Reading Assignment: (1) Text Chapter 58
1. ANATOMY OF THE CENTRAL NERVOUS SYSTEM (CNS)
a. Organization of the nervous system
The nervous system is made up of neurons arranged in:
(1) a highly organized central part:
a. brain (cerebrum, brainstem, and cerebellum)
b. spinal cord – an extension of the CNS beginning at the foramen magnum of the skull, and passing through the canal of the vertebral column down to the level of the 4th lumbar vertebra.
(2) a peripheral part - bundles of nerves (sensory and motor axons) radiating from the brain to all parts of the body.
b. The Ventricles and the Choroid Plexuses of the Brain
As the CNS develops from a hollow tube in the developing embryo, the cavity of the tube develops into the four interconnected ventricles (small cavities) of the brain. In each of the ventricles, certain portions of its lining cells become integrated with the highly vascular, innermost covering of the brain (the pia mater, see below). These tissues, called the choroid plexuses, are attached to the roof of each ventricle, and they secrete cerebrospinal fluid.
Chorioid plexus – infoldings of blood vessels of the pia mater covered by a thin coat of ependymal cells that form tufted projections into the third, fourth, and lateral ventricles of the brain; they secrete the cerebrospinal fluid (1).
c. The Meninges (Membranes) of the Brain and Spinal Cord
The central nervous system is enveloped by fibrous coverings called meninges (Gr. meninx – membrane). The meninges are the three membranes that envelop the brain and spinal cord:
a. Dura mater – outermost covering, toughest, and most fibrous of the three meninges covering the brain and spinal cord. Composed of two layers.
b. Arachnoid mater– a delicate membrane between the dura mater and the pia mater, being separated from the pia mater by the subarachnoid space (1). (arachnoid = resembling a spider web.)
Subarachnoid space – space between the arachnoid and the pia mater. Normally filled with cerebrospinal fluid.
Lumbar cistern – a large subarachnoid space located between the end point of the spinal cord and the end of the dural sac. The spinal fluid pools in the lumbar cistern and this is the usual site for CSF sampling for diagnostic purposes.
c. Pia Mater - “tender mother” -the innermost of the three membranes covering the brain and spinal cord, investing them closely and extending into the depths of the fissures and depressions of the brain (1) . It is very thin and highly vascularized.
d. Cerebrospinal Fluid
(1) Definition The cerebrospinal fluid (CSF) is the fluid contained within the four ventricles of the brain, the subarachnoid space, and the central canal of the spinal cord.
(2) Formation, Circulation, and Absorption – the CSF is formed by the choriod plexuses and is circulated through the ventricles into the subarachnoid space, and into the tiny central canal of the spinal cord. It is absorbed into the venous system (the cerebral venous sinuses). The CSF pools in certain locations called cisterns and the lumbar cistern is the site for CSF sampling (see subarachnoid space, above).
(3) Volume, Composition, and Normal Pressure The volume of CSF in an adult is about 150 ml and the rate of CSF production is 550 ml/day. (The CSF turns over about 3.7 times/day). It is normally clear and colorless- an ultrafiltrate of plasma (1/300 the amount of protein as plasma)
(4) Function – the meninges and the CSF protect the brain when the head receives a blow.
f. The Blood Brain Barrier (and the Blood-CSF Barrier) act as natural anatomical barriers to prevent bloodborne invasion into the brain and CSF.
There are tight junctions between the capillary endothelium cells in the brain and between the epithelial cells in the choroid plexus which effectively prevent proteins from entering the brain and slow the penetration of smaller molecules. The rate of passage of molecules is inversely proportionate to their size and directly proportional to their lipid solubility. This limited exchange of substances into the brain is referred to as the blood brain (or blood-CSF barrier). (2)
Water, CO2, and O2 penetrate the brain with ease as do lipid-soluble forms of steroid hormones - proteins and polypeptides do not. Glucose, the source of energy for the brain, passively penetrates slowly, so it is transported across the walls of the brain capillaries by an active transport system. There are other active transport mechanisms for for Na+, K+, several organic acids, choline, nucleic acid precursors, and neutral, basic, and acidic amino acids. (2)
The blood brain barrier maintains the constancy of the environment of the neurons in the central nervous system. The neurons are dependent upon the concentrations of K+, Ca2+, Mg2+, H+ and other ions that minor variations have far-reaching consequences (2).
Only certain drugs (such as antibiotics) can penetrate the brain successfully. Their penetration is affected by their molecular size, protein binding, and lipid solubility. For example, penicillin and tetracycline enter the brain to a limited extent, while sulfadiazine and erythromycin enter with ease. (2)
The blood-brain barrier tends to break down in areas of infection, or injury (see below).
2. INFECTIONS OF THE CENTRAL NERVOUS SYSTEM
a. General Principles:
(1) The brain and spinal cord are protected from mechanical pressures, deformation and infection because they are enclosed in rigid containers (the skull and vertebral column).
(2) Microbial invasion of the CNS is uncommon, because of the blood brain barrier and the blood-CSF barriers which limit the spread of infection. These barriers break down in areas ofinfection or injury.
(3) A large number of viruses can grow and cause disease if directly inoculated into the brain, but circulating viruses generally fail to invade. CNS involvement by polio viruses, mumps, and measles viruses are seen in only a small proportion of cases. (Remember the iceberg concept of disease!) The factors that determine CNS invasion are not known.
b. What Are the Main Routes of Microbial Invasion of the CNS? (see Lecture 5 and 6)
(1). Via the Bloodstream (hematogenous spread) – commonest route (Ex.'s –meningococcus, pneumococcus, measles virus)
(2). Via peripheral nerve fibers (neuronal spread) -
a. One way spread – (Ex. rabies virus). Rabies virus is introduced into muscle by the bite of a rabid animal, infects the muscle fibers and enters peripheral nerves, travels to the CNS to reach the brain where it multiplies in the neurons. After extensive multiplication of the viruses in the brain, disease results due to dysfunction rather than cytopathic effect).
b. Two way spread – spread of herpes viruses in the axons to be delivered to the dorsal root ganglia (latency), and then back again during reactivation. Travel through peripheral nerves is not used by bacteria but by viruses and by bacterial toxins. Some viruses – like poliovirus use spread via the blood to the CNS, and it can spread along the nerves through nerve fibers)
(3). Local invasion from infected ears or sinuses, local injury, congenital defects, invasion from the olfactory route (amebic meningitis) - rare
c. Manifestations of CNS Disease (see Lectures 11 and 12)
(1) Definition of Disease
(2) Impact of disease in the CNS is profound because of the tissues involved:
a. passage of nerve impulses requires normal functioning in the nerve cells and nerve membranes
b. cellular or tissue edema (tolerable in most tissues) have serious consequences in the brain (enclosed in the rigid box – the skull).
(3) Disease results from the death of infected nerve cells (the lytic infections of polioviruses, the action of bacterial toxins), from interference with the function of the infected nerve cells (rabies virus), or from the host's inflammatory response to CNS invasion (bacterial meningitis, or viral encephalitis)
(4) Once the blood brain barrier or the blood-CSF is breached, neurological disease generally involves the meninges (meningitis) or the brain substance (encephalitis). Brain can also occur. See Text Fig. 58.3 for symptoms)
a. Meningitis – inflammation of the meninges
Invasive microbes reaches the bloodstream (bacteremia, septicemia), they localize in the vascular endothelial cells, and cross the blood-CSF barrier. Once infection has reached the meninges and CSF, the brain substance can in turn be infected if the pia mater is breached.
Two Major Forms of Meningitis: (see Text Table 536. May also be classified as acute and chronic)
(1) Aseptic meningitis – CSF is “clear” (cell counts in 100- 500/ul range – mononuclear cells predominate). Typically caused by viruses (most commonly By enteroviruses other than polioviruses and mumps virus), fungi, mycobacteria
(2) Septic meningitis – CSF is “cloudy” with over 1,000 WBC per ul – neutrophils predominate) Typically caused by bacteria; common in the very young, the very old, and the immunocompromised.
i. Different bacteria cause meningitis in patients of different ages (see Table 58.2)
ii. Acute bacterial meningitis is a life-threatening infection requiring immediate treatment with antibiotics (usually with corticosteroids).
b. Encephalitis – inflammation of the brain (Encephalomyelitis – inflammation of the brain and spinal cord.)
(Encephalopathy – any degenerative disease of the brain)
1. Caused primarily by viruses (see Text - Table 58.3).
2. Herpes simplex causes the most common form in the developed world (see case study Text p. 544).
3. Insect borne viruses – Eastern equine, Western equine, St. Louis, and La Crosse encephalitis viruses seen in the U.S.
4. Rabies is increasing in incidence because of its spread to new geographical regions of the United States.
5. HIV can cause subacute encephalitis, often with dementia
6. Slow virus infections of the brain: e.g. SSPE (see self study assignment and case study – Text p.545)
7. Infection of the brain by prions
a. kuru
b. Creutzfeldt-Jacob disease (CJD)
c. Brain Abscess
1. Usually associated with predisposing conditions – following surgery or trauma.
2. Seen in children with congenital hear disease or chronic infections of the bones and vasculature of the middle ear, mastoid, or sinuses. (see case study Text p. 546)
3. Usually involve mixed bacterial flora
4. Diagnosed clinically and by scans
5. Treatment by surgical drainage and antibiotics (usually a liphophilic and a B lactam antibiotic active against anaerobes is given.)
3. LABORATORY DIAGNOSIS OF CENTRAL NERVOUS SYSTEM INFECTONS
a. Analysis of CSF (See previous handout #9 – Laboratory Diagnosis) GO OVER CHANGES IN THE CNS WITH SEPTIC AND ASEPTIC MENINGITIS
1. Obtained if meningitis is suspected (will be negative for encephalitis or brain abscess).
2. Specimen
a. Obtained by lumbar spinal puncture
b. Three tubes are collected, processed immediately for:
(1) Cell counts and differential stains (performed directly on CSF) See Handout Table 7-2 (Values of cerebrospinal fluid in various infectious conditions – normal, bacterial and viral meningitis) (Text Table 58.4, p. 542)
(2) Gram stain and culture (performed on sediment of centrifuged CSF) CSF IS NORMALLY STERILE!
a. Gram-stained smears guides empirical treatment.
b. If S. pneumoniae suspected – Quellung test – presumptive i.d., N. meningitidis or H. influenzae – direct immunofluorescence with specific antisera to give a presumptive i.d.
c. Culture on blood and chocolate agar – 5% CO2
d. Antibiotic susceptibility testing
c. Protein, glucose, and special studies (antigen testing) (performed directly on CSF). Immunologic tests – can be performed on unprocessed specimens to detect the polysaccharide capsular antigens of S. pneumoniae, N. meningitidis, H. influenzae, and group B streptococci in CSF. Two most frequent tests - latex agglutination, counter immunoelectrophoresis)
b. Brain abscess – culture of wound and abscess specimens - blood agar – look for aerobes and anaerobes
c. Encephalitis – diagnosed clinically and by looking for antibodies in acute and convalescent serum samples
Material in this lecture outline was taken from: Mims, C., J. Playfair, I. Roitt, D. Wakelin, and R. Williams. 1998. Medical Microbiology. Mosby International Ltd., London, UK.
Additional References:
1. Dorland's Illustrated Medical Dictionary (26th ed), W.B. Saunders Co., Philadelphia, PA.
2. Ganong, W. 1997. Review of Medical Physiology (18th ed.), Appleton and Lange, Stamford, CT.