How do nerve cells exchange information?
What do an electric cable and a nerve fibre have in common?
How does the CNS control border traffic?
In the following you will learn how a nerve impulse is created and all about
the insulating layer of neurons.
The body's control centre
The human nervous system processes information from the environment and from
the body itself. It ensures humans can think, feel and act and that the inner
organs function in a complex interaction.
In the centre of this network is the brain that contains up to 100 billion
nerve cells or neurons. Together with the spinal cord it forms the central
nervous system (CNS).
Exchange of information by electricity
Nerve cells
- consist of a cell body, a thread-shaped projection (axon) and several extremely
branched tree-like extensions (dendrites)
- use electricity to communicate: if the stimulation of the cell body exceeds
a certain threshold, voltage builds up - the action potential
- transmit this energy via the axon like a flash
- possess special junctions with other nerve cells: the synapses
- receive information from other nerve cells via these synapses
Myelin as insulation
An insulating layer which covers the axon of the nerve cell like an electrical
cord ensures the quick and smooth transmission of electrical impulses: the
myelin sheath.
- This myelin sheath is formed by certain cells in the CNS, the oligodendrocytes
- The individual myelin sheaths are arranged on the axon like pearls on a
string
- They are separated from each other by Ranvier's nodes
- Thanks to the insulating myelin, nerve impulses can jump from one node to
the next
A nerve fibre covered with myelin can transmit a nerve impulse ten times
faster than one without a myelin sheath.
Protection from outside
The brain and spinal cord are very fragile.
In addition to the bones of the skull and the bony vertebral canal it is
protected by a fluid-filled cushion. This liquid - also known as cerebrospinal
fluid or liquor - is directly connected to the brain tissue fluid.
Protection from inside
The central nervous system protects itself with a special barrier to prevent
harmful substances passing from the blood into the brain.
The blood-brain barrier
- consists of blood vessel walls which at this interface are especially strong
- is built by endothelial cells and supporting cells which form especially
strong connections
- ensures that pathogens and immune cells floating in the blood do not access
the brain and the spinal cord, thus controlling border traffic.
Usually, inflammatory cells are not able to penetrate this barrier -
unless they camouflage themselves and can crack the required access code.
The immune system
How does our body ward off intruders?
Can immune cells communicate with each other?
Why does our body have to protect itself?
Learn more about how our immune system works and what self-tolerance is all
about on the following pages.
The immune system
protects the human body from pathogens such as bacteria, viruses and fungi.
In this regard, a general immune defence is distinguished from a specific
one.
The general or unspecific immune defence includes, among others:
- Leucocytes, a subgroup of the white blood cells
- Phagocytes or macrophages, and
- The complement system
The main role in the specific immune defence is played by a subgroup of white
blood cells - the lymphocytes. These include:
- T cells and
- B cells.
Mediators between such different cell types are the so called cytokines which
are important for the immune response.
In the end, the body has to protect itself from a possible attack using its
own immune defence system: at this point 'self-tolerance' is of
utmost importance.
The general or unspecific immune defence:
- includes the complement system which consists of different proteins constantly
patrolling the blood circulation
- it recognises intruders such as bacteria for example and tries to destroy
them by disintegrating their cell walls
- in this the complement system is assisted by macrophages or dendritic cells
- macrophages ingest the bacteria and digest them
- digested remnants of the bacteria are then deposited on the macrophage's
surface in the form of an antigen
- this 'antigen presentation' activates the specific immune defence
- for this purpose the antigen presenting cell moves into the next lymph node
Specific immune defence: T cells
- T cells are a subgroup of the white blood cells
- they possess special docking stations or 'receptors' which match
specific antigens only - like a key to a lock
- in the lymph node, T cells try to bind to the antigen-presenting cells
- if the antigen matches the receptor the T cell duplicates
- its clones leave the lymph node looking for pathogens whose parts were presented
by the antigen presenting cell
Specific immune defence: B cells
- B cells also belong to a subgroup of white blood cells
- their central function is the production of antibodies
- antibodies are located on the B cell's surface as receptors which
match specific antigens only
- if, for example, a matching bacterial antigen binds to the receptor the
then activated B cell starts dividing and produces specific antibodies
- these antibodies bind to the bacteria
- in doing this, macrophages are attracted again and become involved in the
elimination of the intruders
Cytokines - the silent messengers of the immune system
- cytokines are messenger substances which help the cells of the immune system
to communicate
- they are produced by very different immune cells
- if, for example, a T cell reaches the bacteria which it matches it binds
to them
- then the T cell calls for further assistance from the B cells by releasing
cytokines
Due to interaction of all parts of the immune system, foreign intruders are
successfully warded off and destroyed.
Self-tolerance
Usually a built-in self-protection ensures that the cells of the immune system
do not focus on the body's own healthy cells. This conditioning takes
place in the thymus, an organ of the lymphatic system and located above the
heart. Here is where the selection process of T cells takes place:
- T cells are formed in the bone marrow as immature cells
- in the thymus they develop to become differentiated T cells
- in this process, T cells are confronted by substances from the body itself
to which they try to bind
- if this is unsuccessful, the T cells are considered mature and correctly
programmed: they are released again and continue on their way
- if, however, a T cell finds a matching antigen it is eliminated
- this ';self-tolerance'; ensures that only those T cells survive
and replicate whose receptors do not focus on the body's own molecules.
Causes of multiple sclerosis
What does autoimmune disease mean?
Why do immune cells attack the body's own tissue?
How do inflammatory foci develop in the brain?
The decisive processes leading to the development of multiple sclerosis are
explained to you on the following pages.
A defect with consequences in the maturation process
Multiple sclerosis is an autoimmune disease. It is based on erroneously programmed
T cells which consequently are the cause of a defective maturation in the
thymus:
- during their maturation, T cells usually run through different tests in
the thymus
- these maturity tests are to ensure that T cells are able to distinguish
between the body's own and the body's foreign substances
- therefore the immune cells are presented with the body's own molecules
- T cells which are able to bind to these are usually destroyed so that they
can not attack any of the body's healthy cells
- due to a defect in the selection process a T cell which has bound to the
body's own molecules is overlooked
- the erroneously programmed autoimmune T cell survives, multiplies and, together
with its fellows, continues on its way.
Passing the blood-brain barrier
Normal resting T cells usually have no chance to pass the blood-brain barrier.
An erroneously programmed autoimmune-active T cell, however, succeeds in passing
the barrier. How this comes about has not, however, been definitively resolved.
Destruction of the body's own tissue
Once in the brain, the erroneously programmed T cells begin to attack the
body's own cells:
- their target are the oligodendrocytes, the myelin sheath-forming cells
of the nerve fibres
- the T cells send out cytokines in order to attract other components of the
immune defence such as macrophages, antibodies and the complement system
- destructive lesions develop which affect the myelin sheaths
- at the same time T cells divide and their daughter cells attack further
myelin sheaths: more and more inflammatory foci develop
- in addition, B cells may be involved in this destruction by releasing myelin-specific
antibodies
- the insulation of the nerve fibres is destroyed as the myelin sheaths are
attacked
- consequently nerve impulses are passed on more slowly or not at all.
Symptoms
How do those affected by MS most commonly become aware of it?
Is MS audible?
What does a tickle in the foot has to do with MS?
In the following chapter you will find the answers to these and other questions
regarding the signs and symptoms of multiple sclerosis.
Visual defects
Multiple sclerosis often affects the optical nerves. Around one million nerve
fibres are bundled in each. If the myelin layer is damaged or destroyed different
complaints may occur:
- Loss of visual acuity
- Reduced colour vision
- Pain during eye movements
- (Temporary) blindness
Visual defects are reported as the first symptom by many of those affected.
Coordination problems
MS often affects the cerebellum. It coordinates movements and makes sure
that muscles are contracted and relaxed again. The cerebellum receives and
processes a huge amount of information through its approximately 200 million
nerve fibres and is responsible for an equivalent number of different functions.
These include
- Directed motility: if it is disrupted, this may reveal itself in those
affected through difficulties touching the tip of their nose with their finger
- Balance: MS may cause an insecure, unsteady gait - the so-called gait
ataxia.
- Speech: it may sound staccato-like and blurred.
The unsteady gait in MS is sometimes misinterpreted as drunkenness -
in truth this is only the gait ataxia.
Muscle weakness and paralysis
Muscle weakness is another symptom of MS which often occurs, for example,
in the arms and the legs. Signals from the CNS are no longer or only to a
limited extent received by the muscles.
The loss of muscle strength may even cause symptoms of paralysis and may
in the course of the disease make walking aids necessary. The affected muscles
are often stiff and cramped (spastic) which can also be painful.
Paraesthesiae
The brain not only sends messages to the organs and muscles but also receives
signals from the environment.
Multiple sclerosis may disturb the reception and conduction of stimuli such
as pain, cold and heat. The sensation of numb or tickling feet is one of these
paraesthesiae.
Fatigue
MS patients frequently suffer from an extreme tiredness called fatigue which
is typical of the disease.
The reason for this is that their brain has to work harder than that of a
healthy person in order to achieve the same results. Due to the fact that
nerve conduction is disturbed in many different regions of the network, the
impulses often have to make long detours. This requires energy and is exhausting.
Desire to urinate and loss of libido
The function of the urinary bladder is also frequently disturbed in multiple
sclerosis. With the progression of the disease patients may have the feeling
that they have to go to the toilet all the time.
Disturbed sexual function such as impotency or a reduced sexual desire also
frequently occurs in the course of the disease.
Diagnosis
How is a sample of cerebrospinal fluid collected?
Can MS foci be detected by magnetic fields?
How does a chess board assist in the establishment of diagnosis?
In this chapter you will be introduced to the most important examination
methods for securing the diagnosis of MS.
MS diagnostics
There is no single test for the diagnosis of multiple sclerosis. The diagnosis
is established on the basis of the results of several examinations.
The most important examination methods include:
- Neurological examination
- Evoked potentials (EP)
- Magnetic Resonance Imaging (MRI)
- Lumbar puncture
Muscle strength and reflexes
The essential MS examination methods include the neurological examination.
The physician examines the patient for:
- Muscle strength
- Fine motor skills
- Coordination
- Sensitivity
- Muscle tone and
- Reflexes.
Together with the patient's information these basic neurological diagnostics
may give a first valuable indication of the existence of MS.
Stimulus and response
The determination of the so-called evoked potentials is one of the more specialised
examination methods.
It includes the stimulation of different sensory modalities - e.g.
the eyes are stimulated by the changing pattern of a chess board. Central
neural pathways transmit the stimuli in form of electrical pulses. The time
it takes for the brain to react to the offered stimulus is measured by such
visuallly evoked potentials.
A slowed rate of conduction may be due to an inflammation of the optical
nerve and is an indication for MS.
MS Sectional Image
Magnetic resonance imaging (MRI) is a diagnostic imaging procedure and does
not require the use of X-rays. Sectional images of the body are produced by
means of an artificially created magnetic field.
Small inflammatory lesions and scar formations are clearly visible.
Active inflammatory foci can also be recorded in magnetic resonance imaging
as these occur during an attack. Such foci often disappear again after the
attack subsided.
Temporally offset sectional images may also document different states and
subclinical courses of the disease.
Antibodies in the cerebrospinal fluid (CSF)
A high probability of MS is provided by a lumbar puncture:
- during this procedure, a few millilitres of CSF or liquor are extracted
by means of a thin atraumatic cannula from the vertebral canal
- the puncture site is in the lower part of the lumbar spine; in this region
there is no spinal cord which could be injured in the process
- the CSF is then analysed for inflammatory cells and antibodies indicative
of MS
- these antibodies are identified by means of iso-electric focussing
They appear in the form of a striped pattern, the so-called oligoclonal bands.
McDonald criteria
Whether an established MS, a possible MS or a no MS exists is determined
quickly and with great certainty by means of the so-called McDonald criteria.
The diagnosis focuses on the objective demonstration of signs of the disease
disseminated in time (attacks) and space (MS foci).
If at least two attacks and two foci, which occur at different times and
in different areas of the central nervous system, are objectively demonstrated,
the diagnosis of MS is established. A second attack may also be substituted
by new activity in magnetic resonance imaging.
There are more criteria than the above mentioned.
Course
How long does an attack last?
When will the next attack occur?
Do the disabilities recede completely?
MS has many faces - the following chapter will inform you of the most
important forms of the disease.
Forms of MS
MS does not have a form that is consistent in all patients.
The early phases of the disease are characterised by attacks: they occur
in around 70% of those affected:
- during these phases the symptoms often begin suddenly and for no identifiable
reason
- they last a couple of days or weeks and then subside completely
- it may be weeks, months or even years until the next attack occurs
The recurring attacks are also known as intermittent-remittent course.
Secondary progressive course
After a longer intermittent course, many MS patients experience a transition
to a progressive course. This is called secondary progressive course.
This means that disabilities do not recede completely but slowly progress
independently of relapses.
The time when disabilities no longer recede cannot be predicted. Drugs that
interfere with the immune system can, however, delay this process.
Primary progressive course
Approximately 10% of all MS patients experience a primary progressive course
of multiple sclerosis. This means that the disease is progressive from the
beginning.
The disability constantly increases - often without individually distinguishable
attacks. This form often affects patients with a later onset of the disease,that
is from the age of 40.
Therapy for MS
Can the nerve cells be effectively protected?
Can the passage of incorrectly programmed T cells into the CNS be prevented?
Is it possible to reduce the production of proinflammatory cytokines?
Learn more about the most important drugs used in current treatment of MS
on the following pages.
The focus of the basic therapy of multiple sclerosis is to prevent the development
of inflammatory foci in the brain. An important starting point in this regard
is the blood-brain barrier.
Presently, the most important compounds of basic therapy are:
- Interferon beta
- Glatiramer acetate
For relapses cortisone-pulse therapy is used.
Cortisone:
- is a steroid hormone with a manifold effect and influence almost all body
cells.
- is used in large-dose infusions during an acute MS attack
- is administered between three and five days during pulse therapy
- strengthens the blood-brain barrier: only some incorrectly programmed T
and B cells manage to pass the barrier
- has a strong anti-inflammatory effect by preventing T cells beyond the blood-brain
barrier releasing proinflammatory cytokines
- reduces the activity of B cells and macrophages by inhibiting the release
of cytokines and antibodies
The inflammatory reaction during an attack can be reduced quickly by means
of cortisone.
Interferon beta:
- is a modulator which serves to enable the exchange of information between
cells
- therefore interferes with the immune system and regulates it in different
ways
- reduces adhesion of immune cells to the blood-brain barrier
Through long-term treatment with interferon beta the MS attack rate can be
reduced and progression of the disease delayed.
Glatiramer acetate:
- is a protein molecule similar to the proteins of myelin in the nerve cells
- reprogrammes auto-aggressive T cells
- protects the valuable myelin layer: once the T cells have entered the central
nervous system, they no longer form inflammatory cytokines
- causes reprogrammed T cells to release factors which promote nerve growth
Glatiramer acetate is used to delay the progression of MS and to reduce the
number of attacks.
For more information about further treatment possibilities please refer to
the consensus document regarding escalating immunomodulatory therapy.
