what to do, when gbs pt fails to respond to treatment

8/2/2019 What to Do, When Gbs Pt Fails to Respond to Treatment

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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]

2Winer

www.practical-neurology.com


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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.

2Winer

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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.

Practical Neurology

10.1136/jnnp.2009.176578

what to do, when gbs pt fails to respond to treatment

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