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Quadrigeminal
Cisterna
Interpeduncular
cistern
Apical side
Basolateral
Pontine cistern
ambiens
cistern
Cisterna magna
Table 12.2 Comparison of blood plasma and cerebrospinal fluid
(CSF) composition
CSF Plasma
Protein (mg/dL) 35 7000
Glucose (mg/dL) 60 90
Na+ (mmol/L) 138 138
K+ (mmol/L) 2.8 4.5
Ca2+ (mmol/L) 2.1 4.8
Mg2+ (mmol/L) 2.3 1.7
– –
Cl
(mmol/L) 119 102
pH 7.33 7.41
12
INFECTION IN THE CENTRAL NERVOUS SYSTEM
Fig. 12.3 Subarachnoid cisternae. Enlargements of the subarachnoid
space form cisternae that contain cerebrospinal fluid.
mater (‘arachnoid’ means spider- like). This thin membrane, which completely encloses the wide subarachnoid
space, is composed of fibrous material and cells connected by tight junctions that seal the space. The arachnoid mater covers the surface of the brain like wrapping
paper. However, it does not extend into the individual
sulci. Extending from the arachnoid mater across the
subarachnoid space to the pia mater are numerous thin
extensions, called trabeculae, whose web- like appearance gives the arachnoid mater its name. Together, the
(outer) arachnoid mater and (inner) pia mater form the
leptomeninges. The subarachnoid space is filled with
CSF. Within the fluid are also many major arteries, which
then project deep into the brain tissue. In specific areas,
particularly around the brainstem, the subarachnoid
space enlarges to form cisterns because the arachnoid
mater does not dip into the contours of the brain (Fig.
12.3). The largest of these is the cisterna magna, which
lies between the cerebellum and the medulla. Folds of
the arachnoid mater project through the dura mater into
the superior dural sinuses. These are called arachnoid
villi or arachnoid granulations, and are involved in the
reabsorption of CSF into venous blood (see below). The
proliferation of arachnoid cells can lead to the formation
of meningiomas.
Pia mater
The third layer of the meninges is the pia mater (‘pia’
means gentle). This very fine layer of connective tissue
follows the contours of the brain, dipping down into the
sulci, like shrink- wrap tightly adhering to the CNS surfaces. It is highly vascularised, with small blood vessels,
and is permeable to CSF. Where small arteries enter the
brain, the pia mater is carried down for short distances
into the perivascular space.
side
(blood)
CSF
+
+
Na
+
Na
−
Cl
−
HCO
3
Fig. 12.4 Production of cerebrospinal fluid (CSF) by the epithelial cells
of the choroid plexus. Filled circle, primary active transport; open circles,
secondary active transport; filled rectangles, facilitated diffusion.
H
−
Cl
CO
H
+ H2O
2
H2CO
+
+ HCO
+
3Na
3
−
3
(CSF)
Na+/K+-ATPase
+
2K
+
K
−
Cl
−
HCO
3
Cerebrospinal fluid production and circulation
The CSF that bathes the brain has an ionic content
broadly similar to that of blood plasma, with some small
differences (Table 12.2). Under normal conditions, it con-
tains very little protein, no red cells and very few leucocytes. It contains glucose, at about 60% of the level found
in plasma, has a total volume of approximately 140 mL
and is clear in appearance.
CSF is produced at a rate of approximately 500–600
mL/day. Most of this (60%) is secreted by the choroid
plexuses of the lateral, third and fourth ventricles. The
remaining 40% is produced from the interstitial fluid. The
choroid plexuses consist of loops of capillaries covered
by a layer of specialized epithelial cells. These capillaries,
unlike brain capillaries which form the BBB (see later),
are capillaries that have small openings in their endothelium, known as fenestrae or fenestra, with a diameter of
approximately 60–100 nm. The choroid epithelial cells
selectively transport ions and glucose into the ventricles,
with water following osmotically (Fig. 12.4). The CSF
then flows through the ventricles into the subarachnoid
259THE NERVOUS SYSTEM
12
Superior
Subarachnoid
Arachnoid
granulations
Choroid
Lateral
sagittal sinus
Third ventricle
Aqueduct of Sylvius
Fourth ventricle
INFECTION IN THE CENTRAL NERVOUS SYSTEM
Fig. 12.5 Production and flow of cerebrospinal fluid (CSF). CSF is
secreted into the lateral, third and fourth ventricles, and flows into the
subarachnoid space. Arrows indicate flow of CSF.
Central canal
ventricle
space
space, via the lateral and median apertures of the fourth
ventricle. The ventricles are lined with ependymal cells.
These are simple epithelial cells with numerous microvilli
and one or two cilia on their apical surface. Their basolateral surface is in contact with astrocytic processes. After
leaving the ventricles, the CSF flows through the cisternae at the base of the brain, and then travels across the
cerebral and cerebellar hemispheres (Fig. 12.5). It is aided
by the movement of the microvilli and cilia of the ependymal cells that line the ventricles, and by its reabsorption into the venous sinuses. This reabsorption involves
movement of the CSF into the venous blood. Some of the
fluid drains into cervical lymph nodes via the sheaths
of the cranial nerves and into the spinal veins through
arachnoid projections. In some cases, CSF can accumulate
and lead to hydrocephalus (Box 12.3). Substances injected
into the CSF can travel freely into the brain.
Very little CSF flows through the central canal of the
spinal cord, which is not patent in most adults, but some
CSF flows within the subarachnoid space through the
foramen magnum, towards the lumbar region, reaching
the end of the spinal meninges in about 12 hours. The
meninges of the spinal cord extend to the S2 but the spinal cord extends only as far as the first or second lumbar vertebral level (L1, L2). The space below L2 forms a
large lumbar cistern containing CSF that can be sampled
by lumbar puncture (see Box 4.2). There is little danger
of damaging the freely floating spinal nerves, as they
will drift away from the point of the needle. However,
lumbar puncture should not be performed under circumstances of increased intracranial pressure, as this can
cause herniation of the brain.
plexus
Box
12.2
The meninges enclose the optic nerve all the way to the
retina. This means that raised intracranial pressure will be
transmitted through the subarachnoid space surrounding the optic nerve and the blood vessels of the retina, the
central artery and the central vein. Increased pressure will
compress the central vein, leading to enlargement of the
retinal veins and oedema of the optic papilla, which can be
seen when the rear of the retina, the fundus, is examined
with an ophthalmoscope (see Fig. 7.2B).
Box
12.3
Hydrocephalus (or ‘water on the brain’) is the abnormal
accumulation of cerebrospinal fluid (CSF). This can occur if
the flow of CSF through the ventricles and around the brain
is impaired, if there is a reduction in the reabsorption of
CSF, and rarely, if there is excess CSF production. The commonest cause of hydrocephalus is the obstruction of the
CSF flow from the fourth ventricle into the subarachnoid
space, with a consequent enlargement of the ventricles. In
babies, whose cranial sutures have not yet fused, this causes
enlargement of the head with thinning of the cerebral hemispheres. In adults, because the skull is rigid, the increased
pressure compresses blood vessels and damages brain tissue.
Papilloedema and fundoscopy
Hydrocephalus
An issue related to the circulation of fluids such as
CSF around the brain is that of removal of waste products from brain tissue, which is essential for homeostasis. Research in the last decade has led to the proposal
of the existence of a specialised system to carry out this
main function: the glymphatic (glia- lymphatic) system.
Besides waste elimination, the glymphatic system also
facilitates brain- wide distribution of substances including glucose, lipids, amino acids, growth factors and
neuromodulators. Another important discovery for the
understanding of fluid flow in the brain occurred in
2015, involving meningeal lymphatic vessels. According
to data collected in experimental models, the glymphatic flow is initiated by the CSF moving by convection
through the periarterial space, driven by arterial pulsatility. The astrocyte endfeet facilitate mixing with the
interstitial fluid and waste products therein. The aquaporin-4- 4 (AQP4) water channels expressed on astrocytic endfeet play an essential role in this process; AQP4
reduces the hydraulic resistance of cell membranes and
facilitates water flow into cells and out of cells. Fluids
are then driven towards the perivenous space and along
cranial and spinal nerves; ultimately, the fluid is directed
towards meningeal lymphatic vessels and the general
circulation. Observations in experimental models show
that glymphatic efflux of β- amyloid peptides has an
important role in the diurnal fluctuation in the levels of
these peptides, which suggests that the glymphatic flow
260 SYSTEMS OF THE BODY
12
P
PBM
A
E
Fig. 12.6 Cells forming the blood–brain barrier. The arrow indicates
the inter-endothelial tight junctions. A, Astrocyte; BM, basement
membrane; E, endothelial cell; P, pericyte.
could be targeted in Alzheimer’s disease. The inhibition
of the glymphatic- lymphatic waste flow leads to accelerated protein aggregation and cognitive decline in mouse
models of Alzheimer’s disease, Parkinson’s disease and
traumatic brain injury. It is interesting to note that glymphatic clearance is turned on during sleep and is largely
absent during wakefulness. It has been suggested that
the need for sleep, which is seen across species, may
be linked to this essential need for efficient and regular
brain waste product clearance.
A
E
BM
The blood–brain barrier
The BBB is a specialised microvascular structure at the
interface between blood and brain tissue; its main role
is to control the influx and efflux of substances into and
out of the CNS and so has a fundamental homeostatic
function. Various conditions that affect the CNS, such as
trauma, stroke and multiple sclerosis, can lead to significant disruption of the BBB and impair its function. The
existence of a specialised barrier was first proposed following the seminal observations made by Paul Ehrlich,
who noticed that a peripherally injected dye did not
stain brain tissue. The BBB is extensive; it is the largest
interface for blood–brain exchanges and the surface area
in an adult is between 12 and 18 m2. It is formed from
microvascular endothelial cells, which make up the continuous capillaries of the brain. The capillaries are continuous and non-fenestrated. The endothelial cells are
surrounded by a layer of basement membrane, which
itself is covered by a layer consisting of the endfeet of
astrocytes (Fig. 12.6). The maintenance of the barrier
function is based on the interaction between the microvascular specialized endothelium, the astrocytic foot
processes (which cover close to 99% of the abluminal
surface area of the brain capillary), and also pericytes.
The astrocytic endfeet do not touch the endothelial cells;
together with the pericytes, they are enclosed within
the basement membrane that is important in producing
factors that induce specific characteristics in the endothelial cells, which form the BBB. These characteristics
include high trans- endothelial resistance, which is due
to the length and complexity of the tight junctions and
the adherens junctions between the endothelial cells. The
tight junctions and adherens junctions lead to polarisation of cells, with an abluminal side (the brain tissue
side) and a luminal side (the blood side). Tight junctions
involve many specialised proteins. Three major protein
types are occludins, claudins and junction adhesion molecule proteins. The adherens junctions are established by
homodimers of the transmembrane protein VE- cadherin,
across adjacent endothelial cells. There are also very few
pores, either small or large, that cross the endothelium.
Transcytosis (transcellular transfer of molecules through
receptor- mediated capture, internalisation and transfer
across a cell soma) is limited. It is this ‘tight’ barrier that
prevents bloodborne compounds from freely entering the
brain, unless transported through specific mechanisms.
The brain endothelium is more restrictive, by a factor of 50–100, than other continuous capillaries. The BBB
is not an absolute barrier; small non-polar molecules
can enter through passive diffusion, but the majority of
compounds are subject to specific transport systems. A
key BBB characteristic is the presence of specific types
of transporters that move molecules into and out of the
brain (Fig. 12.7). Thus solutes, such as glucose, lactate,
amino acids and fatty acids, are transported through specific transporters: glucose transporter 1 (GLUT1), monocarboxylate transporter 1 (MCT1), L- type amino acid
transporter 1 (LAT1) and major facilitator superfamily
domain containing 2A transporter (Mfsd2a), respectively.
Other transporters provide receptor- mediated vesicular
transport, such as the transferrin receptor TRF1 and lowdensity lipoprotein receptors. Some of the transporters
have a key role in removing molecules from the CNS, for
example, the lipoprotein receptor- related protein 1 (LRP1)
which is linked to the transport of β- amyloid peptides.
The BBB also expresses efflux transporters. These transporters are expressed on the luminal side of membranes
and use the energy linked to ATP hydrolysis to transport
small molecules up their concentration gradient and into
the blood. They are also referred to as ATP- binding cassette (ABC) transporters. For example, P- glycoprotein
(P- gp), also known as multidrug resistance protein 1
(MDR1), is a multidrug transporter that acts to transport
lipophilic molecules out of the brain. The action of this
efflux pump, while protecting the brain from many xenobiotics, has the effect of reducing the movement of many
therapeutic drugs across the BBB. Another example of a
multidrug resistance protein (MRP) efflux transporter
is the breast cancer resistance protein (BCRP). The existence of these transporters has important consequences
for the treatment of brain- specific illness, as the drugs
have to gain access to the brain by travelling across the
BBB in some way. Drug transporters can be constitutively
expressed or induced, and their presence is a major mechanism underlying treatment resistance.
Several regions of the CNS around the third and
fourth ventricles have fenestrated capillaries that lack
the properties of the BBB; these are the circumventricular
organs (area postrema, subfornical organ, pineal gland
and median eminence of the hypothalamus) (Fig. 12.8).
INFECTION IN THE CENTRAL NERVOUS SYSTEM
261THE NERVOUS SYSTEM
12
Low transcytosis
Efflux transport Selective transport
Arachnoid
Ependyma
Subfornical
eminence
postrema
Blood
CNS parenchyma
Fig.12.7 Modes of substance transport across the BBB. The diagram shows internalisation through transcytosis and transport through specialised
efflux transporters or selective transporters. BCRP, breast cancer resistance protein; GLUT1, glucose transporter 1; LAT 1, L- type amino acid
transporter 1; MRP, multidrug resistance- associated protein; P- gp, P- glycoprotein. (From Profaci C.P. et al (2020). The blood-brain barrier in health
and disease: Important unanswered questions. Journal of Experimental Medicine. 217:1-16.).
INFECTION IN THE CENTRAL NERVOUS SYSTEM
MRPs LAT1
P-gp BCRP GLUT1
Pia mater
$
Brain parenchyma
vascularized with capillaries
possessing blood-brain
barrier properties
B
Subarachnoid space
Capillary
CNS CNS
Choroid
epithelium
Median eminence
Regions of the brain vascularized
with fenestrated capillaries
Choroid fissure
Ventricle
Choroid
plexus
Choroidal
capillary
organ
Organum
vasculosum
of the lamina
terminalis
Median
Neurohypophysis
Area
Fig. 12.8 The choroid plexus and brain regions with typical specialised capillaries with BBB properties or with fenestrated capillaries. (A)
Composition of choroid plexus. Fenestrations of a choroidal segment of a capillary, showing that substances that escape from the blood into
the choroid plexus are stopped by tight junctions (black bars) between choroid epithelial cells. (B) Brain regions with typical specialised capillaries
with BBB properties or with fenestrated capillaries. The diagram illustrates the limited areas in the CNS where there are fenestrated capillaries,
the circumventricular organs, which lack BBB properties. (From (A) Vanderah TW, Gould DJ. (2016) Nolte’s The human brain: an introduction
to neuroanatomy, seventhth ed. Elsevier; (B) adapted from Profaci C.P. et al (2020). The blood-brain barrier in health and disease: Important
unanswered questions. Journal of Experimental Medicine. 217:1-16.).
262 SYSTEMS OF THE BODY
12
They contain receptors which monitor the composition
of the extracellular fluid for hormones and other chemical substances.
The choroid plexus is the site of the blood–CSF barrier. It
consists of (1) a stroma made of fenestrated capillaries, surrounded by connective tissue containing immune cells and
(2) epithelial cells. The epithelial cells are linked through
tight junctions, adherens junctions and gap junctions.
Certain pathogens can access the CNS through loosening
of the tight junctions, leading to paracellular infiltration.
The choroid plexuses can also be the site of development of
tumours such as choroid plexus papilloma and carcinoma.
Meningitis
Meningitis is an inflammation of the pia and arachnoid
mater, often of infectious nature, indicated by an increase
in the number of white cells detected in the CSF. Meningitis
is most commonly caused by a wide variety of infective
agents; however, there are also non-infective causes, such as
contrast medium, certain drugs and also tumours. It is normally confined to the subarachnoid space, rather than the
subdural space. Infective agents can access the CSF directly
via the sinuses or the nasopharynx, through fractures of the
skull or, most commonly, from the blood stream.
Meningitis occurs as a result of either organisms crossing the BBB during systemic infection or a breakdown of
the barrier due to a skull fracture or neurosurgery. A contiguous infection of the middle ear or paranasal sinuses
can lead to infection of the meninges. However, the most
common route is through the blood, and subsequent
crossing of the BBB. Initially, pathogens colonise and
invade epithelial surfaces in the respiratory tract, gastrointestinal tract or lower genital tract. Environmental factors
(e.g. smoking or alcohol abuse) and genetic factors contribute to the susceptibility of individuals to blood stream
infections. Other host factors include complement system deficiency, immunosuppressive treatment and antibody deficits. Bacteria need to survive the environment
of the blood stream, and the polysaccharide capsules of
organisms such as Neisseria meningitidis, Streptococcus
pneumoniae and Haemophilus influenzae provide protec-
tion against attack by opsonins, which are extracellular
proteins that act as tags to induce circulating phagocytes
to phagocytose the pathogens. How the BBB barrier is
breached is not fully understood. It may be that toxins
produced by bacteria in the blood stimulate an increase in
the permeability of either the BBB or the blood–CSF barrier. A further possibility is that organisms cross into the
brain in areas such as the area postrema, a circumventricular organ in the medulla oblongata, devoid of BBB.
Bacterial meningitis
Meningococcal infection is the leading cause of bacterial meningitis in the UK. During 2018–19, Public Health
England confirmed 526 cases of invasive meningococcal
disease. It should be noted that other bacteria can also be
Table 12.3 Possible causes of bacterial meningitis
Neisseria meningitides (meningococcus)*
Streptococcus pneumoniae (pneumococcus)*
Staphylococcus aureus
Haemophilus influenzae (type b)
Escherichia coli
Mycobacterium tuberculosis
Listeria monocytogenes
†
*Major causes of meningitis.
†
Almost eliminated due to vaccination.
associated with meningitis (Table 12.3). Most cases are
sporadic; only approximately 1% of cases are secondary
to other known cases.
There are several different serogroups of N. meningiti-
dis associated with different risk groups. Most meningitis
occurs in children under the age of 4 years, with the greatest
age- specific risk at 6–12 months. This is mainly due to serogroup B, but also to serogroup C. There is a second peak in
meningitis occurrence in late adolescence, largely due to
serogroup C. Serogroup A infection occurs mainly in nonindustrialized countries and is associated with epidemics.
Certain parts of the world, such as sub- Saharan Africa, have
experienced recurring large- scale episodes of meningitis for
over a century. There is clear seasonality: outbreaks begin at
the beginning of the dry season and end at the beginning
of the wet season. This suggests that there are critical specific environmental factors, such as the effect of dry weather
on mucous membranes and the impact of weather changes,
that affect the transmission of respiratory viruses.
Vaccines against the meningococcal serogroups A, B, C,
W and Y are available as single forms or combinations. In
the UK, vaccination against serogroup C was implemented
in England and Wales in 1998, and serogroup B vaccination in 2015. Vaccination programmes worldwide have
resulted in significant decreases in the rate of meningitis
caused by the bacterial strains covered by the vaccines.
Meningococci are ubiquitous Gram- negative diplococci. Many people carry meningococci in the nasopharynx and they are passed from person to person by close
contact, but most strains are non-pathogenic. However,
up to 1% of the population may carry pathogenic strains.
The main risk seems to be the recent emergence of a new
strain, but it is unknown why a small minority develop
meningitis and most people do not.
A particular symptom of meningococcal meningitis
is a haemorrhagic rash (Fig. 12.9). This is due to leakage
of blood from capillaries into the skin. This can produce
petechiae, which are small skin haemorrhages that vary
in size from pinpoints to a few millimetres. The rash
does not blanch on pressure as can be seen clearly when
a glass is pressed on the skin. However, this sign may be
sparse and does not occur in all cases, being most common in the more severe forms of the disease. Septicaemia
is a dangerous complication of meningitis (Box 12.4).
INFECTION IN THE CENTRAL NERVOUS SYSTEM
263THE NERVOUS SYSTEM
12
Fig. 12.9 Meningococcal rash. The rash usually manifests
itself very early on. It will typically appear as red or purple
spots that do not fade upon application of pressure. The
spots are caused by bleeding underneath the skin. (From
https://www.firstderm.com/life- threatening- skin- rashes/.)
There are two other main bacterial causes of men-
INFECTION IN THE CENTRAL NERVOUS SYSTEM
ingitis. These are Haemophilus influenzae type b and
S. pneumoniae. H. influenzae infection usually occurs in
young children (<5 years of age), but since the introduction of the Hib vaccine in 1992, this has all but disappeared in the UK. The few cases that still occur mostly
affect adults with underlying medical conditions, rather
than children. The bacteria can be spread by individuals
who are ill with the infection and by healthy people who
are carriers. S. pneumoniae infection is usually associated
with young infants, the elderly with respiratory infections or otitis media (inflammation of the middle ear lining). In neonates the most common causative agents are
Escherichia coli and group B Streptococcus.
A further cause of bacterial meningitis, which is
more common in developing countries, is infection with
Mycobacterium tuberculosis, which causes tuberculous
meningitis. This form of meningitis is slow in onset, may
occur years after the primary infection and may be preceded by non-specific symptoms.
Other bacteria, such as Staphylococcus aureus and
Listeria monocytogenes, have been associated with meningitis, particularly in immunocompromised patients (see
Table 12.3).
Even in the absence of septicaemia, meningitis is still
a medical emergency, with the main pathology being
cerebral oedema. Once the bacteria survive the passage
through the blood stream, they are ready to invade the
subarachnoid space; high levels of bacteraemia prompt
the entry into this space. It is likely that the weakest
point of entry is offered by post- capillary venules. The
initial adhesion step involves proteins expressed by the
pathogens, such as the bacterial adhesion outer membrane protein porin A (for Neisseria meningitides), which
interact with laminin receptors expressed by brain endothelial cells, and may also involve other factors such as
platelet- activating factor receptor. Ultimately, transcellular and paracellular passage is achieved by the pathogens. In the subarachnoid space there are relatively few
phagocytic cells and also low levels of complement. In
Box
12.4
When the infection due to Neisseria meningitidis spreads in
the blood, a severe form of septicaemia can occur. There is
a large drop in blood pressure, due to reduced peripheral
resistance. This occurs because of the action of the bacterial endotoxin, which, via increases in nitric oxide synthesis, causes relaxation of vascular smooth muscle. There is
increased secretion of a pro- inflammatory cytokine, interleukin- 1, which increases capillary permeability. The flow
through capillary beds becomes very slow, and eventually
clotting factors can accumulate and produce inappropriate
clotting in tissues. This is called disseminated intravascular
coagulation. As well as reducing blood flow still further
and preventing the supply of oxygen and removal of acid
products of metabolism from the tissues, this depletes the
available clotting factors, allowing blood to haemorrhage
from the leaky blood vessels. The severe reduction in blood
flow leads to metabolic acidosis, and eventually to skin and
limb necrosis.
Septicaemia and meningococcal
meningitis
normal CSF, the complement system (part of the innate
immune system that enhances (complements) the ability
of antibodies and phagocytic cells to attack and remove
pathogens and damaged cells from an organism, and
to promote inflammation) level is too low to have effective anti-bacterial impact. Specialised receptors that
detect pathogens—the pathogen recognition receptors
(PRR)—are virtually absent and this enables invading
bacteria to multiply very rapidly, in a matter of hours
after infection. Once the pathogens reach high numbers
they begin to die, because of competition for nutrients,
and this releases bacterial fragments that are recognised
by PRR expressed by immunocompetent cells (e.g. macrophages and dendritic cells) expressed in the tissue
in the immediate vicinity of the CSF. An important category of PRR involved in this phase are Toll- like receptors (TLR), which are cell- membrane receptors that are
part of the innate immune system defences. Some of the
TLR recognise bacterial DNA, lipids and proteins. Other
key receptors are the nucleotide- binding and oligomerization domain NOD- like receptors (NLR), which are
highly conserved cytosolic PRR that detect the presence
of pathogen signals inside host cells. The NLR are key
regulators of the inflammatory response and cell death
pathways. The concerted action of TLR and NLR leads
to activation of transcription factors such as NF- κB, a
master regulator of inflammation cascades, and also
to activation of the complement system. The latter consists of more than 30 distinct molecular components that
synergise and initiate bactericidal attack and thus lead
to further enhancement of the inflammation. There is
increased production of inflammatory cytokines, such as
interleukin- 1 and tumour necrosis factor, which increases
the permeability of the BBB and attracts large numbers
of polymorphonuclear leucocytes. These cells release
264 SYSTEMS OF THE BODY
12
Table 12.4 Some non-bacterial causes of meningitis
Type of organism Examples
Viruses Enteroviruses (Echovirus, Coxsackie virus types
A and B)
Mumps
Poliovirus
Epstein–Barr virus
Herpes viruses (herpes simplex and herpes
zoster)
Human immunodeficiency virus
Fungi Cryptococcus neoformans
Candida spp.
Spirochaetes Leptospirosis, Lyme disease, syphilis
cytotoxic products: reactive oxygen species, reactive
nitrogen species and also proteases, which can initiate
necrotic cell death. Protein leaks across the endothelium,
and water follows, due to the increase in interstitial colloid osmotic pressure, producing cerebral oedema. This
raises intracranial pressure and the associated risk of
herniation. A poor prognostic feature is the depression of
consciousness.
Meningitis can induce significant brain injury, through
initiation of cell death processes (necrotic and apoptotic)
and pathological changes in the vasculature, for example, vasculitis and vasospasm. Cerebral infarction can be
triggered by thrombosis or embolism.
Aseptic and viral meningitis
The term aseptic meningitis is used to describe cases in
which there are clinical signs of meningitis, but bacteria cannot be cultured from the CSF. This type of meningitis can have a wide range of causes, including viral
and other non-bacterial infections, such as with fungi
and protozoa (Table 12.4). Meningitis can also have non-
infective, inflammatory causes such as sarcoidosis (a condition characterised by the formation of small collections
of inflammatory cells in various organs). Despite recent
advancements in molecular diagnosis techniques, aseptic
meningitis remains challenging to diagnose and consequently remains underreported worldwide.
Many different viruses can cause meningitis. As the
incidence of bacterial meningitis decreases, the proportion of meningitis cases caused by viruses is increasing. In the UK, a study published in 2018 estimated the
annual incidence of viral meningitis in adults at 2.73 per
100,000.
Viruses can reach the CNS from the blood stream
or through retrograde transmission from nerve terminals at the periphery. They may also emerge after reactivation of a dormant virus already present in the CNS.
The majority of viral aetiology of aseptic meningitis
remains unknown. Before the introduction of the measles, mumps and rubella (MMR) vaccine, mumps- related
meningitis was the leading cause of viral meningitis. The
mumps virus is neurotropic and can directly infect the
epithelium of the choroid plexus, whereas enteroviruses
are dependent on hematogenous spread. The latter have
been found to be the underlying cause of most viral meningitis cases worldwide.
Viral meningitis has a specific seasonality, being common in summer and autumn. Immunocompromised
patients have a higher risk of developing this type of
meningitis. The penetration of the virus is likely to occur
through respiratory secretions or the faecal- oral route.
The primary infection of the respiratory and gastrointestinal tracts is followed by secondary infection of the
CNS. Viral meningitis has a similar pathophysiology
to bacterial meningitis, with the infection triggering a
strong inflammatory response. There are increased levels of pro- inflammatory cytokines such as interleukin1β (IL- 1β) and interleukin- 6 (IL- 6). Viral meningitis is
usually less severe than bacterial meningitis and is selflimiting, lasting for 4–10 days. In general, there are few
long- lasting major neurological sequelae. However, some
patients do report a higher level of depression, anxiety
and neurocognitive dysfunction a long time after the
infection has cleared. Furthermore, enteroviral meningitis can lead to complications such as meningoencephalitis, myocarditis and pericarditis. Deaths can occur in
immunocompromised patients who are vulnerable to
infection with opportunistic pathogens and fatal sepsis.
Diagnosis and treatment of meningitis
Meningitis is usually diagnosed by a combination of clinical features and laboratory diagnostic tests. Meningitis
usually presents with headache (often of rapid onset),
fever, neck stiffness, photophobia and vomiting. In some
types of meningitis there is also a rash. There may be
altered consciousness, seizures and focal signs (aphasia,
hemiparesis or nerve palsies). The headache may be due
to inflammation of the supratentorial dura innervated by
the trigeminal nerve, while the neck stiffness and reflex
neck retraction are due to reflex contraction of the posterior nuchal muscles supplied by the cervical nerves that
also innervate the infratentorial dura. Patients may show
a positive Kernig’s sign: after flexion of the leg at the hip,
extension of the knee produces lower back pain, indicating irritation of the meninges.
The progression of bacterial meningitis is so rapid
that when meningitis is suspected, treatment should
be started before laboratory results are available. Early
involvement and advice from a clinical microbiologist
can be lifesaving. Intravenous cephalosporin compounds
(ceftriaxone or cefotaxime) can be used as emergency
treatment. A penicillin compound (e.g. benzylpenicillin,
amoxicillin or ampicillin) can also be given immediately,
either intravenously or intramuscularly, by the first doctor to suspect meningitis. A broad- spectrum antibiotic
can be given for protection against both meningococcal
INFECTION IN THE CENTRAL NERVOUS SYSTEM
265THE NERVOUS SYSTEM
12
Identified pathogen
Streptococcus
pneumoniae
Penicillin MIC
Susceptible
<0.06 µg per mL
Penicillin G,
INFECTION IN THE CENTRAL NERVOUS SYSTEM
amoxicillin
or ampicillin
Cefotaxime
or
ceftriaxone
Isolated bacterium
Resistant
>0.12 µg per mL
Cefotaxime or
ceftriaxone MIC
Susceptible
<1.0 µg per mL
Cefotaxime
or
ceftriaxone
Cefepime
or
meropenem
Resistant
>1.0 µg per mL
Vancomycin
plus either
cefotaxime
or ceftriaxone
Vancomycin
moxifloxacin
Drug sensitivity test Recommended therapy Alternative therapy
monocytogenes
plus
Listeria
Amoxicillin,
ampicillin
or penicillin
Trimethoprim-
sulfameth-
oxazole
Susceptible
<1.0 µg per mL
Penicillin G,
amoxicillin
or ampicillin
Cefotaxime
ceftriaxone
meningitidis
Penicillin MIC
or
Neisseria
Resistant
>1.0 µg per mL
Cefotaxime
or
ceftriaxone
Cefepime,
fluoroquinolone
or meropenem
Streptococcus
agalactiae
Amoxicillin,
ampicillin or
penicillin G
Cefotaxime,
ceftriaxone
or
vancomycin
Haemophilus
β-lactamase test
Negative Positive
Amoxicillin
or ampicillin
Cefotaxime,
ceftriaxone,
cefepime,
aztreonam or
fluoroquinolone
influenzae
Cefotaxime
or
ceftriaxone
Cefepime,
fluoroquinolone
or meropenem
Escherichia coli
Amoxicillin
or ampicillin
plus an
aminoglycoside
Cefotaxime,
ceftriaxone
or
vancomycin
Fig. 12.10 Antibiotic therapy regimes for bacterial meningitis. Examples of therapies based on in vitro sensitivity testing. Alternative therapies
are chosen if there are contraindications to the recommended therapy. MIC, Minimum inhibitory concentration. (From de Beek D. et al. (2016)
Community-acquired bacterial meningitis, Nature reviews Disease Primers. 2:1-20.)
and pneumococcal pathogens. Aminoglycosides such as
vancomycin can be added to treatment. An overview of
the therapeutic algorithm for the treatment of bacterial
meningitis, taking into account a determination of bacterial sensitivity in vitro, is shown in Fig. 12.10.
will be predominantly neutrophils, while in other types
of meningitis, especially viral, they are mainly lymphocytes (Table 12.5). Approximately 1%–2% of patients
with bacterial meningitis will have a normal leucocyte
count. The presence of bacteria will make the CSF turbid
or even clearly pus- containing and, reflecting the break-
Cerebrospinal fluid sampling and changes in
cerebrospinal fluid composition
down of the BBB, there will be higher than normal levels of protein. Because of the utilization of CSF glucose
by metabolizing bacteria, levels will be abnormally low
Meningitis can be diagnosed after sampling the CSF
through a lumbar puncture (see Box 4.2, Fig. 4.2).
However, if there are any signs of focal intracranial disease or raised intracranial pressure (see Box 7.2), and
if subsequent neuroimaging reveals any evidence of
impaired CSF circulation, lumbar puncture should not
be carried out due to risk of brain herniation. It is also
contraindicated in severely ill children, as it may lead to
deterioration. Throat swabs can indicate the presence of
meningococcal infection.
Normal CSF is clear and contains very few cells.
Inflammation of the meninges will increase the number
of immune cells present. In bacterial meningitis, these
in bacterial meningitis. CSF pressure is raised, and CSF
flow may be impaired due to adhesions of the meninges
and the presence of pus.
Culture of CSF (and blood) can reveal the type of
bacterial infection present. This is important not only in
order to determine the optimal antibiotic combination to
use in further treatment, but also to obtain data about the
antibiotic sensitivity of the bacteria. While N. meningiti-
dis remains sensitive to penicillin, a significant number of
H. influenzae strains and some S. pneumoniae strains show
antibiotic resistance (Box 12.5).
Bacteria in cases of meningitis can be identified by
examining cultures. Morphology and Gram staining will
266 SYSTEMS OF THE BODY
Table 12.5 Comparison of cerebrospinal fluid in different types of meningitis compared to normal conditions
Type Cell count Cell types Protein Glucose
Bacterial >200/μL Polymorphs >1.5 g/L <40 mg/dL
Viral 50–200/μL Lymphocytes <1.0 g/L Normal (40–70 mg/dL)
Normal <5/μL Lymphocytes <0.45 g/L Normal (40–70 mg/dL)
12
INFECTION IN THE CENTRAL NERVOUS SYSTEM
Box
12.5
Both the penicillins and cephalosporins are β- lactam
antibiotics (they contain a β- lactam ring in their structure), and act by inhibiting one of the final stages of the
synthesis of peptidoglycan, which forms the cell wall of
Gram- positive bacteria. More recent broad- spectrum β-
lactams are also active against some Gram- negative bacteria. However, some bacterial strains have developed
resistance to some of these antibiotics. One of the main
mechanisms of this resistance is the production by bacteria of β- lactamases, enzymes which destroy the antibiotics
by cleaving the β- lactam ring. This has led to the development of β- lactam antibiotics that are β- lactamase resistant, such as flucloxacillin. β- Lactam antibiotics can induce
various adverse effects, including nausea, diarrhoea and
rashes. Chloramphenicol acts in a different way from
the β- lactams, by inhibiting bacterial protein synthesis.
Resistance to chloramphenicol is due to the production by
the bacteria of acetyltransferase enzymes, which inactivate the antibiotic by acetylation. Clavulanic acid is a compound that acts as an inhibitor of β- lactamase; it can be
co- administered with β- lactam antibiotics, to overcome the
impact of β- lactamases.
group of Gram- positive bacteria that are associated with
infections that are very difficult to treat. The increased
resistance of this type of bacterium to antibiotics may
have evolved naturally or could be a consequence of
horizontal gene transfer (e.g. through transfer of gene
material between bacteria through conjugation). MRSA
is a common cause of hospital- acquired infections and
is a significant risk in patients with a weak immune system, or with open wounds or invasive devices, which
provide a route of access and invasion. When MRSA
invades the CNS, there can be development of brain
or spinal epidural abscesses. Vancomycin and teicoplanin are glycopeptide antibiotics that are effective in
most cases, but there are reports of resistance to these
drugs. Alternatively, more recent antibiotics such as the
streptogramins and oxazolidinones can be tried. Thus
second- line therapy may include telavancin, ceftaroline
and linezolid. Phage therapy, that is the use of bacteriophages to attack the resistant bacteria, is used in
some countries, and is the object of renewed interest in
research.
Antibiotic resistance
Methicillin- resistant Staphylococcus aureus (MRSA) is a
differentiate between the three main bacterial causes and
the Ziehl–Neelsen stain identifies acid- fast bacilli such as
Mycobacterium. However, these are only seen in approximately 20% of cases of tuberculous meningitis. Indian
ink can be used to stain fungi.
One of the problems with culturing CSF (and blood)
is that it can take some time and, in the case of tuberculosis, may take many weeks. Newer tests enable the
causative agents to be identified more quickly. Antigen
detection of specific polysaccharides present on the bacterial cell walls, in the CSF or urine, can be used to detect
some bacteria. CSF analysis using the technique of DNA
amplification by the polymerase chain reaction (PCR)
can detect both bacteria and viruses with high sensitivity. PCR is the ‘gold standard’ for viral meningitis and is
increasingly used for bacterial meningitis.
Blood cultures should also be initiated on admission,
before lumbar puncture and the beginning of antibiotic
treatment. Blood PCR analysis is increasingly important.
Treatment of meningitis
It is very important that antibiotic treatment is initiated
immediately on suspicion of bacterial meningitis, as it
is still a condition associated with significant mortality. For example, even when meningococcal meningitis
is diagnosed early and adequate treatment is started,
8%–15% of patients will die, often within 24–48 hours
after the onset of symptoms. The treatments of choice
for meningococcal and pneumococcal infection are benzylpenicillin and cephalosporins (cefotaxime or ceftriaxone); previously, ampicillin and chloramphenicol were
recommended for the treatment of H. influenza meningitis. However, resistance to both these antibiotics has
emerged (see Box 12.5). Specifically, strains of this bacterium produce β- lactamase, which degrade the β- lactam
antibiotics, and others are resistant through reduced
affinity for penicillin- binding proteins. If the causative
agent has not yet been identified, a combination of these
drugs could be used. The antibiotic treatment should be
continued for 7 days after the fever has ceased (14 days
for pneumococcal infections). Antibiotics can be combined with steroids.
Other treatment should be aimed at reducing the fever
and providing pain relief for headaches. Anticonvulsants
should be used for patients with seizures. In cases of septicaemia, fluid balance must be strictly monitored and, if
possible, controlled. Septicaemia can lead very rapidly
267THE NERVOUS SYSTEM
12
to severe shock, disseminated intravascular coagulation
and multi- organ failure.
β- Lactam antibiotics disrupt bacterial cell walls,
releasing more of the lipopolysaccharides that cause the
inflammatory response. In this way, the treatment can
exacerbate the pathology. In cases of infection with H.
influenzae and S. pneumoniae there is evidence that pre-
treatment with steroids (e.g. dexamethasone) can reduce
the subsequent cerebral oedema and reduce the potential after- effects, such as deafness. However, this has not
been shown for N. meningitidis and the need for rapid
antibiotic therapy would make any delay dangerous.
Bacterial meningitis can progress extremely rapidly
and any delay in treatment can increase morbidity and
mortality. The most serious form of meningococcal meningitis involves septicaemia and this accounts for most of
the significant mortality (up to 57%) associated with this
type of meningitis. If septicaemia is not present, the mortality rate drops to 3%, which is lower than that for H.
influenzae (4%–5%) and S. pneumoniae (10%).
There is no specific treatment for viral meningitis.
INFECTION IN THE CENTRAL NERVOUS SYSTEM
Anti-viral drugs such as acyclovir have only proven to be
of benefit in viral encephalitis (see later in the text). Viral
meningitis patients can suffer long- term cognitive and
psychological sequelae.
Tuberculous meningitis is the most serious extrapulmonary complication of tuberculosis—an infection
caused by the bacterium M. tuberculosis, a pathogen
discovered more than a century ago by Robert Koch.
Tuberculosis continues to be a health problem in many
parts of the world. It can affect various organs; the pathogen can persist in the host for a long time and can also
develop multi- drug treatment resistance. WHO guidelines for treatment recommend treatment with rifampicin, isoniazid, pyrazinamide and ethambutol for the
first 2 months, followed by up to 10 months of rifampicin and isoniazid. Pyridoxine (vitamin B6) is added to
avoid isoniazid- induced peripheral neuropathy. Secondline treatments include levofloxacin, moxifloxacin, amikacin, kanamycin and linezolid. There is also focus on
the development of new host- directed therapies, which
could enhance the protective immune response or regulate the pathological immune response to infection.
There is some evidence that dexamethasone used as
adjunctive treatment can lead to survival benefits.
Long- term sequelae of meningitis include hydrocephalus, cranial nerve palsies, visual and motor deficits and
epilepsy. In children, there may be behavioural disturbances, learning difficulties, hearing loss and epilepsy.
Bacterial meningitis during childhood can have a longlasting effect on educational attainment.
Meningitis and meningococcal septicaemia are statutory notifiable diseases in England, Scotland and Wales
and should be reported to the local Consultant in
Communicable Disease Control (CCDC). Any immediate
contacts and family members of a patient with meningococcal meningitis are at increased risk (800- fold) and
should be given antibiotic prophylaxis with rifampicin,
ceftriaxone or ciprofloxacin in order to eradicate bacteria.
Table 12.6 Causes of viral encephalitis
Sporadic
Herpes simplex (HSV)
Herpes zoster
Cytomegalovirus
Epstein–Barr virus
Adenovirus
Human immunodeficiency virus
Epidemic
Arboviruses
Eastern equine encephalitis virus
Japanese B arbovirus
Despite the progress made in recent decades regarding
the management of bacterial meningitis, it remains one of
the most dangerous and widespread infections worldwide.
Prevention of the disease and early initiation of treatment
can limit the morbidity and mortality. Vaccination programmes have made a significant impact, but there is need
for sustained vigilance against new strains. Additionally,
there is increased concern over the emergence of microbial
antibiotic resistance. Apart from improved antibiotics, there
is a need for novel treatment strategies based on modulation of the host immune response and regulation of the
damage induced by the pathophysiological cascades that
lead to production of compounds toxic to host cells during
the invasion by pathogens.
Encephalitis
Viral encephalitis is caused by several viruses (Table
12.6), that can be transmitted by animals, resulting in
sporadic or epidemic infection. Many sporadic infections
cause mild illness with headache and drowsiness, which
is self- limiting, but in more severe cases, patients have
altered behaviour, seizures, confusion or coma. Brain
swelling is common, with its associated risk of brain
damage.
In the UK, the most dangerous form of viral encephalitis is that caused by the HSV. While HSV can be
identified in CSF with the use of viral antigen immunoassays and amplification of viral DNA using PCR techniques, this is usually too slow to be of clinical use. For
this reason, patients with acute encephalitis should be
treated with acyclovir immediately, especially if there
is evidence of brain swelling on computed tomography (CT) scans (Box 12.6). There are no other specific
treatments for encephalitis, except ganciclovir, which is
active against cytomegalovirus. Patients may need treatment for seizures and cerebral oedema. Encephalitis
may occasionally be caused by other organisms, such as
Mycoplasma, Rickettsia (typhus) and Histoplasma.
268 SYSTEMS OF THE BODY