Marie Salomonov; 4163930

CEREBROSPINAL FLUID The cerebrospinal fluid (CSF) is a clear, colourless liquid which surrounds the spinal cord and brain. It has an important role in the immunological protection, metabolism and homeostasis of the CNS, as it provides a chemically stable environment, distributes nutritive materials and removes waste products; it also protects the brain from physical shocks and supports the venous sinuses (Agamanolis; 2013). CSF is found in the ventricular system inside the brain, major cisterns of the brain (e.g. cisterna magna, mesencephalic cistern), central canal of the spinal cord and in the subarchnoid space. In an adult the volume of CSF is between 140 to 270 ml and the rate of its production ranges between 0.2 to 0.7 ml per minute (Agamanolis; 2013). Apart from its function, this essay will describe CSF secretion and distribution and it will also briefly discuss some of its possible abnormalities and what these may indicate, emphasising the diagnostic use of CSF analysis. Production, Secretion and Absorption of the CSF The whole process of CSF production and secretion is achieved by combined processes of active transfer, diffusion and pinocytosis from arterial blood. Capillary filtration and epithelial secretory mechanisms are in place in order to control the chemical stability of the fluid (Kadel et al.; 2013).

Figure 1

Schematic diagram of CSF production and interfaces between blood, brain and CSF

Arrows indicate the passage of CSF from its formation at the choroid plexus to its absorption at the arachnoid villi (Terlizz et al.; 2006)

Marie Salomonov; 4163930

Some of the CSF is formed along ventricular walls and blood vessels and flows through perivascular channels, however, most of the CSF is produced in the lateral and fourth ventricles by a network of capillaries with fenestrated endothelial cells called choroid plexuses. These capillaries are covered by smooth ependymal cells, a type of As blood plasma enters the neuroglial cells with bulbous microvilli, which are linked by tight junctions that prevent the blood plasma from directly entering the ventricles. ependymal cells it is filtered while passing into the ventricles, forming CSF. The ependymal cells are thus said to control the composition of the CSF and maintain a blood-CSF barrier (Agamanolis; 2013). The circulation of CSF is propelled by the movement of cilia of ependymal cells as well as by the pulsation of the choroid plexus. From the lateral ventricles where most of the CSF is produced, the CSF passes through the foramen of Monro into the third and then through the cerebral aqueduct into the fourth ventricle. Most of the CSF then passes through a space within the meninges of the brain, and the the two subarachnoid space, through the medial foramen of Magendie lateral
Figure 2 Cerebrospinal fluid dynamics

foramina

of

Luschka

(Gray;

1918). Until it is reabsorbed into the venous circulation by the arachnoid granulations, the CSF then circulates

Arrows indicate the circulation of CSF (Brian et al.; 2002)

over the cortical surface of the brain and down the spinal canal. The CSF flowing over the cortical surface extends into the sulci in extensions of the subarachnoid space along blood vessels (Virchow-Robin spaces). In these perivascular spaces small solutes freely diffuse between the CSF and interstitial fluid and through the ependymal lining of the ventricular system. This process serves the movement of brain metabolites and thus helps to maintain the chemically stable environment of the CNS. Interstitial fluid flow across the ependymal surface into the ventricular system is also thought to be the source of a small amount of CSF (extrachoroidal CSF production) (Kandel et al.; 2013).
2

Marie Salomonov; 4163930

CSF leaves the cerebrospinal spaces in various locations and this process is often described as a dual as the fluid is reabsorbed to the venous circulation as well as drained into lymphatic vessels by way of perineural course. The return of CSF to the blood is managed through arachnoid granulations (clusters of villi) and villi which are located in the dural sinuses of the meninges and act as one-way valves between these sinuses and the subarachnoid space, whereas the absorption of CSF into the lymphatic system takes place around the cranial and spinal canal. It was established that the greater the CSF pressure is, the higher the rate of its absorption, suggesting that the rate of CSF absorption correlates with the CSF pressure (Gray; 1918). CSF Pressure Normal CSF pressure measured by a lumbar puncture is 8-15mmHg when the patient is lying on side lateral decubitus position, or 16-24mmHg for a sitting patient. It is usually assumed that the pressures are equal throughout the neuraxis when the patient is lying down, thus the CSF lumbar pressure can be used to estimate intracranial pressure. The Monro-Kellie doctrine states that an increase in volume of either brain tissue, blood, CSF, or other brain fluids will increase intracranial pressure, as the bone rigidity fixes the total cranial volume. Arterial and intracranial venous pressure changes can also affect intracranial pressure (influencing intracranial blood volume and CSF dynamics) (Kandel et al.; 2013). Several pathological conditions are characterised by an increased intracranial pressure, including brain oedema (increase in brain volume because of increased water content), or hydrocephalus (increase in volume of the cerebral ventricles) (Agamanolis; 2013). Normal CSF Composition and Pathological Abnormalities Under normal physiological conditions the CSF is clear in colour and together with the extracellular fluid of the brain it is in steady state and in osmotic equilibrium with the blood plasma. Compared to blood plasma, CSF is more acidic and has lower concentrations of K+, Ca2+, bicarbonate and glucose (Kandel et al.; 2013). In the table below, the average values of the major blood plasma and CSF constituents are compared.

Marie Salomonov; 4163930

Table 1 Comparison of Blood Plasma and Cerebrospinal Fluid Composition CSF* Water (%) Protein (mg/dL) Glucose (mg/dL) Osmolarity (mOsm/L) Na+ (mEq/L) K+ (mEq/L) Ca2+ (mEq/L) Mg2+ (mEq/L) Cl- (mEq/L) pH 99 35 60 295 138 2.8 2.1 0.3 119 7.33 Blood Plasma* 93 7000 90 295 138 4.5 4.8 1.7 102 7.41

*Average or representative values (Kandel et al.; 2013)

CSF analysis is a very useful tool when diagnosing diseases. variety Sample of of CSF neurological is usually

obtained by a and cell

lumbar puncture and More sophisticated

analysed for levels of protein and glucose count. methods (e.g. detection of oligoclonal bands) can be used to diagnose an ongoing inflammatory condition, such as multiple sclerosis. CSF of patients with multiple sclerosis also often contains myelin protein fragments and myelin 2013). basic Recent (Agamanolis;
Figure 3 Lumbar Puncture

studies showed that presence of three

The procedure involves insertion of a needle between the third and fourth lumbar vertebrae in the back and extracting a fluid sample. (2007 Terese Winslow)

specific protein biomarkers (amyloid 1-42, tau protein and P-Tau181P) in the CFS can indicate Alzheimers disease (Meyer et al.; 2010). Low glucose levels in CFS are often caused by leukocytes and/or tumour cells presence, as these consume glucose. Low glucose levels in the CSF may thus indirectly indicate suppurative, tuberculous and fungal infections or sarcoidosis as well as meningeal dissemination of tumours (Ravel; 1995). If blood is found in the CFS, it can indicate a subarachnoid haemorrhage and neutrophils and mononuclear cells might be indicative of meningeal irritation. Following
4

Marie Salomonov; 4163930

subarachnoid haemorrhage, the CFS colour changes to blonde (xanthochromia). This is caused by oxyhemoglobin and bilirubin. Sometimes this faint yellow, or even brown colouration can be observed by haemorrhagic infarcts, jaundice, and brain tumours. In patients with brain tumours (e.g. medulloblastoma), tumour cells may be found in the CSF. This usually indicates dissemination of the tumour in the subarachnoid space. A mononuclear inflammatory reaction is also one of the markers of brain tumours which can be found in the CSF (Ravel; 1995). Pleocytosis (increased inflammatory cells) may indicate infectious as well as noninfectious processes. Acute suppurative meningitis is indicated by polymorphonuclear pleocytosis, whereas mononuclear cells can be seen in viral infections, such as meningoencephalitis or aseptic meningitis, as well as tuberculous meningitis, multiple sclerosis, syphilis and neuroborreliosis (Agamanolis; 2013). Severe increase in CSF protein can be seen in individuals with Guillain-Barr syndrome and protein in CSF may also rise up to 500 mg/dL in patients suffering from bacterial meningitis. In inflammatory diseases of meninges (meningitis, encephalitis) the increase of protein is more moderate. Moderate protein increase can be also observed in patients suffering from subarachnoid haemorrhage, intracranial tumours, and cerebral infarction (Seehusen et al.; 2003). Challenges of Drugs Targeting the CNS Finally, after the brief description of possible pathologies which can be identified from patients CSF samples, the challenges of treatments of the different CNS pathologies should not be omitted in the conclusion. As described at the beginning of this essay, the CSF has an important role in immunological protection and maintenance of a chemically stable environment of the CNS which is distinct from the rest of the bodys environment. The tight junctions between the cerebral endothelial cells, between choroid plexus epithelial cells and at the blood-brain interface constitute the underlying control mechanism of the brains internal environment. This mechanism is based on diffusion restriction (tight junctions in the blood-brain and blood-CSF barriers) and different transport mechanisms which allow transport of allowed molecules (electrolytes, glucose, vitamins, peptides and amino acids) in and out of the brain and CSF (Saunders et al.; 1999). Analysis of a sample of the CSF allows for diagnosis of various neurological diseases, as the CSF composition can reveal certain biological markers specific to different diseases. If the delicate environment of the CNS is affected by an infection, or exhibits other
5

Marie Salomonov; 4163930

pathological symptoms, the drugs used to treat these must have specific physical and chemical properties in order to penetrate the above described barriers and get to their site of action. The barriers protecting CNS present a significant limiting factor as far as

pharmacological treatments of CNS diseases are concerned. It is assumed that lipid solubility and molecular size are one of the key factors which determine whether or not the drug can enter the CNS (Saunders et al.; 1999), however identification of chemical features which would allow entry of drugs into the brain and are important for the barriers permeability remain to be of major interest in the development of new CNStargeting drugs.

Marie Salomonov; 4163930

References Agamanolis; Neuropathology An illustrated interactive course for medical students and residents; Neuropathology-web.org, 2013. http://neuropathologyweb.org/chapter14/chapter14CSF.html. [Accessed on 13/4/2013]. Brian et al.; Atlas of Anaesthesia, Volume 2: Chapter 7; Current Medicine, 1998; Springerimages.com, 2002. http://www.springerimages.com.ezproxy.nottingham.ac.uk/Images/MedicineAndPublic Health/2-ACA0201-07-026. [Accessed on 15/4/2013]. Gray; Anatomy of the Human Body; Lea & Febiger, 1918; Bartleby.com, 2000. www.bartleby.com/107/. [Accessed on 13/4/2013]. Kandel et al.; Principles of Neural Science, Fifth Edition; McGraw-Hill Companies, Inc., 2013. Meyer et al.; Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people; Archives of Neurology, 2010; 67(8):949-956. Ravel; Clinical Laboratory Medicine: Clinical Application of Laboratory Data; Mosby, Inc., 1995. Saunders et al.; Barrier Mechanisms in the Brain, I. Adult Brain; Clinical and Experimental Pharmacology and Physiology, 1999; 26(1):11-19. Seehusen et al.; Cerebrospinal Fluid Analysis; American Family Physician, 2003; 68(6):1103-1108. Terlizz et al.; The function, composition and analysis of cerebrospinal fluid in companion animals: Part I Function and composition; The Veterinary Journal, 2006; 172(3):422-431.