H. Reiber
Cerebrospinal fluid. The cerebrospinal fluid (CSF) [Latin: liquor cerebrospinalis; German: Liquor (CSF), French: liquide cephalo-rachidien (LCR), Spanish: liquido cefalorracideo (LCR)] is aclear fluid containing few or no cells. Its protein concentration is very low, and its salt concentration is similar to that of blood.
Its two main physiological functions are:
• To cushion the brain against sudden movement or physical shock.
• To drain brain- and blood-derived CSF molecules into venous blood.
For the practical purposes of clinical medicine, it functions as:
• A contributing element in the diagnosis of neurological disease.
• A source of information in brain research.
• An aid to treatment monitoring.
CSF analysis plays an important role in the laboratory-supported diagnosis of neurological diseases, but its relevance depends on knowledge-based interpretation of the results. This chapter details the relevant physiological background.
CSF physiology. CSF is produced in the choroid plexus of the ventricular system, flows from the ventricles through the two lateral apertures (foramina of Luschka) and the median aperture (foramen of Magendie) into the cisterns (Fig. 1.1), and divides into the cerebral and the spinal subarachnoid space. The subarachnoid space is the space between the arachnoidea mater (the middle cerebral membrane) and the pia mater (the innermost membrane lining the cerebral tissue).The CSF drains without filtration (“bulk flow“) into the venous blood viathe arachnoid villi in the pacchionian bodies (Davson and Segal, 1996; Zettl et al., 2005). Arachnoid villi are found both in the cranium (sagittal sinus) and in the spinal subarachnoid space (spinal nerve roots).
The driving force of CSF flow is the pressure difference between arterial and venous blood.
CSF volume. In adults, the total volume of CSF is about 140mL, with the ventricles containing 12 to 23 mL on aver age and the spinal subarachnoid space containing about 30 mL. The CSF volume is influenced by heart function, respiration, coughing, and body posture, all of which cause random movements to and fro and the mixing of CSF from regions with differing flow rates.
CSF flow. In humans, CSF flow begins around the time of birth, when the arachnoid villi are maturing, and peaks about 4 months after birth, when the villi have matured. This peak in the flow rate is accompanied by a trough in protein concentration (Fig. 1.2). In adulthood, mean CSF production is 500 mL/day, and the flow rate is 0.4 mL/min. With increasing age, CSF production in the ventricles decreases and the flow rate declines to only 0.1 mL/min (May et al., 1990). CSF flow is made visible by imaging procedures (for references see Reiber, 2003).
Fig. 1.1 Subarachnoid space, CSF flow, and molecular diffusion. Produced by the choroid plexus of the ventricular system (1, first and second lateral ventricles; 2, third ventricle; 3, fourth ventricle with the two lateral apertures), the CSF flows through various apertures (4, interventricular foramen, also called foramen of Monro; 5, cerebral aqueduct, also called aqueduct of Sylvius; followed by the lateral foramina of Luschka and the median foramen of Magendie) into the cisterns (6, cerebellomedullary cistern; 7, inter-peduncular cistern; 8, chiasmatic cistern; 9, ambient cistern), after which the subarachnoid space branches into a cerebral and a spinal space, and branch. Passing through these, the CSF then drains through the arachnoid villi into the venous blood.
Fig. 1.2a,b Albumin CSF/serum quotient (QAlb; see also Table 3.1). Threshold reference values for the age-related QAlb are calculated as follows: QAlb =(4+ age in years/15) × 10−3 (for ages of >5 years).
a Around the time of birth (point 1), the albumin quotient is very high, since the arachnoid villi are still immature and the CSF flow is restricted. However, as the villi mature, the rate at which the CSF flows into the venous blood increases and the albumin quotient drops. It reaches its lowest value about 4 months after birth (point 3) when the villi are fully mature, and then slowly rises again during adult life as CSF production slows.
b The IgG quotient as a function of the albumin quotient shows that the selectivity of the barrier function is fully developed at birth (point 1). With the changing flow rate, the IgG/albumin ratio in the CSF changes hyperbolically (points 1–3 correspond to those in a).
Brain area of relevance in CSF analysis. Various observations have led to the recognition of a defined cerebral region that is of relevance in CSF analysis (Felgenhauer, 1998):
• The albumin concentration in lumbar CSF does not change if there is local dysfunction of the blood–brain barrier in the frontal, temporal, or parietal region (e. g., stroke, MS plaque).
• Local intrathecal synthesis of proteins far away from the subarachnoid space has no effect on the concentration of these proteins in the CSF; for example, brain metastases of a CEA-synthesizing tumor located in the frontal brain far away from the subarachnoid space do not change CEA levels in the cerebrospinal fluid.
Thus, the “catchment area” for CSF in the brain parenchyma is limited. This is partly because of the long diffusion distances and partly because the intercellular fluid moves very slowly (CSF flows 10 times faster). Furthermore, in the cerebellar subarachnoid space the CSF flows toward the convexity (Fig. 1.1) and drains into the superior longitudinal sinus: local changes in protein levels in this brain region are there fore not detectable in the lumbar CSF.
This physiological spatial limitation to the study of changes in the brain by CSF analysis is another example of why we have to distinguish between the blood–brain barrier and the blood–CSF barrier function.
References
Davson H, Segal MB (eds). Physiology of the CSF and blood–brain barriers. Boca Raton: CRC Press; 1996
May C, Kaye JA, Atack JR, Schapiro MD, et al. Cerebrospinal fluid production is reduced in healthy aging. Neurology 1990; 40: 500–503
Reiber H. Proteins in cerebrospinal fluid and blood: barriers, CSF flowr ate and source-related dynamics. Restor Neurol Neurosci 2003; 21: 79–96
Zettl UK, Lehmitz R, Mix E (eds). Klinische Liquordiagnostik. Berlin: Walter de Gruyter; 2005
|
Ab |
antibody |
|
ABGA |
anti-basalganglia antibody |
|
ACE |
angiotensin-convertingenzyme |
|
AchR |
acetylcholinereceptor |
|
ACLA |
anti-cardiolipin antibody |
|
ACTH |
adrenocorticotropic hormone |
|
ADEM |
acutedemyelinatingencephalomyelitis |
|
ADC |
AIDSdementia complex |
|
AECA |
anti-endothelial cell antibody |
|
AFP |
alpha fetoprotein |
|
Ag |
antigen |
|
AHLAI |
acutehemorrhagicleukoencephalitis antibodyindex |
|
AIDP |
acute inflammatory demyelinatingpoly-neuropathy |
|
AIDS |
acquired immunodeficiency syndrome |
|
AIP |
acuteintermittent porphyria |
|
ALD |
adrenoleukodystrophy |
|
ALL |
acutelymphoblastic leukemia |
|
ALS |
amyotrophic lateral sclerosis |
|
ALS |
5-aminolevulinic acid |
|
ALT |
alanine aminotransferase |
|
AMA |
anti-mitochondria antibody |
|
AMAN |
acutemotor axonal neuropathy |
|
AMSAN |
acute motorand sensoryaxonal neuropathy |
|
ANA |
antinuclear antibody |
|
ANab |
antineural antibody |
|
ANCA |
anti-neutrophilcytoplasmic antibody |
|
ANNA |
anti-neuronal nuclear antibody |
|
APAAP |
alkalinephosphatase anti-alkaline phosphatase |
|
APase |
alkaline phosphatase |
|
ApoE |
apolipoproteinE |
|
APP |
amyloid precursor protein |
|
APS |
antiphospholipid syndrome |
|
aPTT |
activated partialthromboplastin time |
|
ASA |
acetylsalicylic acid |
|
ASL |
antistreptolysin (titer) |
|
ASAT |
aspartateaminotransferase |
|
ATG |
anti-thymocyte globulin |
|
ATPase |
adenosinetriphosphatase |
|
bAk |
Bundesarztekammer (GermanMedical Association) |
|
bDNA |
branched DNA |
|
BGA |
blood gasanalysis |
|
BHI |
brain-heart infusion |
|
BJP |
BenceJones protein |
|
BMI |
bodymassindex |
|
bp |
base pair |
|
CADASIL |
cerebralautosomaldominantarteriopathy with subcortical infarcts andleukoencephal-opathy |
|
CANOMAD |
chronic ataxic neuropathy, ophthalmoplegia, IgMparaprotein, cold agglutinins, and disialosyl antibodies |
|
CC |
cell count |
|
CCT |
cranial computed tomography |
|
CD |
clusterofdifferentiation |
|
CDC |
Centersfor Disease Control andPrevention |
|
CT |
computedtomography |
|
CDG |
carbohydrate-deficient glycoprotein |
|
cDNA |
complementaryDNA |
|
CDR |
complementarydeterminingregion |
|
CDT |
carbohydrate-deficienttransferrin |
|
CEA |
carcinoembryonic antigen |
|
CEE |
Central European encephalitis |
|
CFT |
complementfixation test |
|
CHD |
coronary heart disease |
|
CIDP |
chronic inflammatorydemyelinatingpoly-neuropathy |
|
CJD |
Creutzfeldt-Jacob disease |
|
CK |
creatine kinase |
|
CMT |
Charcot-Marie-Toothdisease |
|
CMV |
cytomegalovirus |
|
CNPase |
cyclic nucleotidephosphohydrolase |
|
CNS |
central nervoussystem |
|
COHb |
carboxyhemoglobin |
|
COX |
cytochrome coxidase |
|
CPE |
cytopathic effect |
|
CPEO |
chronic progressiveexternalophthalmoplegia |
|
CREST |
calcinosis, Raynaud'sphenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia |
|
CRH |
corticotropin-releasing hormone |
|
CRMP |
collapsin-responsive mediator protein |
|
CRP |
C-reactive protein |
|
CSF |
cerebrospinalfluid |
|
CV |
coefficient of variation |
|
CZF |
cerebellar zincfinger |
|
DAD |
diabetes mellitusand deafness |
|
DGUOK |
deoxyguanosine kinase |
|
DNA |
deoxyribonucleic acid |
|
dsDNA |
double-strandedDNA |
|
DST |
dexamethasone suppression test |
|
DTR |
deep tendon reflexes |
|
EBV |
Epstein-Barr virus |
|
EEG |
electroencephalogram |
|
EDTA |
ethylenediaminetetraacetic acid |
|
EIA |
enzymeimmunoassay |
|
EITB |
enzyme-linkedimmunoelectrotransfer blot |
|
ELISA |
enzyme-linked immunosorbent assay |
|
EM |
electron microscopy |
|
EMA |
epithelialmembraneantigen |
|
ENA |
extractable nuclear antigen |
|
ERG |
electroretinogram |
|
ESR |
erythrocyte sedimentationrate |
|
ET |
essentialthrombocythemia |
|
FABP |
fatty-acid-binding protein |
|
FFI |
fatal familial insomnia |
|
FDG-PET |
positron emissiontomographyusing fluoro-deoxyglucose |
|
FIA |
fluorescence immunoassay |
|
FITC |
fluorescein isothiocyanate |
|
FPIA |
fluorescence-polarization immunoassay |
|
FRDA |
Friedreich'sataxia |
|
FSH |
follicle-stimulatinghormone |
|
FSHD |
facioscapulohumeral muscular dystrophy |
|
FSME |
Fruhsommer-Meningo-Encephalitis (r CEE, TBE) |
|
FT3 |
free triiodothyronine |
|
FT4 |
free thyroxine |
|
FTA-ABS |
fluorescenttreponemal antibodyabsorption |
|
FTD |
frontotemporal dementia |
|
FTDP-17 |
frontotemporal dementia with parkinsonism linkedtochromosome 17 |
|
FTLD |
frontotemporal lobar degeneration |
|
GAD |
glutamate decarboxylase |
|
GalNAc |
N-acetylgalactosamine |
|
GBS |
Guillian-Barre syndrome |
|
GC |
gaschromatography |
|
GFAP |
glial fibrillaryacidic protein |
|
GGT |
gamma-glutamyl transferase |
|
GH |
growthhormone |
|
GLG |
gasliquid chromatography |
|
GOT |
glutamate oxaloacetate transaminase |
|
GPL |
IgG-phospholipid antibody unit |
|
GPT |
glutamate pyruvate transaminase |
|
GROD |
granular osmophilic deposits |
|
GSS |
Gerstmann-Strausslersyndrome |
|
HAI |
hemagglutination inhibition assay |
|
Hb |
hemoglobin |
|
HbA1c |
glycosylated hemoglobin |
|
HBV |
hepatitis Bvirus |
|
HbS |
sickle cell hemoglobin |
|
HC |
homocysteine |
|
hCG |
human chorionic gonadotropin |
|
HCP |
hereditarycoproporphyria |
|
Hct |
hematocrit |
|
HCV |
hepatitis Cvirus |
|
HD |
Huntington'sdisease |
|
HDL |
high-density lipoprotein |
|
HE |
hematoxylin-eosin |
|
HIV |
human immunodeficiency virus |
|
HLA |
human leukocyteantigen |
|
HMSN |
hereditarymotor sensoryneuropathy |
|
HNA |
hereditary neuralgicamyotrophy |
|
HNPP |
hereditaryneuropathywith liabilityto pressurepalsy |
|
HSAN |
hereditary sensory andautonomic neuropathy |
|
HPLC |
high-pressure liquid chromatography |
|
HRP |
horseradishperoxidase |
|
HSP |
heatshock protein |
|
HSS |
Hallervorden-Spatzsyndrome |
|
HSV |
herpes simplexvirus |
|
IBM |
inclusionbodymyositis |
|
ICAM |
intracellular adhesion molecule |
|
ICP |
intracranial pressure |
|
IDL |
intermediate densitylipoprotein |
|
IEF |
isoelectric focusing |
|
IF |
intrathecal fraction |
|
IFT |
indirect immunofluorescence test |
|
Ig |
immunoglobulin |
|
IHA |
indirect hemagglutination |
|
IL |
interleukin |
|
INCAT |
Inflammatory NeuropathyCause and Treatment(group) |
|
INR |
international normalizedratio |
|
INSTAND |
Institutefor Standardizationand Documentation in theMedical Laboratory |
|
IRMA |
immunoradiometric assay |
|
ITPA |
intrathecal Treponema pallidum antibody |
|
JCV |
John Cunningham virus |
|
kDa |
kilodalton |
|
KSS |
Kearns-Sayre syndrome |
|
LAL |
Limulus amebocyte lysate |
|
LAMP |
lysosome-associatedmembrane protein |
|
LBD |
Lewybody dementia |
|
LC |
liquidchromatography |
|
LDH |
lactate dehydrogenase |
|
LDL |
low density lipoprotein |
|
LEMS |
Lambert-Eatonmyasthenic syndrome |
|
LH |
luteinizinghormone |
|
LHON |
Leber'shereditaryoptic atrophy |
|
LIA |
luminescenceimmunoassay |
|
LP |
lumbarpuncture |
|
LPL |
lipoprotein lipase |
|
LS |
Leigh'ssyndrome |
|
mAb |
monoclonal antibody |
|
MAD |
myoadenylate deaminase |
|
MADD |
myoadenylate deaminase deficiency |
|
MAG |
myelin-associatedglycoprotein |
|
Mb |
megabase |
|
MBP |
myelin basic protein |
|
MCH |
meancorpuscularhemoglobin |
|
MCTD |
mixedconnective tissuedisease |
|
MCV |
meancorpuscular volume |
|
MELAS |
mitochondrial encephalomyelopathy, lactic acidosis, and strokelikeepisodes |
|
MERRF |
myoclonus epilepsy with ragged-red fibers |
|
MetHb |
methemoglobin |
|
MFS |
Miller-Fischer syndrome |
|
MG |
myastheniagravis |
|
MGUS |
monoclonal gammopathy of undetermined significance |
|
MHC |
majorhistocompatibilitycomplex |
|
MID |
multi-infarctdementia |
|
MLD |
metachromaticleukodystrophy |
|
MMA |
methylmalonic acid |
|
MMN |
multifocal motor neuropathy |
|
MND |
muscle-specific tyrosine kinase |
|
MNGIE |
myoneurogenicgastrointestinal encephalopathy |
|
MOG |
myelin oligodendrocyte glycoprotein |
|
MPL |
IgM-phospholipid antibody unit |
|
MPO |
myeloperoxidase |
|
MPS |
mucopolysaccharidosis |
|
MRI |
magnetic resonanceimaging |
|
mRNA |
messengerRNA |
|
MRZ |
measles, rubella, (varicella) zoster |
|
MS |
multiple sclerosis |
|
MS |
mass spectrometry |
|
MSA |
multiple system atrophy |
|
MuSK |
muscle-specific(receptortyrosine)kinase |
|
MW |
molecular weight |
|
NAB |
neutralizingantibody |
|
NAD |
nicotinamideadeninedinucleotide |
|
NADH |
reducedform of nicotinamide adenine dinucleotide |
|
NADH-TR |
ADHtetrazoliumreductase |
|
NARP |
neuropathywith ataxia andretinitis pigmentosa |
|
NASBA |
nucleic-acid-sequence-basedamplification |
|
NAT |
nucleic acid amplification technique |
|
NC |
nitrocellulose |
|
NCL |
neuronal ceroid lipofuscinosis |
|
NF |
neurofilament |
|
NFT |
neurofibrillarytangle |
|
NHL |
non-Hodgkinlymphoma |
|
NMO |
neuromyelitis optica |
|
Nova |
neuro-oncological ventral antigen |
|
NSE |
neuron-specific enolase |
|
OCB |
oligoclonalIgG band |
|
OD |
optical density |
|
oGTT |
oralglucose tolerancetest |
|
OKT3 |
anti-CD3 monoclonalantibody |
|
OMS |
Opsoclonus-myoclonussyndrome |
|
OSP |
oligodendrocyte-specific protein |
|
Osp |
outersurface protein |
|
OTC |
ornithinetranscarbamylase |
|
PA |
progressiveaphasia |
|
PAGE |
polyacrylamide gelelectrophoresis |
|
PAI |
plasminogen activator inhibitor |
|
PACNS |
primaryangiitis of thecentral nervoussystem |
|
PAN |
polyarteritis nodosa |
|
PANDAS |
pediatric autoimmune neuropsychiatric dis-ordersassociated withstreptococcal Infections |
|
PAP |
peroxidase-anti-peroxidase |
|
PAS |
periodic-acid - Schiff |
|
PBG |
porphobilinogen |
|
PBG-D |
porphobilinogendeaminase |
|
PCA |
Purkinjecellantibody |
|
PCD |
paraneoplastic cerebellardegeneration |
|
PCNSL |
primaryCNS lymphoma |
|
PCR |
polymerase chain reaction |
|
PCT |
procalcitonin |
|
PDH |
pyruvatedehydrogenase |
|
PEEP |
positive end-expiratory pressure |
|
PEM |
paraneoplastic encephalomyelitis |
|
PERM |
progressive encephalitis with rigidity and myoclonus |
|
PET |
positron emissiontomography |
|
PHF |
pairedhelical filaments |
|
Pi |
inorganic phosphate |
|
pI |
isoelectric point |
|
PLAP |
placentalalkaline phosphatase |
|
PLP |
proteolipid protein |
|
PML |
progressivemultifocal leukoencephalopathy |
|
PMP |
peripheral myelinprotein |
|
PM-Scl |
polymyositis scleroderma |
|
PNP |
polyneuropathy |
|
PNS |
peripheral nervoussystem |
|
POEMS |
polyneuropathy, organomegaly, endocrinopathy, Mprotein, and skin changes |
|
POLG |
polymerase gamma |
|
PPSB |
prothrombincomplex |
|
PrP |
prion protein |
|
PT |
prothrombintime |
|
PTT |
partial thromboplastin time |
|
PVDF |
polyvinylidene difluoride |
|
RBC |
redblood cell(count) |
|
RBP |
retinol-bindingprotein |
|
REAL |
Revised European American Lymphoma (classification) |
|
RIA |
radioimmunoassay |
|
rilibAk |
Richtlinien derBundesdrztekammer (Guidelines of theGermanFederal MedicalSociety) |
|
RNA |
ribonucleic acid |
|
RNP |
ribonucleoprotein |
|
RRA |
radioreceptor assay |
|
rRNA |
ribosomalRNA |
|
RT-PCR |
reverse transcriptase polymerasechain reaction |
|
RyR |
ryanodine receptor |
|
SAE |
subcortical arteriosclerotic encephalopathy |
|
SAH |
subarachnoid hemorrhage |
|
SAP |
sphingolipid activator protein |
|
SCA |
spinocerebellar ataxia |
|
sCD25 |
interleukin-2 receptor |
|
sCJD |
sporadicCreutzfeldt-Jacobdisease |
|
Scl-70 |
scleroderma 70-kDa antigen |
|
SCLC |
small-cell lung carcinoma |
|
SD |
standard deviation |
|
SD |
semanticdementia |
|
SDH |
succinatedehydrogenase |
|
SDS |
sodiumdodecyl sulfate |
|
SEP |
somatosensory evoked potential |
|
SGLPG |
sulfate-3-glucuronyl-neolactose paragloboside |
|
SGPG |
sulfate-3-glucuronyl paragloboside |
|
SGTC |
secondary generalizedtonic-clonic (seizures) |
|
SIADH |
syndrome of inappropriate antidiuretic hormone |
|
SIRS |
systemic inflammatoryresponse syndrome |
|
SLE |
systemic lupus erythematosus |
|
TPHA |
Treponemapallidum hemagglutination |
|
SMA |
spinal muscularatrophy |
|
TPLA |
Treponemapallidum latex agglutination |
|
SMN |
survival motorneuron |
|
TPO |
thyroidperoxidase |
|
SNE |
subacute necrotizing encephalopathy |
|
TPOAb |
thyroid peroxidase antibody |
|
SNV |
Sin Nombre virus |
|
TP-PA |
Treponemapallidum particle agglutination |
|
SPECT |
single photon emission computed tomography |
|
TRAb |
thyrotropin receptor antibody |
|
SPP |
spastic paraplegia(paraparesis) |
|
TRH |
thyrotropin-releasinghormone |
|
SPS |
stiffpersonsyndrome |
|
TSD |
Tay-Sachs disease |
|
SS |
Sjogren'ssyndrome |
|
TSH |
thyroid-stimulatinghormone |
|
SSN |
subacute sensoryneuronopathy |
|
TT |
thrombin time |
|
SSPE |
subacute sclerosingpanencephalitis |
|
TTR |
transthyretin (prealbumin) |
|
TBE |
tick-borne encephalitis |
|
vCJD |
variant Creutzfeldt-Jacob disease |
|
TBG |
thyroxine-binding globulin |
|
VDRL |
Venereal Disease Research Laboratory |
|
TCA |
trichloroacetic acid |
|
VEP |
visual evoked potential |
|
TDM |
therapeuticdrugmonitoring |
|
VGCC |
voltage-gated calciumchannels |
|
TFPI |
tissue factorpathway inhibitor |
|
VGKC |
voltage-gated potassiumchannels |
|
TGA, TgAb |
hyroglobulin antibody |
|
VLCFA |
verylongchain fattyacids |
|
TIA |
transientischemic attack(s) |
|
VLDL |
very lowdensity lipoprotein |
|
TLC |
thin-layer chromatography |
|
VlsE |
variable lipoprotein surfaceantigen of Borrelia |
|
TLE |
temporal lobe epilepsy |
|
VP |
variegate porphyria |
|
TNF |
tumor necrosis factor |
|
VZV |
varicella-zoster virus |
|
TP |
thymidinephosphorylase |
|
WHO |
World HealthOrganization |
|
Tp |
Treponemapallidum |
|
WNV |
West Nile virus |