This paper was prepared by Dr Graham Cleator, Head, Division of Virology, Clinical
Sciences Building, Manchester Royal Infirmary
Herpes Simplex viruses belong to a group of viruses called the human herpes viruses.
Other members of the group include:
- Varicella zoster, the cause of chickenpox and shingles.
- The Epstein-Barr virus, the cause of glandular fever.
-
Cytomegalovirus (CMV), another virus occasionally causing a glandular-fever-like
illness.
Other more recently described human herpes viruses are human herpes viruses 6,7and
8. The role of these viruses in causation of human diseases is not, as
yet, fully explained.
Herpes Simplex Encephalitis (HSE) occurs at any age, to either sex and at any time
of year. In the UK up to 200 cases per annum are recorded but, because the
condition is probably under diagnosed this figure is presumably an underestimate
of the true incidence of the condition.
Infection by HSV-1 (Herpes simplex virus -1) usually occurs early in life through
asymptomatic infection of the mouth and throat. The virus attaches to and
enters sensory nerves in the throat and moves within these nerves to nuclei in collections
of nerve cells called "ganglia" ( e.g. the trigeminal ganglia) Here the
virus establishes a latent, life-long infection. Because most individuals are infected
with the virus early in life this means that a high proportion of the population
carry herpes simplex virus in latent form, i.e. they are infected for life.
In some people this may, from time to time, reactivate to produce recognisable lesions,
i.e. cold sores around lips and nose.
While HSV- I is widespread, HSE is of course rare. How HSV gains access to
the brain is not known, but here are various hypotheses, Firstly, viruses may enter
the brain from the blood stream. To do this the virus must be small, present
in large numbers and able to cross the blood/brain barrier (BBB). Taking into account
the properties of the virus this is a possible but probably infrequent route of
entry to the central nervous system (CNS). Secondly, there is a direct route,
via nerves, from the nose to the olfactory lobes of the brain. This route
of infection certainly occurs in various animal “models” of HSE but the
relevance to the human disease is uncertain. The virus may "move "from
its site of latency via nerves to the base of the skull, cross the meninges and
infect the brain. There is however little evidence to support this suggestion. A
further possibility is that the virus moves from its site of latency in the trigeminal
ganglia ”backwards” to the spinal cord and then upwards into the
brain. The appropriate nerve pathways exists to support this suggestion but to date
there is no definite evidence to support this or indeed any of the other suggested
routes.
Whichever way HSV- I gains access to the brain, in the acute illness, the damage
that results from the viral infection and associated inflammation is often severe.
Early in infection, the virus shows a distinct predilection for certain parts of
the brain. Typically it is initially present in the limbic cortices. It may
then spread to the adjacent frontal and temporal lobes. It is the destruction
of tissue in these areas together with brain swelling from the inflammation which
causes many of the symptoms associated with HSE.
HSE usually develops over a period of days but, like any other viral infection,
depending, for example, upon the immunity of the patient, the disease may
take a variable course. Typically it begins with "flu-like" symptoms
followed by neurological deterioration which may include personality and behavioural
changes, and perhaps fits and dysphasia. If untreated it may lead to progressive
impairment of consciousness, coma and death.
Diagnosis
The rapid onset and development of HSE presents a dilemma to the clinician.
During the early stages, when treatment would be most effective, the symptoms can
be very general, so there may be several possible diagnoses.
Most hospitals do an EEG (an electro-encephalogram to monitor the brains electrical
activity), plus brain imaging by a CT scan ( computerised tomography), or, for a
clearer picture, an MRI (magnetic resonance imaging). These procedures, together
with careful and continuous clinical assessment provide data which may be suggestive
of HSE and, importantly, may exclude other conditions. However the diagnostic procedure
now accepted as providing an aetiological diagnosis of HSE is the polymerase chain
reaction (PCR). This is a test that has been developed using the methods of
modern molecular biology. The PCR is not used exclusively for the diagnosis
of HSE but is also used in many other areas of research and diagnosis. In
principle the test is simple (they always are when they have been developed!) but
because the test is so sensitive great care must be exercised at all stages of the
procedure. The risk of producing false results is always present especially
if suitable care and precautions are not taken during taking specimens and in the
PCR laboratory.
Polymerase chain reaction
The principle of the PCR, in this context, is that when the Herpes virus infects
the brain it will infect cells and multiply. During this multiplication the
virus produces more and more new virus particles. Each particle consists of
virus DNA and a protein coat. It is the viral DNA which carries the relevant
information which lead to new rounds of multiplication etc. Some of this DNA
will spread from the site of infection and be liberated into the cerebrospinal fluid
(CSF). The CSF is the fluid which is found in the ventricles of the brain
and circulates down through the spine and back to the brain. It is the fluid
which is taken during a lumbar puncture. When a patient is admitted to hospital
with suspected HSE a lumbar puncture should be taken immediately and a sample sent
to the virus laboratory for examination by PCR. Other laboratory and diagnostic
tests will be carried out at this time and acyclovir therapy started as soon as
the CSF has been taken. The CSF may contain only a few copies of the viral
DNA. These are undetectable by most laboratory procedures even though they
are there! What the PCR does is to produce, in the laboratory, many more copies
(millions more) of the original DNA. So much new DNA is produced that it can
be easily detected. The new DNA can also be tested to ensure it is really
Herpes virus DNA and not a contaminant. This data is the important laboratory
diagnostic information that the clinician needs. If the sample can be transported
to a suitable virus laboratory rapidly a definitive aetiological diagnosis can be
produced within a matter of hours. In our laboratory and others throughout
the world we have demonstrated that an accurate diagnosis is possible on the first
day or two of neurological illness i.e. when the patient may only be showing minimal
symptoms. In general, the test is useful for about 10 - 20 days after the
onset of neurological disease and then usually become negative. At this time
a further procedure for the detection of Herpes virus antibody in the CSF can be
used. This also provides an accurate diagnosis. This latter test is
often (ideally) used as a follow up to the initial PCR test(s).
These developments mean that a specific diagnosis can be reached rapidly.
However there are always problems! Firstly not all laboratories are equipped
to perform the relevant PCR test. These tests are expensive and specialist
laboratory facilities are needed. This means that CSF samples may have to
be transported considerable distances, with a consequent time delay, before
a test is carried out. Also when a patient is admitted to hospital, because
of the 'vague' nature of the symptoms (in some cases) a lumbar puncture may not
be taken immediately. This is unfortunate because we now have an accurate
test which provides a diagnosis at the very time when treatment is most helpful
to the patient. The situation is further confused because the attending
clinician may be faced with a very difficult situation if the symptoms are vague
and perhaps suggest a diagnosis other than encephalitis. However, a PCR test
should always be carried out as soon as possible in all suspected cases of HSE.
It is now clear that the clinician needs as much information as possible on how
the virus laboratory can be used in helping to resolve diagnostic problems.
Lastly, concerning diagnosis, it is important to understand that even with the use
of PCR diagnostic problems still remain. False PCR results can occur.
In the future procedures may be introduced to minimise this problem. It is
clear that, although PCR plays a central role in the diagnosis of HSE, other procedures
for patient evaluation including clinical examination, brain imaging etc. are of
crucial importance in helping to recognise the disease at the time when the patient
is admitted to hospital. The combination of clinical skill and the interpretation
of all the investigative data as well as PCR results are all important. The
correct pathway to rapid and efficient diagnosis clearly necessitates high levels
of clinical skills together with the informed use of laboratory procedures, in particular
PCR. Diagnosis of HSE therefore requires close collaboration between clinical
and laboratory staff.
Treatment
The role of Acyclovir is central to the treatment of HSE. If therapy can be started
during the first few days of the illness there is a dramatic reduction in the mortality
rate - c.80% down to 25%.. The provision of high levels of nursing care and
the management of complications such as brain oedema (i.e. swelling) are also key
factors which may influence the outcome of HSE. As experience with the use
of Acyclovir has grown it has become apparent that the currently accepted 10 day
course of treatment may not always be sufficient to provide effective treatment.
Rare cases of “relapse” of encephalitic illnesses have and are being noted.
Trials of new treatment protocols are currently under consideration and no doubt
will be implemented in an effort to provide more effective treatment. Also
new derivatives of Acyclovir have been produced and have the potential to improve
the outcome of HSE still further. Some of these new drugs have been purposely
“designed” to have properties which will allow them to gain access to
the brain more efficiently than Acyclovir. If these drugs are introduced for
the treatment of HSE the prospect for the clinical outcome of patients improves
still further.
The reduction in mortality has led to a paradoxical situation. There are without
doubt more survivors, but many may suffer from permanent neurological and/or psychological
deficits, for example amnesia (memory loss). For a child with a potentially
long life ahead this is a particularly distressing situation. Improvements
are still needed in both diagnosis and treatment.
Recent recognition of mild cases of HSE and the suggestion that latent infection
of the brain can occur add a further dimension to this disease. If a patient
suffers repeated episodes of mild (undiagnosed and not debilitating) HSE, there
could be progressive damage to the brain. The relationship of such episodes
to the development of various psychological disorders must now be given serious
consideration and form the basis of future research programmes.
The message is that our understanding of conditions such as viral encephalitis is
continually developing. However, these are complex conditions and whilst it
is unlikely that encephalitis will be preventable (in the foreseeable future) the
prospect for the rapid and efficient diagnosis for many of these conditions will
improve during coming years. The consequence of improved and rapid diagnosis
is that early treatment (which is so important) can and will increasingly be introduced.
Last modified: January 2003