]. 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 mediates or generates 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 [14]. These astrocytes are separated by gap junctions that affect the movement of constituents from the CSF into the brain.
COMPOSITION OF THE CSF — Chemical and microscopic analysis of CSF constituents include protein, glucose, and sometimes infectious, inflammatory, or neoplastic cells, which can aid in the diagnosis or exclusion of many central nervous system (CNS) conditions.
Color
Normal findings — Normal CSF is clear and colorless. However, 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 [8].
Xanthochromia — RBCs rapidly lyse after entry into CSF. Xanthochromia (a yellow or pink discoloration of the CSF supernatant after centrifugation) is caused by the breakdown of hemoglobin first to oxyhemoglobin (pink) and later to bilirubin (yellow). Although xanthochromia is generally identified visually [15], laboratory analysis with spectrophotometry may be more sensitive [16-18]. Spectrophotometry can be used to analyze blood breakdown products as they progress from oxyhemoglobin to methemoglobin and finally to bilirubin.
●Role in assessing subarachnoid hemorrhage – The presence of xanthochromia can help distinguish a subarachnoid hemorrhage from a traumatic tap [16,19,20]. Xanthochromia can be detected as soon as two hours after RBCs have entered the subarachnoid space, and therefore this is often used to diagnose subarachnoid hemorrhage. By contrast, xanthochromia should not be present in acute bleeding due to a traumatic tap. 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 [16,21-23]. The detection of xanthochromia in subarachnoid hemorrhage is discussed separately. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Findings in SAH'.)
●Nonhemorrhagic causes – Xanthochromia can also be seen in the setting of nonhemorrhagic causes such as increased CSF concentrations of protein (≥150 mg/dL) or systemic hyperbilirubinemia (serum bilirubin >10 to 15 mg/dL) [8].
Cell counts
Normal cell counts — The CSF is normally acellular. However, up to five WBCs and five RBCs are considered normal in adults when the CSF is sampled by nontraumatic lumbar puncture (LP) [24]. More than three polymorphonuclear leukocytes (PMNs)/microL is abnormal in adults.
Higher cell counts may be regarded as normal in infants and young children. The CSF cell profiles in neonates and children are discussed separately. (See "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Interpretation of CSF parameters' and "Bacterial meningitis in the neonate: Clinical features and diagnosis", section on 'Interpretation of CSF parameters'.)
The CSF cell count determination should be performed promptly after collection 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.
[23,25]
WBC pleocytosis — CSF pleocytosis, or increases in the CSF WBC concentration, can occur in both infectious and noninfectious inflammatory states. A CSF pleocytosis is a somewhat nonspecific finding, so the numerical count and types of WBCs in the CSF must be correlated with other diagnostic tests (eg, Gram stain) and/or with clinical findings such as the presence of fever or meningismus. (See 'CSF in disease states' below.)
A WBC pleocytosis may also be seen in the setting of a traumatic LP. 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 LP is suspected, and the peripheral WBC count is not abnormally low or high, the formula in the following calculator can be used to determine the adjusted WBC count in the presence of CSF RBCs (calculator 1) [26,27]. Another strategy for estimating the adjusted WBC count is to subtract 1 WBC for every 500 to 1500 RBCs measured in the CSF.
Other CSF findings in traumatic taps are discussed below. (See 'Elevated RBC count' below.)
Elevated RBC count — The presence of RBCs in a CSF sample indicates recent bleeding. Intra-axial bleeding, such as from an acute subarachnoid hemorrhage, is an important pathologic cause of an elevated CSF RBC count. Alternatively, needle trauma during LP frequently causes a "traumatic tap" and introduces blood into the CSF. Some infections (eg, herpes simplex meningoencephalitis) and other hemorrhagic intra-axial lesions may also result in bleeding into the CSF.
Pathologic hemorrhagic conditions must be distinguished from a traumatic tap. Findings suggestive of acute subarachnoid hemorrhage or other intra-axial source of bleeding include:
●Elevated RBC count (eg, >2000 cells/microL)
●No substantial clearance of RBC counts from CSF tube 1 to tube 4
●Xanthochromia (see 'Xanthochromia' above)
●Opening pressure elevation (>20 cm H20)
The CSF diagnosis of subarachnoid hemorrhage is discussed in greater detail separately. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Findings in SAH'.)
Cytology — Cytologic examination and flow cytometry are performed to identify malignancy involving the CNS (picture 1) when the cause of a CSF pleocytosis is uncertain or when a CNS malignancy is suspected clinically [28]. In such instances, at least 10 to 15 mL of fluid should be sent to the pathology laboratory for prompt examination. Cytology should ideally be performed within one hour of collection in specialized laboratories with experienced staff [24].
Repeat testing may be warranted when initial results are negative when clinical suspicion for malignancy is high. The specificity of CSF cytology for malignancy can approach 100 percent, but sensitivity is lower. False negatives have been associated with low-volume CSF samples, delays in processing, and single CSF samples assessed [29].
Cytologic examination of CSF for the diagnosis of tumors of the CSF is discussed in greater detail in separate topic reviews:
●(See "Clinical features and diagnosis of leptomeningeal disease from solid tumors", section on 'Cytology'.)
Cellular analysis to assess for bacterial or fungal infections in the CSF, including histology and cell culture, is discussed below. (See 'Central nervous system infection' below.)
Chemical composition — Chemical constituents of CSF commonly assessed include protein level and glucose concentration. Patterns of abnormal protein and/or glucose levels are associated with specific disease states. Specialized testing to identify specific proteins or other chemical constituents may be performed in selected patients for confirmatory testing.
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 or disruption of the blood-CSF barrier in pathologic processes.
Normal protein levels — The normal CSF total protein concentration ranges from 23 to 38 mg/dL (0.23 to 0.38 g/L) in adults [8]. The extreme lower and upper CSF protein concentrations in normal individuals have been reported as 9 to 93 mg/dL (0.09 to 0.93 g/L) [23,25]. Higher CSF protein concentrations are associated with older age, male sex, diabetes mellitus, spinal stenosis, and arterial hypertension [25].
CSF protein concentrations in premature and term neonates normally range between 20 and 170 mg/dL (0.2 and 1.7 g/L) [30].
Elevations of total protein — Elevations in the CSF protein concentration can occur in many conditions including infectious and noninfectious conditions and those associated with obstruction of CSF flow. (See 'Tumors and other structural conditions' below.)
CSF protein can also be elevated due to bleeding, such as 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.
In some cases, the presence of an isolated elevation of the CSF protein is nonspecific and does not necessarily indicate a pathologic process is present.
Immunoglobulins and oligoclonal bands — Immunoglobulins are typically assessed in the CSF to identify inflammatory conditions. In healthy persons, immunoglobulins are present in peripheral blood but are almost totally excluded from the CSF in healthy individuals (the blood to CSF ratio of immunoglobulin G [IgG] is normally 500:1 or more).
The presence of CSF immunoglobulins is assessed by calculating the IgG index and/or identifying CSF oligoclonal bands.
●IgG index – The IgG index is a rapid quantitative measurement of intrathecal IgG synthesis that can be used to support the diagnosis of an inflammatory disorder of the CNS [31,32]. It is calculated by dividing the CSF/serum IgG ratio by the CSF/albumin ratio. An IgG index >0.7 is supportive of independent intrathecal production of immunoglobulin [33].
●Oligoclonal bands – Oligoclonal bands refer to elevations in a limited number of immunoglobulin classes within the CSF. Oligoclonal bands may occur in any disorder that either disrupts the blood-brain barrier or causes intrathecal production of IgG.
Neuroinflammatory conditions such as multiple sclerosis commonly feature oligoclonal bands in CSF analysis. (See "Evaluation and diagnosis of multiple sclerosis in adults", section on 'CSF analysis and oligoclonal bands'.)
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. However, the diagnostic specificity of this finding alone is limited because many diseases can result in oligoclonal bands in the CSF.
Other structural proteins — Several infectious, inflammatory, or paraneoplastic antibodies may also be identified in CSF analysis to aid with diagnosis. Specific testing varies by clinical features and results of initial diagnostic testing. Examples of CSF antibodies include:
●Treponemal and nontreponemal tests for syphilis (see "Neurosyphilis", section on 'Spinal fluid examination')
●Autoantibody testing in multiple sclerosis (see "Evaluation and diagnosis of multiple sclerosis in adults", section on 'Autoantibody testing')
●Autoimmune encephalitis antibodies (table 1) (see "Overview of paraneoplastic syndromes of the nervous system", section on 'Antibody screening')
In addition, several CNS proteins may be identified in some traumatic, neuroinflammatory, or neurodegenerative conditions. Common CNS proteins that may be found in the CSF in some conditions include:
●Tau protein
●14-3-3 protein
●Real-time quaking-induced conversion (RT-QulC)
●s100b
●Neuron-specific enolase
Beta-trace protein — Beta-trace protein and related proteins such as beta-2 transferrin are CSF-specific proteins that may be assessed in patients with clear otorrhea or rhinorrhea to identify a CSF leak. (See "Cranial cerebrospinal fluid leaks", section on 'CSF-specific proteins'.)
Glucose — Glucose is present in the CSF at a concentration related to serum glucose concentration. Pathologic processes such as bacterial meningitis may cause abnormal reductions in CSF glucose levels.
Normal glucose levels — Typical normal CSF glucose levels in adults are reported to be 45 to 80 mg/dL (2.5 to 4.4 mmol/L) [34]. However, the CSF glucose level varies with serum glucose and shows large hourly diurnal variations related to food intake [35]. The normal CSF-to-serum glucose ratio ranges from 0.5 to 0.8 [36-38].
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 [39].
Hypoglycorrhachia — Low CSF glucose concentration (hypoglycorrhachia) may occur in a variety of infectious and noninfectious pathologic conditions.
●CSF glucose concentrations less than 18 mg/dL (1.0 mmol/L) are strongly predictive of bacterial meningitis [40]. Abnormally low CSF glucose concentrations can also occur in mycobacterial, mycoplasmal (M. pneumoniae), treponemal, and fungal CNS infections (table 2). During recovery from meningitis, CSF glucose concentration tends to normalize more rapidly than the CSF cell count and protein concentration. (See 'Central nervous system infection' below.)
By contrast, the CSF glucose concentration is typically normal during viral CNS infections, although low concentrations have been reported in patients with some forms of viral meningoencephalitis. (See 'Central nervous system infection' below.)
●Low CSF glucose concentrations can also occur in noninfectious conditions including leptomeningeal carcinomatosis, leukemia, CNS lymphoma, severe subarachnoid hemorrhages, and neurosarcoidosis [41-44]. Hypoglycorrhachia occurs in these conditions because of cellular or inflammatory infiltrates that disrupt the active transport of glucose into the CSF (table 2) [45].
Salicylate poisoning has also been reported to cause low CSF glucose concentration, but this has not been well-documented, and this association is speculative [46-48].
In the setting of systemic hyperglycemia, CSF glucose should also be elevated. The finding of a "normal" absolute CSF glucose concentration may constitute hypoglycorrhachia when CSF glucose is less than 50 percent of serum glucose (normal CSF-to-serum glucose concentration ranges from 0.5 to 0.8).
Elevated CSF glucose — Elevated CSF glucose concentrations only occur in the setting of hyperglycemia. 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 [35].
CSF glucose levels rarely exceed 300 mg/dL (16.7 mmol/L), even in patients with severe hyperglycemia.
Lactate — CSF lactate concentration may be elevated in several conditions such as infectious meningitis, subarachnoid hemorrhage, and hypoxic-ischemic cerebral injury [49-52].
Normal CSF lactate levels are 16 to 49 mg/dL (0.9 to 2.7 mmol/L), but specific thresholds may vary somewhat by laboratory [38].
CSF lactate has been suggested as a useful test to differentiate acute bacterial from viral meningitis. Lactate is often elevated in acute untreated bacterial meningitis (>6 mmol/L) and normal in viral meningitis (<2 mmol/L) [53]. Two meta-analyses that included 25 studies (1692 patients) and 31 studies (1885 patients) assessing differentiating features in bacterial and aseptic meningitis concluded that the diagnostic accuracy of CSF lactate was excellent (area under the curve 0.98), superior to that of CSF WBC count, glucose, and protein concentration [54,55], although sensitivity was lower in patients who received antimicrobial treatment prior to LP [55].
CSF IN DISEASE STATES
Central nervous system infection — Elevated white blood cells (WBCs) in the CSF raises suspicion for an infectious process. Polymorphonuclear neutrophils (PMNs) predominate early in the CSF of patients with infectious meningitis. PMNs are found in as many as two-thirds of patients with meningitis due to enteroviruses; a shift to lymphocytic predominance usually occurs within 12 to 24 hours [56,57]. Lymphocytes rarely predominate in the early phases of untreated bacterial meningitis. (See "Aseptic meningitis in adults".)
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, selected autoimmune conditions, subarachnoid hemorrhage, obstructive hydrocephalus, and chemical meningitis.
CSF findings seen in central nervous system (CNS) meningeal infections depend upon the specific condition:
●Acute bacterial meningitis – The classic CSF findings in bacterial meningitis are:
•Elevated WBC count >1000/microL, usually with a neutrophilic predominance;
•Elevated protein >250 mg/dL;
•Low glucose <45 mg/dL (2.5 mmol/L).
Opening pressure may also be elevated (>20 cm H2O) in bacterial meningitis.
●Acute viral meningitis – Typical CSF findings include [40]:
•Elevated WBC count <250/microL (and almost always <2000/microL), usually with a lymphocytic predominance;
•Elevated protein <150 mg/dL (and almost always <220 mg/dL);
•Normal or modestly low glucose typically >50 percent of serum glucose. However, moderately reduced values are occasionally seen with mumps, enteroviruses, lymphocytic choriomeningitis (LCM), herpes simplex, and herpes zoster viruses [58-62].
(See "Aseptic meningitis in adults", section on 'Cerebrospinal fluid'.)
●Fungal meningitis – CSF findings in fungal meningitis are variable: in some cases, the chemical and cellular findings resemble that of bacterial meningitis; in other cases, only modest elevations in WBC count and protein occur, and the CSF glucose concentration is normal [63]. (See "Candida infections of the central nervous system", section on 'CSF analysis' and "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in patients without HIV", section on 'Cerebrospinal fluid'.)
●Viral encephalitis – CSF findings in viral encephalitis are often similar to those of viral meningitis, especially when the infection is present in both CNS regions (ie, meningoencephalitis). However, the CSF abnormalities can vary widely in patients with viral encephalitis depending on the causative virus, as well as the severity and the duration of illness. In some cases, the CSF white cell count may be only mildly elevated or even normal [64-66]. (See "Viral encephalitis in adults", section on 'Cerebrospinal fluid findings'.)
Chemical analysis and culturing of the CSF are also an integral part of the evaluation of patients with suspected meningitis or encephalitis. Gram stain (picture 2 and picture 3 and picture 4 and picture 5 and picture 6) and cell culture can help identify the causal agent for bacterial and fungal infections. (See "Clinical features and diagnosis of acute bacterial meningitis in adults" and "Viral encephalitis in adults" and "Aseptic meningitis in adults".)
Autoimmune and inflammatory conditions — CSF analysis may help identify several CNS noninfectious autoimmune and inflammatory conditions and systemic conditions that can cause CNS complications.
●Multiple sclerosis – CSF findings in the evaluation of patients with multiple sclerosis often show modestly elevated WBC counts (<50 cells/microL) with a lymphocytic predominance. Protein and glucose concentrations are typically normal. Oligoclonal bands and elevated IgG index are found in most patients with multiple sclerosis. (See "Evaluation and diagnosis of multiple sclerosis in adults", section on 'CSF analysis and oligoclonal bands'.)
●Other primary CNS inflammatory disorders – A pattern of elevated protein with an elevated WBC count is common in several other CNS inflammatory disorders. Specific findings may help distinguish these disorders from multiple sclerosis and other disorders. However, there is considerable variability in CSF findings.
•Transverse myelitis – Some patients have elevated CSF protein and a lymphocytic WBC pleocytosis, while others have mild and nonspecific findings. Glucose concentration is typically normal. (See "Transverse myelitis: Etiology, clinical features, and diagnosis", section on 'Lumbar puncture'.)
•Neuromyelitis optica spectrum disorder (NMOSD) – Elevated protein concentration may be found along with a WBC pleocytosis that may have a neutrophilic predominance. WBC counts may be >50 cells/microL during acute attacks. (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis", section on 'Cerebrospinal fluid'.)
•Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) – Protein concentrations may be normal or modestly elevated; WBC lymphocytic pleocytosis is common. (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis", section on 'Cerebrospinal fluid'.)
•Acute disseminated encephalomyelitis (ADEM) – Protein concentrations may be normal or slightly elevated; WBC pleocytosis typically <100 cells/microL may be present. (See "Acute disseminated encephalomyelitis (ADEM) in adults", section on 'CSF analysis'.)
●Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy – The characteristic CSF pattern in these conditions is an elevated protein with a normal WBC count, commonly called an albuminocytologic dissociation. Protein levels may be normal or modestly elevated in the first week after symptom onset and increase to 200 mg/dL in the following two to three weeks. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis", section on 'Cerebrospinal fluid analysis' and "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis", section on 'Lumbar puncture'.)
●Syndrome of headache and neurologic deficits with CSF lymphocytosis (HaNDL) – The HaNDL syndrome is characterized by a lymphocytic WBC pleocytosis on CSF analysis. WBC count may be >100 cells/microL. Protein concentration may be elevated, but glucose levels are normal, and cultures must be negative. CSF opening pressure assessed during lumbar puncture (LP) may also be elevated. (See "Syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL)", section on 'Lumbar puncture'.)
●Systemic inflammatory conditions – CSF abnormalities are also commonly found in patients with neurologic features of some systemic inflammatory conditions such as sarcoidosis and Behcet syndrome. A nonspecific inflammatory pattern may be present including a WBC pleocytosis; protein and glucose concentrations are variable. (See "Neurologic sarcoidosis", section on 'Lumbar puncture' and "Clinical manifestations and diagnosis of Behçet syndrome", section on 'Neurologic disease' and "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus".)
Intracranial hypertension or hypotension — Conditions characterized by abnormal (high or low) intracranial pressure often feature a normal CSF composition unless due to a secondary (underlying) cause. As an example, CSF protein and cell counts are typically normal in patients with idiopathic intracranial hypertension but may be elevated in those with intracranial hypertension due to subarachnoid hemorrhage.
●Idiopathic intracranial hypertension (pseudotumor cerebri) – Intracranial pressure is elevated >20 cm H20, and CSF chemical composition is normal. (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis", section on 'Lumbar puncture'.)
●Obstructive hydrocephalus – Mass lesions that impair CSF circulation can lead to obstructive hydrocephalus that may cause progressive neurologic dysfunction. Hydrocephalus is typically identified on neuroimaging. LP is contraindicated in patients with obstructive hydrocephalus, but CSF analysis may be performed as a part of diagnostic or therapeutic ventriculostomy. In this setting, CSF findings include elevated pressures. CSF composition is variable depending on underlying cause. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'ICP monitoring'.)
●Meningitis/encephalitis – Increased intracranial pressure can be associated with infectious etiologies such bacterial meningitis and cryptococcal meningitis. Infection can alter the balance between CSF production and reabsorption and have potential to cause hydrocephalus and/or intracranial hypertension. In some cases (eg, severe cryptococcal meningitis), a ventriculoperitoneal shunt may be needed. (See "Clinical features and diagnosis of acute bacterial meningitis in adults", section on 'Clinical features' and "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV", section on 'Clinical manifestations'.)
●Intracranial hypotension – Intracranial hypotension can occur spontaneously or as a complication of LP. Intracranial pressure, if assessed, is often low in the acute setting but may be normal for patients with chronic spontaneous intracranial hypotension. CSF composition is typically normal. (See "Post dural puncture headache" and "Lumbar puncture: Technique, contraindications, and complications in adults", section on 'Other syndromes related to intracranial hypotension' and "Spontaneous intracranial hypotension: Pathophysiology, clinical features, and diagnosis", section on 'The role of lumbar puncture'.)
Cerebrovascular disease — CSF analysis is a key component of the diagnosis of acute subarachnoid hemorrhage when head computed tomography (CT) is negative. CSF may be obtained in the evaluation of other cerebrovascular conditions when etiology to presenting symptoms or initial neuroimaging is nondiagnostic unless the presence of a space occupying lesion precludes performing an LP.
●Subarachnoid hemorrhage – Classic CSF findings in acute subarachnoid hemorrhage include elevated pressure, xanthochromia, and highly elevated red blood cell (RBC) counts (eg, >2000 cells/microL). Xanthochromia may not be present until two to four hours after onset of subarachnoid hemorrhage but thereafter typically persists for weeks. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Lumbar puncture for most patients'.)
●Cerebral venous thrombosis – Inflammatory CSF findings in cerebral venous thrombosis are nonspecific and may include elevations of protein concentration as well as both WBC and RBC counts. Elevated pressure may also be documented in some patients with cerebral venous thrombosis due to impaired circulatory outflow. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Lumbar puncture'.)
Tumors and other structural conditions
●Primary or metastatic brain tumors – CSF findings in primary and metastatic brain tumors are often normal or nonspecific unless the leptomeningeal surface or intraventricular space is involved, in which case cytology may be helpful. Elevated intracranial pressure may also be noted in some patients. (See "Uncommon brain tumors", section on 'Choroid plexus tumors'.)
●Meningeal tumors – Leptomeningeal metastases (also called carcinomatous meningitis) may be identified by positive CSF cytology or flow cytometry. Other common CSF findings include an elevated protein concentration, lymphocytic WBC pleocytosis, and low glucose level. Xanthochromia may be present if recent bleeding has occurred or if the protein concentration is >150 mg/dL. The sensitivity of these abnormalities is variable. (See "Clinical features and diagnosis of leptomeningeal disease from solid tumors", section on 'Cerebrospinal fluid'.)
●Froin syndrome from spinal tumors – Spinal neoplasms or other extra-axial lesions such as abscesses that block CSF circulation can produce xanthochromia, dramatically elevated protein concentrations (>500 mg/dL), and hypercoagulated CSF [67-70]. Stagnation of CSF caudal to the spinal site of blockage leads to hyperproteinosis.
Neurodegenerative conditions — CSF composition in several neurodegenerative conditions is often nonspecific and may include modest elevations in protein levels. Specialized assays have been used in research settings or adjunctive diagnostic parameters.
●Prion diseases – Creutzfeldt-Jacob disease and other human prion diseases may feature elevated Tau protein and/or the presence of the 14-3-3 protein or a positive real-time quaking induced conversion test (RT-QuIC). In addition, assays to detect disease-associated prion protein have also been developed. (See "Creutzfeldt-Jakob disease", section on 'Cerebrospinal fluid protein markers'.)
●Alzheimer disease and other dementias – CSF findings in common causes of dementia are typically nonspecific, but elevated Tau protein and low levels of amyloid beta peptides may be found in some patients with Alzheimer disease. (See "Clinical features and diagnosis of Alzheimer disease", section on 'Role of biomarkers'.)
Others — Other conditions that have been associated with abnormal CSF findings include:
Acute seizure – Up to one-third of patients with a seizure may have mild abnormalities in CSF parameters, most typically a mildly elevated protein or lymphocytic WBC pleocytosis [71-73]. CSF lactate may also be elevated, but hypoglycorrhachia is uncommon.
●Medications – Several medications can rarely cause aseptic meningitis. CSF findings classically include an elevated protein concentration with a lymphocytic WBC pleocytosis and normal glucose, although findings may vary. Agents include:
•Nonsteroidal antiinflammatory drugs [74,75]
•Glucocorticoids [74]
•Antimicrobials (eg, trimethoprim-sulfamethoxazole, cephalosporins, amoxicillin) [76-79]
•Monoclonal antibodies (eg, adalimumab, infliximab, ipilimumab) [82-85]
•Antiseizure medications (eg, lamotrigine, carbamazepine) [86-88]
Intrathecal contrast agents and medications delivered into the intrathecal space may also cause a chemical inflammatory response leading to a CSF pleocytosis in some patients [89-92].
●Neurosurgical procedures – Postoperative meningeal inflammation can occur in the weeks following neurosurgical instrumentation and can cause a CSF profile similar to that of bacterial meningitis, including a neutrophilic pleocytosis and hypoglycorrhachia [93]. However, this is a diagnosis of exclusion after infection has been ruled out.
SUMMARY
●CSF physiology – Cerebrospinal fluid (CSF) is produced continuously within the choroid plexus and circulates throughout the intracranial ventricular system as well as the cranial and spinal subarachnoid spaces before being resorbed into venous system via the arachnoid villi (figure 1). (See 'Circulation' above.)
●CSF volume and pressure – The typical CSF volume in adults is 90 to 200 mL. The normal rate of CSF production is approximately 20 mL per hour. 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 20 to 25 cm H2O. (See 'CSF volume and pressure' above.)
●CSF composition
•Color – CSF is typically clear and colorless. 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. RBCs lyse rapidly in CSF, leading to a yellow or pink discoloration of the CSF known as xanthochromia. (See 'Xanthochromia' above.)
•Cells – The CSF is normally acellular. However, up to five WBCs and five RBCs are considered normal in adults when the CSF is sampled by lumbar puncture (LP). More than three polymorphonuclear leukocytes (PMNs)/microL is abnormal in adults. (See 'WBC pleocytosis' above.)
•Cytology – Cytologic examination and flow cytometry are typically used to evaluate for malignancy involving the central nervous system (CNS) (picture 1) and may be performed when the cause of a CSF pleocytosis is uncertain or when a CNS malignancy is suspected clinically (picture 2). (See 'Cytology' above.)
•Chemistry – CSF evaluation commonly includes protein level and glucose concentration. Patterns of abnormal protein and/or glucose levels are associated with specific disease states. Specialized testing to identify specific proteins or other chemical constituents (eg, IgG index or oligoclonal bands) may be performed in selected patients. (See 'Chemical composition' above.)
-Normal CSF total protein concentrations typically range from 23 to 38 mg/dL (0.23 to 0.38 g/L) in adults, although concentrations as high as 93 mg/dL (0.09 to 0.93 g/L) have been reported in some healthy individuals. (See 'Protein' above.)
-Normal CSF glucose levels in adults typically range from 45 to 80 mg/dL (2.5 to 4.4 mmol/L). However, the CSF glucose level varies with serum glucose and can demonstrate large hourly diurnal variations related to food intake. The normal CSF-to-serum glucose ratio ranges from 0.5 to 0.8. (See 'Glucose' above.)
●CSF findings in specific conditions
•CNS infection – CSF evaluation is an integral part of the evaluation of patients with suspected meningitis or encephalitis. Although there is some overlap, specific findings may help differentiate bacterial, viral, and fungal infections. (See 'Central nervous system infection' above.)
•Autoimmune and inflammatory conditions – CSF analysis may help identify several CNS inflammatory conditions such as multiple sclerosis (elevated protein and WBC pleocytosis with oligoclonal bands) and Guillain-Barré syndrome (albuminocytologic dissociation). In addition, CSF pleocytosis may be found in some systemic conditions that can cause CNS complications (eg, neurosarcoidosis). (See 'Autoimmune and inflammatory conditions' above.)
•Intracranial hypertension and hypotension syndromes – Conditions characterized by abnormal (high or low) intracranial pressure often feature a normal CSF composition unless due to the underlying cause (eg, bacterial or fungal meningitis). (See 'Intracranial hypertension or hypotension' above.)
•Cerebrovascular diseases – CSF findings of an elevated RBC count or xanthochromia can be a key component of the diagnosis of acute subarachnoid hemorrhage. Abnormal CSF findings may also be present in other acute cerebrovascular conditions. (See 'Cerebrovascular disease' above.)
•Tumors – Leptomeningeal metastases may be identified by positive CSF cytology or flow cytometry. Other common CSF findings include an elevated protein concentration, lymphocytic WBC pleocytosis, and low glucose level. The sensitivity of these abnormalities is variable. (See 'Tumors and other structural conditions' above.)
CSF findings in primary and metastatic brain tumors are often normal or nonspecific.
•Other conditions – Neurodegenerative conditions such as Alzheimer disease may feature modest elevations in CSF protein levels. Specialized assays have been used in research settings or adjunctive diagnostic parameters. (See 'Neurodegenerative conditions' above.)
Certain medications or acute seizures may produce a mildly elevated protein or lymphocytic WBC pleocytosis. (See 'Others' above.)
ACKNOWLEDGEMENT — The UpToDate editorial staff acknowledges Kimberly S Johnson, MD, who contributed to earlier versions of this topic review.
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