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Urinalysis & Body Fluids

Chemical Testing

We have completed our physical examination of the CSF, gathering clues from its color and clarity. Now, we move to the chemical analysis, where we will precisely measure the key solutes within the fluid. This is our direct, quantitative interrogation of the blood-brain barrier’s integrity and the metabolic state of the central nervous system

The fundamental principle to remember is that CSF is a selective ultrafiltrate of plasma, not a simple filtrate. Therefore, disease often manifests in one of two ways:

  1. Barrier Breakdown: The barrier becomes “leaky,” causing the CSF’s chemical composition to become pathologically similar to plasma (e.g., high protein)
  2. Metabolic Changes within the CNS: Processes occurring within the CNS (e.g., infection, malignancy) alter the CSF composition by consuming or producing certain analytes (e.g., consuming glucose, producing lactate)

Our analysis is performed on Tube #1, the tube most likely to be contaminated by a traumatic tap, as these chemical tests are least affected by slight blood contamination compared to cell counts. And for many of these tests, a simultaneously drawn plasma sample is not optional - it is essential for proper interpretation

Core Tests: Protein, Glucose, & Lactate

These three tests form the cornerstone of the CSF chemical workup for nearly every patient

CSF Total Protein

  • Physiology: The blood-brain barrier is highly restrictive to large molecules. As a result, CSF protein concentration is less than 1% of the concentration in plasma. This makes it the most sensitive indicator of the barrier’s integrity
  • Reference Range: 15 - 45 mg/dL (may be slightly higher in infants and the elderly)
  • Methodology: Because the concentration is so low, standard serum protein methods are not sensitive enough. We use specialized methods like turbidimetry (precipitating the protein with an acid) or dye-binding (e.g., Coomassie brilliant blue)
  • Clinical Significance of ELEVATED Protein (Hyperproteinorrhachia): This is the most common and significant abnormal finding
    • Mechanism: Indicates a breakdown of the blood-brain barrier or, less commonly, increased production of protein within the CNS
    • Causes
      • Meningitis (Bacterial, Fungal, Viral): Inflammation makes the barrier leaky, allowing plasma proteins to flood in. Levels are typically highest in bacterial and tuberculous meningitis
      • Hemorrhage (SAH or Traumatic Tap): Direct contamination with high-protein plasma
      • Guillain-Barré Syndrome: A classic cause of markedly elevated protein (often >200 mg/dL) with a normal cell count. This is called albuminocytologic dissociation and is a key diagnostic feature
      • Multiple Sclerosis (MS): Mildly elevated protein due to the intrathecal (within the CNS) production of immunoglobulin G (IgG)
  • Clinical Significance of DECREASED Protein: Less common. Can indicate a CSF leak following trauma or a lumbar puncture

CSF Glucose

  • Physiology: Glucose is not a passive diffusible substance. It is actively transported across the blood-brain barrier by specific glucose transporters (GLUT1). Therefore, its level is dependent on the plasma level but is maintained at a lower concentration
  • Reference Range: Normally ~60-70% of the simultaneous plasma glucose value. (Absolute range is ~50-80 mg/dL, but this is meaningless without the plasma result)
  • CRITICAL PRE-ANALYTICAL POINT: A blood glucose sample must be drawn 1-2 hours prior to the lumbar puncture to allow for equilibration between blood and CSF. An LP should never be performed for meningitis workup without a paired plasma glucose
  • Clinical Significance of DECREASED Glucose (Hypoglycorrhachia): This is a critical, “panic” finding. It indicates that something within the CNS is actively consuming glucose
    • Mechanism: Impaired transport across the BBB and, more importantly, active glycolysis by cells within the CSF
    • Causes
      • Bacterial Meningitis: The classic cause. Glucose is consumed by both the bacteria and the massive number of responding neutrophils. The level is often severely decreased (<40 mg/dL)
      • Tuberculous and Fungal Meningitis: These organisms also consume glucose, leading to a moderately to severely decreased level
      • Malignancy (Carcinomatous Meningitis): Tumor cells have a high metabolic rate and consume glucose
  • What it is NOT: Viral Meningitis. In most cases of viral meningitis, the CSF glucose level is NORMAL. This is the single most important chemical differentiator between bacterial and viral meningitis

CSF Lactate

  • Physiology: Lactate is the end-product of anaerobic glycolysis. In the CNS, high levels indicate tissue hypoxia or anaerobic metabolism by invading organisms or inflammatory cells
  • Reference Range: < 25 mg/dL
  • Clinical Significance of ELEVATED Lactate: This is an extremely useful and often underutilized test for differentiating the cause of meningitis
    • Levels > 35 mg/dL: Highly suggestive of Bacterial, Fungal, or Tuberculous Meningitis. The massive neutrophilic response and bacterial metabolism create an anaerobic environment, leading to a rapid and significant rise in lactate
    • Normal Lactate (<25 mg/dL): Highly suggestive of Viral Meningitis.
    • It is particularly useful in patients who have been pre-treated with antibiotics, where a Gram stain may be negative, but the lactate level will remain high, indicating a bacterial process

Specialized Protein Analysis

CSF Protein Electrophoresis & Oligoclonal Banding

  • Clinical Question: Is the patient’s immune system producing antibodies specifically within the CNS, independent of the systemic immune system? This is the central question in the diagnosis of Multiple Sclerosis (MS)
  • Methodology
    1. A paired CSF and serum sample are required
    2. High-resolution agarose gel electrophoresis is performed on both samples, side-by-side
    3. The proteins are separated, and the gel is then specifically stained for Immunoglobulin G (IgG)
  • Interpretation: The IgG staining patterns are compared
    • Normal: No distinct bands are seen in the gamma region of either sample
    • Systemic Immune Reaction (e.g., lupus, systemic infection): Multiple discrete bands (oligoclonal bands) are seen in both the serum AND the CSF. This is a “mirror” pattern and is not indicative of MS
    • Multiple Sclerosis: Two or more discrete oligoclonal bands are present in the CSF’s gamma region that are NOT present in the paired serum sample. This pattern is the hallmark of intrathecal synthesis of IgG and is found in >90% of patients with MS. It is a cornerstone of the diagnosis

Other CSF Analytes

  • Glutamine
    • Physiology: Ammonia, a waste product of protein metabolism, is toxic to the CNS. Astrocytes detoxify it by combining it with glutamate to form glutamine
    • Clinical Significance: In severe liver disease (hepatic encephalopathy), the liver cannot clear ammonia from the blood. High levels of ammonia cross into the CNS, leading to an increased production of glutamine. A high CSF glutamine level is an indirect measure of excess CNS ammonia and consciousness disturbance
  • LDH (Lactate Dehydrogenase)
    • Physiology: An intracellular enzyme. High levels indicate cellular damage
    • Clinical Significance: Can be fractionated into its isoenzymes to help determine the source of cellular damage (e.g., high LD-1 and LD-2 suggest CNS tissue damage, while high LD-4 and LD-5 suggest leakage from neutrophils in bacterial meningitis)

Conclusion

The chemical analysis of CSF is a masterclass in diagnostic interpretation. It is a story told in concentrations and ratios. A high protein level tells us the barrier is broken. A low glucose level tells us something is being consumed. A high lactate level points a finger directly at bacterial infection. And the unique pattern of oligoclonal bands can unlock the diagnosis of Multiple Sclerosis. When combined with the physical and microscopic findings, these chemical results provide a detailed, quantitative, and often definitive picture of the patient’s CNS pathology