Cerebrospinal Fluid Diagnostics

Cerebrospinal fluid (CSF) diagnostics (synonyms: analysis of CSF, cerebrospinal fluid analysis, CSF examination) is primarily used to diagnose diseases affecting the central nervous system (CNS). The cerebrospinal fluid is obtained by a cerebrospinal fluid puncture (see “Cerebrospinal fluid puncture”). The cerebrospinal fluid (CSF) is a clear, colorless fluid containing only a few cells that washes around the central nervous system in the subarachnoid space. The approximately 120-200 ml of CSF is formed by the choroid plexus (80%), the cerebral parenchyma, and the ependymal cells of the ventricles and spinal canal (spinal cord canal) (20%) and circulates in the CSF space with constant production and reabsorption. Outflow occurs via the arachnoid villi. Approximately 500 ml of CSF is produced daily.

The procedure

Material needed

• CSF punctate: 3 x CSF (sterile; discard the first 5 drops for this purpose!).
• 5-10 ml serum

Notice:

• Note the time of the cerebrospinal fluid puncture.
• Cytology: cell count within 1-2 hours.
• For microbiological diagnosis, due to the lability of the pathogens, ensure transport at 37 °C in a sterile vessel.
• For all clinical-chemical, serological and immunological investigations, the CSF should be transported or stored at +4 – +8 °C.
• Because CSF collection cannot be repeated without renewed heavy patient stress (and associated risks), all medically indicated tests should be requested immediately.

Confounding factors

• Not known

Indications

• Inflammation of the central nervous system (CNS).
• Infectious diseases of the central nervous system (bacterial, viral, mycotic, parasitic infections) – e.g. meningitis (meningitis), encephalitis (brain inflammation).
• CSF circulation disorders
• Autoimmune diseases – e.g. multiple sclerosis (MS).
• Diseases of the central nervous system with or without disease of the peripheral nervous system – e.g. Creutzfeld-Jakob disease, amyotrophic lateral sclerosis (ALS).
• Neoplasia of the central nervous system – e.g. solid tumors, leukemia (blood cancer), lymphoma (collective term for lymph node enlargement or lymph node swelling and tumors of the lymphatic tissue).
• Neurodegenerative diseases – e.g. Alzheimer’s disease.
• CT-negative subarachnoid hemorrhage (SAB).
• Trauma
• Unclear disorders of consciousness

Note: The onset of symptoms usually determines the timing of the first diagnostic puncture:

• 1st/2nd day in purulent meningitis.
• 3rd-5th day for viral meningitis.
• 3rd-5th day in Guillain-Barré polyradiculitis.
• 5th-7th day in flu-like preliminary stage of herpes simplex encephalitis.
• 2nd-3rd week in tuberculous meningitis.

Examination of cerebrospinal fluid/normal values

The examination of the CSF in the laboratory is composed of basic elements and additional components depending on the individual problem. The basic examination includes the determination of:

• Color: crystal clear
• Cell count, CSF cell differentiation.
  • Leukocytes: adults < 4 cells/µl, lymphocytes & monocytes (70: 30).
  • Lymphocytes and monocytes (70: 30).
  • Segment nucleated granulocytes
  • Erythrocytes: absent in all age groups.

  Typical constellations of findings:

  • < 30 µl: multiple sclerosis (MS), neuroborreliosis, viral encephalitis in (HIV, VZV and others), Guillain-Barré syndrome (GBS),
  • > 30 – < 300 µl: acute viral meningitis, acute neuroborreliosis, tuberculous/mycotic meningitis, brain abscess,
  • > 300 µl: purulent meningitis.
• Cytology:
  • Neutrophil granulocytes: acute process, bacterial meningitis, early phase of viral meningitis.
  • Phagocytosed bacteria (meningococci, staphylococci, et al.)
  • Lymphocytes/monocytes: chronic process, multiple sclerosis (MS), viral meningitis, late phase of bacterial meningitis.
  • Eosinophils (> 5%): parasitoses, tuberculosis.
  • Tumor cells (blasts, lymphoma cells, cells of solid tumors).
• Glucose (50-60% of blood glucose) [unremarkable in viral meningitis].
• Lactate <2.1 mmol/l [unremarkable in viral meningitis].
• Proteins and immunoglobulins (CSF protein profile):
  • Total protein protein concentration [normal: 1/200 of serum protein concentration, < 50 mg/dl].
  • Quantitative protein differentiation: maker protein is albumin.
  • Protein electrophoresis
  • IgA, IgM, IgG
  • Alpha2 macroglobulin

Albumin CSF/serum quotient (ratio formation of albumin concentration in CSF to serum).

Age	Albumin quotientQAlbumin = 10 x 10-3
Birth	8.0 to 28.0
1st month of life	5.0 to 15
2nd month of life	3.0 to 10
3rd month of life	2.0 to 5.0
4. month of life to six years	0.5 to 3.5
up to 15 years	< 5,0
up to 40 years	< 6,5
up to 60 years	< 8,0

The level of the albumin-liquor/serum ratio allows inference of the possible causative disease:

Albumin quotientQAlbumin = 10 x 10-3	Possible disease
Up to 10≈ barrier disorder is “mild”	Alcoholic polyneuropathy (generic term for certain disorders of the peripheral nervous system affecting multiple nerves). Amyotrophic lateral sclerosis (ALS). Chronic HIV encephalitis Multiple sclerosis (MS) Varicella zoster ganglionitis
Up to 20≈ barrier disturbance is “moderate”	Diabetic neuropathy (collective term for many diseases of the peripheral nervous system). Cerebral infarction Cerebral cortex atrophy Opportunistic meningoencephalitis – combined inflammation of the brain (encephalitis) and meninges (meningitis). Viral meningitis
10 to 50≈ barrier disturbance is “severe”	Guillain-Barré syndrome (GBS). HSV encephalitis Meningopolyneuritis (Bannwart’s)
> 20≈ barrier disturbance is “light”.	Purulent meningitis “Stop cerebrospinal fluid” in case of disc prolapse or tumor. Tuberculous meningitis

Immunoglobulins

Parameter	Standard values
IgA	up to 0.6 mg/dl
IgM	up to 0.1 mg/dl
IgG	up to 4.0 mg/dl

Detection of intrathecal immunoglobulin synthesis.

The proportion of each Ig (intrathecal fraction) can be read from the 20% to 80% lines. This allows a comparison between IgA, IgG and IgM (i.e. weighting and determining the dominance of a particular Ig). This is referred to as a 1-class, 2-class or 3-class reaction with IgG or IgA or IgM dominance. The following is an assignment of typical constellations of findings to individual diseases:

Reaction type	Disease
Strong dominance of IgG (IgA < 20%, IgM < 50%).	Chronic HIV encephalitis HSV encephalitis Multiple sclerosis (MS)
1-class reaction ⇒ immunoglobulin G ⇒ immunoglobulin A	HIV encephalitis, SSPE Meningitis tuberculosa
2-class reaction ⇒ IgG > IgM ⇒ IgG = IgM ⇒ IgG + IgA ⇒ IgG + IgM	Multiple sclerosis Viral meningitis Purulent meningitis, neuro-Tbc TBE, progressive paralysis
3-class reaction ⇒ IgG dominance ⇒ IgM dominance ⇒ IgA dominance ⇒ IgG + IgA + IgM	Neurosyphilis Neuroborreliosis Adrenoleukodystrophy Mumps meningoencephalitis, opportunistic infections.

If an infectious cause is suspected, pathogen detection is performed on:

Stage diagnostics	Pathogen
Basic diagnostics	Borrelia TBE Herpes simplex
2nd stage	Adeno viruses Enteroviruses (ECHO, Coxsackie) Rubella (German measles)
3rd step	CMV Morbilli (measles) Listeria Toxoplasma Varicella zoster virus

In fulminant courses, all pathogens in question must be examined immediately! As a rule, the following further examinations are performed:

• Bacteriological examinations (Gram stain and culture).
• Mycological examinations
• Parasitological investigations (protozoa)
• Pathogen-specific antibodies / antigen detection (pathogen detection or confirmation; v. a. bacteria, fungi).
• PCR (gold standard for viruses; complementary for TB, other bacteria and parasitoses).
• CNS-derived proteins (neurodegeneration, Alzheimer’s dementia (AD), Creutzfeldt-Jakob disease (CJD)).

If slow virus infections are suspected:

• Neuron-specific enolase (NSE).

If neoplasia is suspected:

• CEA quotient (serum, CSF).
• Β2-microglobulin
• Cytology
• Lymphocyte differentiation