GLUCOCORTICOIDS are widely
used in clinical practice,
predominantly as anti-inflammatory
drugs and in immunosuppressive
regimens. They have a number of
possible applications in
neurological patients and are clearly
beneficial in certain
conditions.
There are,
however, many
conditions in which
benefit is presumed or
expected, yet there
remains no convincing
evidence to support
their use; in other
cases, outcome can be
worsened.
This article will
emphasise those cases
in which
glucocorticoids are
indicated and will
highlight some of the cases in which
they are best avoided.
Mechanism of action of
glucocorticoids
The predominant use of
glucocorticoids (GCs) as anti-
inflammatory medication makes it
tempting to think of them as drugs
that simply reduce the activity of
various components of the
inflammatory response.
This is far from the truth – GCs
have widespread negative and positive
influences on a variety of different
genes, upregulating and downregulating
DNA transcription and interfering with
intracellular signalling pathways.
GCs act by binding to the
glucocorticoid receptor (GR). The
receptor-ligand complex acts either as a
dimer, binding to DNA and modifying
gene transcription, or as a monomer,
interfering with intracellular signalling
and modifying activity of other cellular
transcription factors, including many
that are active during inflammation.
The beneficial effect of this is a
reduction in inflammation and
suppression of the immune response,
but this is accompanied by a number of
adverse effects. One such adverse effect is the increase in blood glucose
concentration, brought about by
upregulation of genes involved in the
breakdown of glycogen, fat and
protein reserves.
Clinically, this catabolism is
manifest as muscle wasting, thinning of
skin and osteoporosis;
the risk of diabetes is
also elevated. In
addition,
glucocorticoids
increase blood
pressure, can cause
gastrointestinal
ulceration, increase the
risk of infections and
stimulate both
appetite and urine
formation – arguably
the most difficult
adverse effects that
owners have to contend with.
For some time, it was hoped that the beneficial effects of GCs were
controlled by the action of GC
monomers on intracellular signalling,
whereas detrimental effects were
predominantly triggered by dimer
binding to DNA. Researchers therefore
targeted drug discovery towards those
that would act as monomers but not as
dimers, in the hope of avoiding side
effects. Unfortunately, such drugs are
not the golden bullets once hoped for
and, for the time being at least, it
seems we shall have to accept the
adverse effects.
Role in autoimmune and
inflammatory diseases
Glucocorticoids form the mainstay of
therapy in conditions in which the
immune system turns its attention on
the body’s own tissues.
Good examples of this include
steroid responsive meningitis-arteritis
(SRMA), which – as the name suggests
– tends to respond well to treatment
with prednisolone.
Treatment of granulomatous
meningoencephalomyelitis (GME) – a
presumptive autoimmune disease in
which there is an aggressive immune
cell infiltration into the brain and/or
spinal cord – also relies heavily on
prednisolone.
Supplementary immunosuppression
using drugs such as cytosine
arabinoside occasionally seems to be
beneficial in patients with GME, since
the response to treatment with
prednisolone alone can be poor.
However, there remains no convincing
evidence that these treatments are
superior to prednisolone alone and
GCs should remain the cornerstone of
treatment.
Autoimmune diseases affecting
other neuromuscular tissues can also
respond well to prednisolone treatment
– polymyositis and masticatory myositis
are good examples. Where the benefit
becomes less clear is in inflammatory
conditions affecting the peripheral
nerves.
A relapsing inflammatory
polyneuritis that responds to
prednisolone is well recognised but
seems to occur relatively rarely.
Polyradiculoneuritis, in which there is
an inflammatory response centred on
the nerve roots as they arise from the
spinal cord, is more common but
seems not to respond to prednisolone.
One could take the view that steroids
are worth trying anyway, but the
adverse effects of muscle weakness and
wasting need to be considered when
trying to treat these cases.
Focal cranial neuropathies are
sometimes treated with glucocorticoids
but the evidence for their use is not
convincing. Idiopathic facial paralysis in
dogs seems likely to be an
inflammatory condition affecting this nerve – results of MRI scanning
certainly support this view. Although
the balance of evidence indicates that
glucocorticoids improve outcome in
people with facial neuropathy, there is
no equivalent evidence that the same
occurs in companion animals.
Role in neoplasia
In the late 1950s and early 1960s,
Joseph Galicich and Lyle French noted
that patients with glioma given
dexamethasone could improve
dramatically, sometimes overnight.
They later showed that this
improvement tended to continue for
several days, usually reaching a plateau
after around five days, and calculated
the most effective dose for achieving
this.
Subsequent studies showed that
dexamethasone acted by reducing the
severity and extent of peritumoural
oedema, a feature of many brain
tumours, including mengingiomas and
gliomas that are common in
companion animals.
Although there are no studies to
confirm the beneficial effect of
steroids in dogs with brain tumours,
few would argue against their use in
such cases.
Glucocorticoids also have a well-established therapeutic role in the
treatment of lymphoma, since they
stimulate apoptosis of neoplastic
lymphocytes. In this respect, CNS
lymphoma is no different from
lymphoma elsewhere in the body – in
fact, steroids are arguably more
important in the former because of the
difficulty many other anti-neoplastic
drugs have in achieving a therapeutic
concentration in the CNS.
A similar direct impact of GCs on
the growth of primary brain tumours is
not likely to be significant in most
cases. Some studies show a reduction
in glioma growth, whilst others show a
reduced susceptibility to apoptosis in
tumour cells as a result of GCs, which
might hinder the benefit of other
chemotherapeutic agents and
radiotherapy.
Role in trauma
The reduction in peri-tumoural
oedema with GC treatment prompted
many human clinicians to adopt GCs
to treat the oedema that follows CNS
trauma.
The only question for many was
what dose to give and a study was
therefore established comparing high
and low doses of dexamethasone – no
placebo arm was included, since it was
deemed unethical to deny patients the
presumed benefit of steroids.
Surprisingly, there was no
improvement in outcome in patients
given the higher doses – only an
increased risk of infection.
Around the same time,
experimental studies showed that very
high doses of methylprednisolone
sodium succinate (MPSS) were
required to improve recovery – far
higher doses than had been used in the
initial trial described above. Another
human clinical trial was therefore
established, using an equivalent dose
of MPSS in people, and the initial
conclusion was that steroids are
beneficial.
Critical care clinicians were urged
to use the drug in human patients with
spinal cord injury and this study is
widely used as the rationale for using
the drug in companion animals
suffering spinal cord injuries.
However, the clinical improvement
noted in this trial was scant and there
are statistical reasons to be suspicious
that even this result was spurious; as a
result, most now consider this trial to
show no evidence for using high dose
GCs.
In the veterinary world, the
available evidence also shows no
benefit for using high dose
methylprednisolone, even with
adherence to the high doses shown to
be necessary in experimental studies.
The temptation to reach for
dexamethasone as an alternative to
methylprednisolone should also be
avoided.
Retrospective analysis of dogs
given dexamethasone not only shows
no evidence of benefit but the risk of
gastrointestinal adverse effects and
urinary tract infections increases.
In general, many clinicians – both
medical and veterinary – now avoid
using glucocorticoids following spinal
cord injury, since the increased risk of
adverse effects outweighs the
(unproven) benefits.
Brain trauma
For the same reason that spinal cord
injury patients have been treated with
glucocorticoids (i.e. to reduce oedema),
those with head trauma have tended to
be treated similarly.
Whilst there is little evidence in
companion animals to support or
refute their use, large scale medical
trials in human patients generally
indicate a poorer outcome for patients
given GCs – i.e. an increased mortality
in treated patients. It is therefore
difficult to justify using these drugs
following head injury.
Role in chronic disease
For clients who elect not to pursue a
definitive diagnosis and simply require palliative treatment, GCs are often useful. Dogs with brain tumours often
improve with prednisolone – not
unusually alongside anti-seizure
medication.
In cases with type II intervertebral
disc disease, when owners choose not
to treat surgically, GCs can also prove
helpful, though any improvement is
limited and tends to be relatively short-
lived.
Recently, Janssens et al described
the use of epidural steroid injection in
dogs with confirmed lumbosacral
disease; this shows some promise,
though further evaluation of the
technique is necessary.
Practical application of steroids
When confronted by an animal with
neurological disease, it is tempting to
reach for corticosteroids. However, in
the absence of confirmed autoimmune
disease or of a brain tumour, the
adverse effects can easily outweigh any
potential benefit and may even be
detrimental. Use of GCs before
undertaking diagnostic tests can also
hamper efforts to reach a definitive
diagnosis.
Whilst the impact can be dramatic
when used appropriately, these factors
need to be weighed carefully before
embarking on a course of drugs with
such wide-ranging effects.
