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MSC: Disease of major orgns > Cerebrospinal Fluid (CSF) Formation, Function & Analysis > Flashcards

Cerebrospinal Fluid (CSF) Formation, Function & Analysis Flashcards

1
Q

What are parts of the nervous system?

A

The central nervous system (CNS) is composed of:

  • the brain
  • the spinal cord

The peripheral nervous system (PNS) is composed of:

  • spinal nerves that branch from the spinal cord
  • cranial nerves that branch from the brain
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2
Q

What are the parts of the brain?

A

3 main parts of the brain

  • Cerebrum – performs higher functions eg. interpreting touch, vision, hearing, speech, emotions, learning
  • Cerebellum – coordinates muscle movements
  • Brainstem – automatic functions eg. breathing, heart rate, temperature, digestion
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3
Q

What is the Cerebral Cortex?

A

The cerebral cortex is the outer layer of neural tissue of the cerebrum:

  • Grey matter typically contains nerve cell bodies
  • White matter typically contains nerve axons
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4
Q

What are cell types in CNS?

A
  • Neuronal cells – sensory neurons, motor neurons, interneurons
  • Oligodendrocytes – provide support & insulation to axons
  • Astrocytes/Astroglia – many supportive functions
  • Ependymal cells – epithelium lining of ventricular system and production of CSF
  • Microglia – macrophage, immune defence in CNS
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5
Q

What is the structure of the blood brain barrier?

A
  • Endothelial cells of the capillary wall
  • Astrocyte end-feet surrounding the capillary
  • Pericytes embedded in the capillary basement membrane
  • Tight junctions between endothelial cells composed of transmembrane proteins eg occludinand claudins
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6
Q

What is the function of the blood brain barrier?

A
  • Prevent circulating pathogens from entering the brain
  • Allow diffusion of small, hydrophobic molecules. e.g. O2, CO2
  • Active transport of metabolic products e.g. glucose, specific proteins
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7
Q

What are ventricles within the brain?

A
  • Within the brain there are 4 interconnected cavities known as the ventricles. There are 2 lateral ventricles, the left and right, one for each hemisphere. The third ventricle in the midline between the left and right ventricles The fourth ventricle which is central canal of the spinal cord
  • Within each ventricle is a region of choroid plexus, a network of ependymal cells specifically involved in the production of CSF
  • There are several foramina, openings acting as channels, that connect the ventricles
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8
Q

How is CSF formed?

A
  • Predominantly formed by plasma ultrafiltration through the capillary walls of the choroid plexuses in the lateral ventricles.
  • However as much as 30% of CSF is formed by fluid shifts across various other vascular beds within the CNS eg cerebral arteries & dorsal root ganglia
  • Solutes enter the CSF by a variety of processes: Active transport via specific transporters in choroid epithelial cells, Facilitated diffusion, Passive diffusion
  • In adults, the total volume of CSF is approx 135 mL produced at a rate of 500 mL/day so the fluid is typically exchanged every 6 hrs
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9
Q

What is the function of CSF?

A
  • Buoyancy: Allows the brain to maintain its density without being impaired by its own weight
  • Protection: As CSF completely surrounds the brain and spinal cord it cushions these structures against injury
  • Chemical stability: CSF removes metabolic waste back to the blood stream
  • Prevention of brain ischaemia: By decreasing the amount of CSF, total intracranial pressure is decreased, facilitating blood perfusion
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10
Q

What are differentials that are tested for with CSF?

A
  • Meningitis (acute inflammation of the meninges caused by infection) - fever, headache, stiff neck
  • Encephalitis – confusion, reduced GCS
  • De-myelination – reduced mobility
  • Acute onset of headache
  • Neuropathy
  • Focal neurological symptoms (? Tumour)
  • Dementia
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11
Q

How is CSF collected?

A
  • Usually collected by lumbar puncture (LP) where CSF is drawn from between 2 vertebrae.
  • May be done in radiology “x-ray guided LP”
  • CSF may be collected from other regions eg ventricular drain. The anatomical site is important as the constituents of CSF vary due to different flow rates around the subarachnoid space
  • Ideally 4 sequential samples of CSF are collected into numbered sterile containers. In total 10-12 mL of CSF taken
  • If during the LP the needle inadvertently caused peripheral blood to contaminate the CSF samples (a “traumatic tap”), the earliest fractions will be the most affected.
  • Paired blood samples should be taken at the same time (glucose, proteins, bilirubin)
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12
Q

What are some possible side effects as a result of taking CSF samples?

A
  • Potentially uncomfortable and distressing
  • Post-lumbar puncture headache
  • Bleeding
  • Infection
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13
Q

What are tests done on the CSF samples?

A
  • 1: CSF glucose (fluoride oxalate tube)
  • 2: Gram stain and culture
  • 3: CSF cell counts
  • 4: CSF proteins & spectrophotometry if required
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14
Q

What are usual test performed on CSF samples?

A
  • Pressure measurement
  • CSF appearance
  • Total and differential cell counts
  • Culture and gram stain
  • Glucose (and lactate)
  • Protein
  • Special studies: Cytology, Viral testing, Oligoclonal bands, Xanthochromia
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15
Q

What is a Pressure measurement?

A
  • A manometer is connected to the LP needle
  • Typically the initial hydrostatic pressure is between 80-180 mmH2O when the patient is lying on their side (higher if patient is sat upright)
  • Gives an indication of the intracranial pressure
  • There are much more accurate ways of measuring intracranial pressure but the techniques are more invasive
  • Some LPs are therapeutic. CSF is removed to relieve pressure in patients with intracranial hypertension
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16
Q

How does CSF appear?

A

Typically crystal clear & colourless, exceptions:

Turbidity caused by:

  • White cells (>200 per mm3)
  • Red cells (>400 per mm3)
  • Bacteria
  • Contamination by epidural fat

Clots may be present when protein concentrations are markedly elevated due to excess fibrinogen

Colour:

  • Yellow-bilirubin
  • Red (pink/orange)-oxyhaemoglobin
  • Brown-methaemoglobin
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17
Q

What are total cell counts?

A

Red cells (erythrocytes)

  • Normal Range: <10 per mm3
  • Causes of raised count: Intracranial bleed, Traumatic LP

White cells (leukocytes)

  • Normal Range: <5 per mm3
  • Causes of raised count: Depends on differential cell count (next slide), Traumatic LP
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18
Q

What are differential cell counts seen on stains?

A

Predominant cell are Polymorphs. Causes are:

  • Bacterial meningitis
  • Brain absess
  • Early coxsackie or echovirus infections

Predominant cell are Lymphocytes. Causes are:

  • Viral meningitis
  • TB meningitis
  • Chronic inflammatory CNS diseases eg MS
19
Q

What does culture and gramstain of CSF achieve?

A
  • Identifies if bacteria are present and differentiates them into 2 large groups; gram positive and gram negative
  • Initial differential diagnosis of meningitis can be based on cytological and biochemical characteristics of CSF but the gold standard for diagnosis is microbiological culture. However the sensitivity of CSF culture may be limited if antibiotics have already been administered.
  • Real time PCR is an alternative
20
Q

What is the usefulness of measuring CSF glucose?

A
  • CSF glucose is derived solely from the plasma via a specific membrane transporter
  • Primary source of metabolic energy for the brain as it has no significant glycogen stores
  • CSF glucose is usually approx. 2/3rds plasma level therefore it can only be interpreted in relation to the plasma concentration on a sample taken 15 min either side of LP
  • This ratio is maintained up to a plasma glucose concentration of 20 mmol/L but in severe hyperglycaemia the CSF glucose may appear disproportionately low
  • As CSF glucose takes 2-4 h to equilibrate with blood it may appear higher in diabetics following insulin or oral hypoglycaemic treatment
21
Q

What disease cause a fall in CSF:Plasma Glucose ratio?

A

CSF:plasma glucose falls below <0.6 in a number of conditions:

  • Bacterial meningitis (ratio is usually normal in viral meningitis)
  • Hypoxia
  • Hypoglycaemia
  • SAH
  • Meningeal carcinoma
22
Q

What does CSF Lactate increase?

A

Normal concentration <2.5 mmol/L as a product of metabolism within CNS. It is increased in:

  • Bacterial meningitis
  • Cerebral hypoxia (cerebral infarct)
  • Inherited disorders of the pyruvate dehydrogenase complex, and mitochondrial electron transport chain-mitochondrial myopathies
23
Q

What are examples of CSF protein?

A

Albumin (0.25 g/L)

Beta-trace (0.025 g/L)

IgG (0.02 g/L)

Transthyretin (0.017 g/L)

Transferrin (0.014)

24
Q

What are examples of plasma proteins?

A
  • Albumin (45 g/L)
  • IgG (10 g/L)
  • Fibrinogen (3 g/L)
  • Transferrin (3 g/L)
  • Alpha-2-macroglobulin (2.5 g/L)

Protein levels typical increase when moving down the CNS:

Lumbar CSF> Cisternal CSF> Ventricular CSF

25
Q

Why is measurement of CSF proteins useful?

A

BBB integrity

  • Infections Malignancy
  • Congenital abnormalities

Cell damage within the CNS

  • Toxic damage
  • Metabolic problems

Local synthesis-within the CNS

  • Inflammatory responses
  • Panic mechanisms
26
Q

What pathologies may cause a increase in CSF total protein?

A

Reference range <0.4 g/L

  • Acute bacterial meningitis (94% of cases)
  • Leukocytosis
  • Presence of blood (increase of 1mg per 1000 RBCs, they lyse but protein remains)
  • Trauma
  • CNS tumours
  • Cerebral infarct
  • Sarcoid, lupus, MS
  • Chronic CNS infections (syphilis, TB)
27
Q

What are causes of Multiple Sclerosis?

A
  • Viral trigger?
  • Genetic trigger?: MS is not usually inherited but having certain genes may make you more susceptible. If you have a first degree relative (parent or sibling) who has MS, you are more likely to develop the condition than the rest of the population.
  • Environmental trigger?: MS is more common in countries further away from the equator

Ultimately a breach in the BBB and a cascade of immune reactions leads to demyelination

28
Q

What are symptoms of Multiple Sclerosis?

A
  • Numbness
  • Tingling
  • Cognitive dysfuction
  • Depression
  • Fatigue
  • Muscle spasms
  • Weakness
  • Dizziness
  • Vision problems
  • Pain
  • Bladder sysfunction
  • Bowel Dysfucntion
  • Walking Difficulty
29
Q

What is the pathogenesis of Multiple Sclerosis?

A
  • MS is an inflammatory demyelinating condition
  • An abnormal immune response damages myelin, the fatty protein that insulates and protects axons
  • Nerve impulses transmitted to and from the CNS are disrupted
  • Damaged areas of myelin are known as lesions or plaques (swelling of axonal cylinders and infiltration of inflammatory cells)
  • Chronic plaques are largely devoid of myelin
30
Q

What are types of MS?

A
  • Progressive-relapsing multiple sclerosis: Steady decline since onset of superimposed attacks
  • Secondary progressive multiple sclerosis: Initial relapsing-remitting multiple scleoriss that suddenly begins to have decline without periods of remission
  • Primary progressive multiple scleroris: Steady increase in disability without attacks
  • Relapsing-remitting multiple sclerosis: Unpredictable attacks which may or may not leave permanent deficits followed by periods of remission
31
Q

How is Multiple Sclerosis diagnosed?

A

NICE guidance 2014 (CG186) – Multiple sclerosis in adults

Refer to the 2010 “McDonald” criteria for diagnosis

  • Number and timing of symptomatic attacks
  • Evidence of lesions disseminated in time and space: MRI and Evoked potentials
  • Presence of oligoclonal IgG bands in CSF
  • Exclusion of other diagnoses
32
Q

How is MRI used in multiple sclerosis?

A
  • Produces images of the brain that show up plaques
  • MRI is less useful in older people and in other inflammatory conditions such as acute encephalomyelitis where its specificity is lower
33
Q

How is Evoked Potential testing used for multiple sclerosis?

A
  • Measures the time it takes for messages to travel to your brain, usually from your eyes.
  • Lesions affecting the optic nerve (the most common site in MS) may be detected by visual evoked potentials which display attenuation of amplitude & Prolonged latency
34
Q

What are oligoclonal bands?

A
  • In normal CSF immunoglobulins are not produced within the CNS but only come from the blood by filtration across blood-CSF barriers
  • In MS, B lymphocytes migrate from the blood into the brain where there is clonal expansion and differentiation into plasma cells which secrete immunoglobulins intrathecally (local synthesis within the CNS ONLY)
  • Oligoclonal banding is a characteristic discrete banding pattern of immunoglobulins (usually IgG) seen in the gamma globulin region when separated electrophoretically
  • Oligoclonal bands within the CSF are characteristic of MS but they may also be seen in other autoimmune conditions and infections of the CNS
35
Q

How are oligoclonal bands detected?

A

Isoelectric focusing (IEF)

  • Electrophoretic separation based on the iso-electric points of proteins (pI)
  • pI is the pH point at which the protein has an overall net charge of zero.
  • Agarose gel with a pH gradient
  • Proteins migrate until they reach the pH point in the gradient at which the charge of the protein equals zero ie the pI
  • Protein transfer from gel onto nitrocellulose
  • Immunodetection with enzyme-labelled anti-human IgGFc (or other part of molecule)
  • Chromogenic development
36
Q

What is seen for the test results in Multiple Sclerosis?

A
  • Type 1 pattern – normal
  • Type 2 pattern – oligoclonal bands present in CSF only, consistent with MS
  • Type 3 pattern – matching bands in CSF & serum with extra bands in CSF
  • Type 4 pattern – identical pattern of bands in CSF & serum, consistent with systemic IgG synthesis NOT MS
  • Type 5 pattern – abnormal identical pattern of bands in CSF & serum, consistent with a monoclonal paraprotein
37
Q

What are drawback on using oligoclonal bands?

A

Unfortunately in MS, the pattern of bands in either CSF or serum does not correlate with:

  • The nature of the disease
  • The duration of the disease
  • The severity of the disease
38
Q
  • How is Multiple Sclerosis treated?
A
  • Treatment for relapses – steroids
  • Treating specific MS symptoms eg gabapentin for involuntary eye movements, painkillers for musculoskeletal pain
  • Treatment to reduce the number of relapses (disease modifying therapies) eg alemtuzumab, natalizumab, ocrelizumab
  • Haematopoietic stem cell transplantation
  • Biotin trials – activates enzymes involved in myelin production
39
Q

What are markers of CSF?

A

Used to identify CSF leakage from the nose (rhinorrhoea) or the ear (otorrhoea). A confirmed CSF leak means the CNS is open to the risk of infections

  • Beta-2-transferrin
  • Beta trace protein (BTP)
40
Q

What is Beta-2-transferrin?

A
  • Carbohydrate free form of transferrin aka asialo-transferrin. (Previously also referred to as “tau protein” however this term is now discouraged)
  • Formed by the loss of all sialic acid groups from transferrin due to the presence of neuraminidase in the CNS
  • Not found in blood, mucus or tears, making it a highly specific marker of CSF
41
Q

How is Beta-2-transferrin analysed?

A
  • Electrophoresis on a high resolution agarose gel
  • Protein transfer onto nitrocellulose membrane
  • Immunochemical detection with anti-transferrin antibody followed by chromogenic detection
42
Q

How is Beta-2-transferrin interpreted?

A
43
Q

What is Beta Trace Protein?

A
  • Also known as prostaglandin D2 synthase, a low MW protein of about 24 kDa
  • Mainly synthesized in the CNS by glial cells & the choroid plexus, concentrations are much higher in CSF than in serum or plasma
  • Virtually all circulating BTP is filtered by the kidneys therefore the plasma concentration is mainly dependent on the GFR and serum BTP can be used as a marker of renal function
  • Alternative to beta-2-transferrin, measurement can be automated using nephelometry/turbidimetry, quantitative result
44
Q

What are normal Beta trace protein levels?

A
  • BTP in serum = <0.70 mg/L
  • BTP in CSF = 8.89-25.9 mg/L

MSC: Disease of major orgns (23 decks)

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