Cerebrospinal Fluid (CSF) Interpretation

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This guide provides a structured approach to cerebrospinal fluid (CSF), including typical CSF results for specific disease processes. Reference ranges vary between labs, so always follow local guidelines.Β 

A lumbar puncture is usually required to obtain a sample of CSF for analysis. The most common indication for a diagnostic lumbar puncture is to investigate cases of suspected CNS infection (e.g. meningitis). CSF interpretation is also used to diagnose important non-infective pathologies, including subarachnoid haemorrhage.


Normal CSF

To understand CSF abnormalities in certain disease states, it is important to understand normal CSF composition.

Normal CSF is acellular. However, up to 5 white blood cells (WBCs) and 5 red blood cells (RBCs) per microlitre (Β΅L) are considered normal after lumbar puncture.

White blood cell analysis in CSF usually separates WBCs into lymphocytes and polymorphonuclear leukocytes (PMNs).

PMNs include neutrophils, eosinophils, basophils and mast cells. In β€˜normal’ CSF, WBCs should be predominantly lymphocytes. The presence of PMNs in the CSF, particularly neutrophils, suggests bacterial meningitis.

The blood-brain barrier is effective against large molecules (e.g. protein) but allows the passage of smaller molecules (e.g. glucose). As such, CSF is generally a low-protein fluid with copious glucose.Β 

Normal CSF ranges (adults)

Appearance: clear and colourless

White blood cells (WBC): 0 – 5 cells/Β΅L, predominantly lymphocytes.

Red blood cells (RBC): 0 – 5/Β΅L

Protein: 0.15 – 0.45 g/L (or <1% of the serum protein concentration)

Glucose: 2.8 – 4.2 mmol/L (or β‰₯ 60% serum glucose concentration)

Opening pressure: 10 – 20 cm H2O

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Meningitis

Meningitis is caused by inflammation of the meninges, usually secondary to viral or bacterial infection.

Viral infection is the most common cause. However, bacterial meningitis carries a much higher morbidity and mortality burden. CSF analysis is a vital investigation to separate bacterial from viral aetiology.

Table 1. CSF findings in bacterial vs viral meningitis

Β  Normal CSF Bacterial meningitis Viral meningitis
Appearance Clear/colourless Cloudy/turbid Usually clear
White blood cells (WBCs) 0-5/Β΅L
Primarily lymphocytes
Elevated, >100/Β΅L
Primarily PMNs
Elevated, >100/Β΅L
Primarily lymphocytes
Protein 0.15-0.45g/L Elevated, >0.5g/L Elevated, >0.5g/L
Glucose 2.8 – 4.2mmol/L
>60% serum glucose
Low
Β <40% serum glucose
Normal >60% serum glucose
Opening pressure 10-20cm H2O Elevated (>25cm H2O) Normal or elevated

Relevant further investigations in suspected meningitis include:2

  • CSF microscopy, gram stain & culture
  • CSF polymerase chain reaction (PCR)
  • Blood cultures
  • Imaging to rule out other intracranial pathology (e.g. CT / MRI head)

Bacterial meningitis

Bacterial meningitis typically presents with headache, fever, neck stiffness and photophobia. A characteristic non-blanching (petechial) rash is often present in meningococcal disease. Patients are often systemically unwell and require urgent treatment with IM/IV antibiotics following local antibiotic guidelines.3

Treatment should not be delayed to obtain CSF analysis. The presence of turbid CSF with high opening pressure, elevated polymorphonuclear leukocytes and low serum glucose is highly suggestive of bacterial infection. Gram stain and CSF culture / bacterial PCR confirm the diagnosis.

Gram staining

The appearance of causative bacterial organisms on Gram stain:3

  • Gram-positive diplococci: pneumococcal infection (Streptococcus pneumoniae)
  • Gram-negative diplococci: meningococcal infection (Neisseria meningitidis)
  • Gram-positive rods / coccobacilli: listerial infection (Listeria meningitidis)

Viral meningitis

Viral meningitis is typically more insidious in onset than bacterial infection but causes similar symptoms (headache, fever, neck stiffness and photophobia). Patients are less likely to be systemically unwell at the time of presentation. The most common causative agents are herpes viruses (HSV / VSV) and enteroviruses.5 Treatment is with an intravenous antiviral agent, most commonly aciclovir.

CSF with a markedly raised lymphocyte count and elevated protein but normal glucose is highly suggestive of viral infection. Diagnosis can be confirmed with a positive CSF viral PCR.

Other causes of meningitis

Rarely, meningitis can be caused by mycobacterial (TB) infection in those with specific epidemiological risk factors, or fungal infection in the severely immunosuppressed. Meningitis can also be non-infective (e.g. in paraneoplastic syndromes).Β 

Tuberculosis meningitis

Tuberculous meningitis should be suspected in those exposed to a patient with pulmonary tuberculosis, or those with known risk factors for TB (e.g. people from areas of high disease prevalence, homelessness, immunosuppression etc).

CSF typically shows high protein, low glucose levels, and elevated WCC with lymphocyte predominance. In early TB meningitis, there may be PMN predominance, and thus CSF analysis can appear very similar to bacterial meningitis. To confirm the diagnosis, CSF is sent for acid-fast-bacilli smear and cultureΒ alongside TB polymerase chain reaction (PCR).

Appearance:Β opaque, if left to settle it forms a fibrin web

Opening pressure:Β elevated

WBC: elevated (typically lymphocyte predominance)

Glucose level: low

Protein level:Β elevated (1-5 g/L)

Fungal meningitis

Fungal meningitis is rare, most commonly seen in cases of profound immunosuppression,Β such as untreated HIV. CSF analysis can vary depending on the pathogen involved, and diagnosis can be confirmed by CSF fungal culture or specific antigen tests (e.g. cryptococcal antigen).

Appearance:Β clear or cloudy

Opening pressure:Β elevated

WBC: elevated (typically more modest elevations seen)

Glucose level:Β low

Protein level:Β elevated


Non-infective CNS pathology

CSF interpretation also plays a key role in many non-infective neurological disorders.

Subarachnoid haemorrhage (SAH)

Appearance: blood-stained initially, with xanthochromia (yellowish) >12 hours later

Opening pressure: elevated

WBC: elevated (WBC to RBC ratio of approximately 1:1000)

RBC: elevated

Glucose level: normal

Protein level: elevated

The classical presentation of subarachnoid haemorrhage is thunderclap headache. Modern CT scans have a sensitivity of over 99% when performed within 6 hours of symptom onset. Sensitivity decreases progressively after this time.7

It is vital not to miss a diagnosis of subarachnoid haemorrhage, as β€˜re-bleeds’ can be devastating. In most cases, they occur secondary to potentially treatable cerebral aneurysms. In cases where clinical suspicion of SAH is high, but CT is not diagnostic, CSF analysis is performed to assess for xanthochromia.

Xanthochromia

Xanthochromia is the yellow discolouration of CSF caused by the presence of bilirubin. A lumbar puncture must be performed >12 hours after symptom onset to assess for xanthochromia. During this time, the red blood cells in the CSF will have been broken down, releasing their oxygen-carrying molecule heme, which is further metabolised by enzymes in the CSF to form bilirubin. The presence of bilirubin and other RBC breakdown products in the CSF is confirmed in the laboratory by spectrophotometry. The presence of xanthochromia is diagnostic of SAH.

Occasionally, a traumatic lumbar puncture (β€˜traumatic tap’) will lead to a high number of RBCs in the CSF. In these cases, the absolute number of RBCs will generally decrease in each bottle of CSF collected (as the RBCs are due to local trauma rather than being present throughout the CSF), and xanthochromia will not be present as the RBCs are yet to be broken down.

Multiple sclerosis (MS)

Appearance: clear

Opening pressure: normal

WBC: 0 – 20 cells/Β΅L (primarily lymphocytes)

Glucose level: normal

Protein level: mildly elevated (0.45 – 0.75 g/L)

CSF electrophoresis: oligoclonal bands present

Multiple sclerosis can present with various neurological deficits and be challenging to diagnose. Oligoclonal bands of immunoglobulin on CSF electrophoresis can be key to diagnosing MS alongside classical MRI findings.

Guillain-BarrΓ© syndrome (GBS)

Appearance: clear

Opening pressure: normal or elevated

WBC: normal

Glucose level: normal

Protein level: markedly elevated (>5.5 g/L)

Guillain-BarrΓ© syndrome is characterised by rapidly progressive ascending weakness. CSF interpretation is usually performed to aid diagnosis and exclude alternate pathologies.

CSF generally shows a normal cell count andΒ raised protein in cases of GBS. However, this may not be seen in the first week of the illness.


CSF interpretation examples

Case 1

A 28-year-old man presents with a 12-hour history of high fever, severe headache, confusion, photophobia and neck stiffness. He has no significant past medical history and takes no regular medication. He is drowsy and looks unwell.Β 

CSF results

Appearance: cloudy

Opening pressure: 30 cm Hβ‚‚O

WBC: 936 cells/Β΅L (>95% PMN cells)

Glucose level: < 40% of serum glucose

Protein level: 3 g/L

The most likely diagnosis is bacterial meningitis. This patient has presented with meningeal symptoms, fever and confusion, which have progressed rapidly over the last 12 hours. The CSF is cloudy on inspection, the white cell count is significantly raised, and glucose levels are low.

The history and CSF results strongly suggest bacterial meningitis, and he should be treated empirically whilst culture results are awaited.

Case 2

A 38-year-old woman presents with 24 hours of headache, photophobia, mild neck stiffness, and coryzal symptoms. She is fully orientated, and her observations are stable.

CSF results

Appearance: clear

Opening pressure: 23 cm Hβ‚‚O

WBC: 150 cells /Β΅L (primarily lymphocytes)

Glucose level: normal

Protein level: 90 mg/dL

The most likely diagnosis is viral meningitis.Β  This patient has presented with a history of meningitic symptoms alongside coryzal symptoms, suggesting a viral illness. The CSF findings are more suggestive of viral meningitis, given the clear appearance of the CSF, the mildly raised WCC (consisting mainly of lymphocytes), raised protein level and normal glucose. Further investigations, including CSF PCR, would be useful in identifying the specific causative virus.

Case 3

A 52-year-old man presents with a sudden onset severe headache. The headache started 14 hours ago. Since the headache, he has felt nauseated. He is otherwise well and fully orientated. Clinical examination is largely unremarkable, but he does appear to have some mild neck stiffness.

CSF results

Appearance: yellowish

Opening pressure: 23 cm Hβ‚‚O

WBC: normal

Red cell count: raised

Glucose level: normal

Protein level: 80 mg/dL

Xanthochromia: positive

The most likely diagnosis is subarachnoid haemorrhage (SAH). The typical history of a sudden severe headache and meningitic symptoms (neck stiffness) strongly suggest SAH. CT head is the first-line investigation, however sensitivity decreases after six hours from symptom onset. As a result, lumbar puncture is used to rule out SAH.

The CSF typically shows a persistently raised red cell count (due to blood in the CSF from the initial bleed). Within several hours, the red blood cells in the cerebrospinal fluid are broken down, releasing their oxygen-carrying molecule heme, which is metabolised by enzymes to bilirubin, a yellow pigment. This yellow pigment can be detected, and its presence is called xanthochromia.


Editor

Dr Chris Jefferies


References

  1. UpToDate. Cerebrospinal fluid: Physiology and utility of an examination in disease states. July 2021. Available at [LINK].
  2. Patient.info Professional. Cerebrospinal Fluid. February 2016. Available at [LINK].
  3. NICE Clinical Knowledge Summaries. Bacterial meningitis and meningococcal disease. July 2020. Available at [LINK].
  4. UpToDate. Clinical features and diagnosis of acute bacterial meningitis in adults. October 2022. Available at [LINK].
  5. UpToDate. Aseptic meningitis in adults. November 2022. Available at [LINK].
  6. UpToDate.Β Tuberculous meningitis: Clinical manifestations and diagnosis.Β April 2023. Available at [LINK].
  7. UpToDate. Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis. September 2022. Available at [LINK].

 

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