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WHAT TO DOPract Neurol 2009; 9: 227230
When theGuillain-Barrepatient fails to
respond totreatmentJ B Winer
Most patients with Guillain-Barre syndrome (GBS) respond to treatment with
intravenous immunoglobulin, but it is not uncommon for some to continue todeteriorate for a period after treatment has been started. This may reflect thenatural history of the disease, or an error in diagnosis. This article reflects myown view of what to do in this situation, with a review of what few data thereare to guide decision making.
A
patient with clinically typical
Guillain-Barre syndrome (GBS) is
admitted and given five days of
intravenous immunoglobulin (IVIg)
at a conventional dose of 0.4 gm/kg per day.His cerebrospinal fluid (CSF) is normal on day
4 of the illness and the nerve conduction
studieslimited to conduction velocities in an
upper and lower limbcome back as normal.
He continues to deteriorate, requiring ventila-
tion. After a further two weeks there is nosign of improvement. What should I do now?
J B Winer
Consultant Neurologist and
Honorary Senior Lecturer in
Neurology, University Hospital
Birmingham, Edgbaston,
Birmingham B15 2TH, UK;[email protected]
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THE CORRECT DIAGNOSIS?This scenario is not unusual and in a busy
regional centre we see such patients several
times a year. My first reaction is to make sure
the diagnosis is correct. The diagnosis of GBS
is usually straightforward and conditions that
can cause diagnostic difficulties in the first48 hours, such as hypokalaemia or acute
polymyositis, are usually recognised fairly
quickly (box). I have seen neuromyelitis optica
cause more prolonged diagnostic difficulty,
especially in a ventilated patient who cannot
complain of visual difficulties. Nerve conduc-
tion studies are usually abnormal in GBS,
even early in the course of the disease,
provided detailed studies are performed (in a
recent study 85% of patients had abnormal
values1). These abnormalities may be limited
to prolonged distal motor latencies or small
and dispersed muscle action potentials, or
sometimes just prolonged F wave latencies. If
the nerve conduction studies remain normal
on repeat testing then I wonder about
lymphoma or malignant meningitis with root
infiltration. These two disorders are usually
associated with a CSF pleocytosis but a
modest increase in cell count (up to 50/ml)
is not incompatible with the diagnosis of GBS.
A high CSF cell count always makes me think of
Lyme disease and HIV. Although a raised CSFprotein is helpful in making the diagnosis, it is
frequently normal in the first week when the
examination is usually performed. Repeat
studies are seldom done but usually show a
later rise in protein. I have seen an ependy-
moma present with a rapidly progressive lower
motor neuron problem in the legs, with only
equivocal nerve conduction studies consistent
with proximal root damage. The CSF usually
helps here but breast carcinoma can present
with a normal CSF and a subacute neuropathy
that causes confusion. Porphyria or acute toxin
exposure are always difficult to diagnose,although a detailed history can help.
IS THERE ANY VALUE INRE-TREATMENT?Let us assume that we are certain of the
diagnosis and the patient has not responded
to IVIg, the value of which in GBS has been
established by a number of clinical trials;2 so
we should feel reasonably secure that we
have given the correct first line treatment.
Many neurologists would give a secondcourse of IVIg in this situation and this is
certainly reasonable. However, although both
IVIg and plasma exchange produce significant
shortening of the time taken to recover, no
randomised clinical trial has so far addressed
the value of re-treatment. A Dutch trial of a
second course of IVIg in patients not respond-
ing to the first course has been proposed
(Hughes R, personal communication). Trials in
GBS have become very much more difficult to
do because of the widespread use of IVIg insmall local hospitals so that single units cannot
mount a trial alone, and large multicentre trials
are very expensive.
Lack of response to IVIg will of course occur
in a significant number of patients and is
entirely consistent with the randomised trials
which simply confirm the statistical on
average benefit of treatment of the popula-
tion. Furthermore, an apparent lack of response
to IVIg is to be expected in some patients who
may still go on to benefit from treatment.
Consider the figure to illustrate this.In the figure the response of a patient with
severe GBS is charted. He receives IVIg within 24
hours of admission at pointA andthedotted line
depicts his progress compared to a supposed
untreated patient (continuous line). Both
patients eventually reach grade 1 of the most
commonly used disability scale but the treated
patient has a path with a lower trajectory and a
more rapid recovery. At pointB both patientswill
have shown some deterioration, even the
treated patient, but he can clearly be seen tohave responded to treatmentin the long run.
Nerve conduction
studies are usually
abnormal in GBS,
even early in the
course of thedisease
Diagnoses to consider in the differential of Guillain-Barresyndrome
Central nervous system disordersl Transverse myelitisl Neuromyelitis optical Brainstem strokel Cord tumour
Peripheral disordersl Systemic or peripheral nerve vasculitisl Hypokalaemial Polymyositis/dermatomysositisl Porphyrial Toxins (eg lead, hydrocarbons)l Botulisml
Myasthenia
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WHAT ABOUT THE PATIENT WHORESPONDS AND THENRELAPSES?The other common scenario is the patient who
responds to IVIg but then appears to deterio-
rate at a later date. Should these patients be
retreated? About 3% of patients with GBS willturn out to have a more chronic disease which
in time will fulfil the diagnostic criteria for
chronic inflammatory demyelinating polyradi-
culoneuropathy (CIDP). Such patients would be
expected to relapse and may eventually need
treatment with corticosteroids or recurrent
doses of IVIg. Recognition of these patients is
difficult and I usually allow at least one relapse
in the first two months before labelling a
patient as CIDP.
In a recent randomised trial a significantdeterioration of more than one clinical grade
was considered by consensus, a reasonable
threshold for giving a second course of IVIg.
But what is the evidence that more IVIg is any
better than waiting for spontaneous improve-
ment? There is some weak evidence that a
higher dose of IVIg is a little better than a
lower dose3 and therefore one could argue
that some patients may require more IVIg to
stop the immune process than others.
Consistent with the hypothesis that more
IVIg might help in these cases, is theobservation that some patients who show a
good response to IVIg can have a relapse at
about six weeks after treatment, which is
recognised in the literature as a treatment
related fluctuation.4 This is assumed to
reflect the therapeutic effect of the IVIg
wearing off. Anecdotal data support the
treatment of these patients with a further
course of IVIg.5 This is costly and associated
with a further risk of IVIg-related complica-
tions, which rarely includes both renal failureand stroke. We clearly need further rando-
mised trials to guide practice.
WHAT ABOUT PLASMAEXCHANGE IF THE PATIENT FAILSTO RESPOND TO IVIG?The multicentre trial comparing treatment of
GBS with plasma exchange followed by IVIg
failed to find a significant advantage over IVIg
or plasma exchange alone.6 There was how-
ever a slight trend towards a better outcomefrom the combined treatment and therefore
some have argued that it is more rational to
treat with plasma exchange if the IVIg fails to
produce a documented improvement rather
than repeat the IVIg. But there is of course
the inevitable consequence of washing out
the IVIg still present in the blood which is at
the very least undesirable and some wouldargue illogical. Furthermore, plasma exchange
has more complications than IVIg even
though it was well tolerated in clinical trials;
it is also more complex and therefore difficult
to deliver to sick patients, especially if they
have prominent autonomic failure, which is
not uncommon in severe GBS.
WHAT DO I DO?In practice I usually try and wait for
improvement unless there is clear evidenceof either continuing deterioration of one
disability grade two weeks after treatment,
or a relapse of this severity. If this occurs I re-
treat with a further course of 0.4 g/kg of IVIg
per day for a further five days. (I accept that
at present there is no formal evidence but this
may come in time!) If the patient still does
not improve then I reconsider the diagnosis. I
have occasionally gone on to treat such
patients with plasma exchange. There is no
doubt that some patients with CIDP do
FigureHypothetical course of an attack of Guillain-Barre syndrome. Change in disability grade over weeks.
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respond to plasma exchange and not to IVIg
and by analogy this might apply to GBS as
well. Unfortunately the time window for
effective treatment of GBS may be too short
for several attempts at treatment.
ACKNOWLEDGEMENTSThis article was reviewed by Hugh Willison,
Glasgow, UK.
REFERENCES1. Hadden RD, Cornblath DR, Hughes RA, et al.
Electrophysiological classification of Guillain-Barre
syndrome: clinical associations and outcome.
Plasma Exchange/Sandoglobulin Guillain-Barre
Syndrome Trial Group. Ann Neurol 1998;44:7808.
2. Hughes RAC, Raphael J-C, Swan AV, et al.
Intravenous immunoglobulin for Guillain-Barre
syndrome. Cochrane Database Syst Rev2006;(1):CD002063.
3. Raphael J-C, Chevret S, Harboun M, et al, for the
French Guillain-Barre syndrome Study Group.
Intravenous immune globulins in patients with
Guillain-Barre syndrome and contraindications to
plasma exchange: 3 days versus 6 days. J Neurol
Neurosurg Psychiatry 2001;71:2358.
4. Kleyweg RP, van der Meche FG. Treatment related
fluctuations in Guillain-Barre syndrome after high-
dose immunoglobulins or plasma-exchange.
J Neurol Neurosurg Psychiatry 1991;54:95760.
5. Farcas P, Avnun L, Frisher S, et al. Efficacy of
repeated intravenous immunoglobulin in severe
unresponsive Guillain- Barre syndrome. Lancet
1997;350:1747.6. Plasma Exchange/Sandoglobulin Guillain-Barre
Syndrome Trial Group. Randomised trial of plasma
exchange, intravenous immunoglobulin, and
combined treatments in Guillain-Barre syndrome.
Lancet 1997;349:22530.
PRACTICE POINTS
l IVIg 0.4 gm/kg per day for 5 days is the standard treatment for GBS.l A small percentage of patients with GBS will develop CIDP with progressive
deterioration or relapses.l Treatment-related fluctuation leading to a deterioration of one grade
usually responds to re-treatment with the same regime of IVIg.l Patients who appear initially not to respond to IVIg may still benefit from
that treatment as measured by the time taken to recover.l Some patients who fail to respond may benefit from a second course of
IVIg, or plasma exchange.
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