Published Ahead of Print on September 22, 2010 as 10.1212/WNL.

0b013e3181f88345

Pain in Guillain-Barre syndrome

A long-term follow-up study

L. Ruts, PhD, MD
J. Drenthen, MD
J.L.M. Jongen, PhD,
MD
W.C.J. Hop, PhD
G.H. Visser, PhD, MD
B.C. Jacobs, PhD, MD
P.A. van Doorn, PhD,
MD
On behalf of the
Dutch GBS Study
Group

Address correspondence and

reprint requests to Dr. L. Ruts,
Erasmus MC, University Medical
Center, Department of
Neurology, Room BA-450,
s-Gravendijkwal 230, 3015 CE
Rotterdam, the Netherlands
l.ruts@erasmusmc.nl

ABSTRACT

Background: Pain in Guillain-Barre

syndrome (GBS) may be pronounced and is often overlooked.
Objectives: To obtain detailed information about pain in GBS and its clinical variants.
Methods: This was a prospective cohort study in 156 patients with GBS (including 18 patients
with Miller Fisher syndrome [MFS]). We assessed the location, type, and intensity of pain using
questionnaires at standard time points during a 1-year follow-up. Pain data were compared to
other clinical features and serology.

Results: Pain was reported in the 2 weeks preceding weakness in 36% of patients, 66% reported
pain in the acute phase (first 3 weeks after inclusion), and 38% reported pain after 1 year. In the
majority of patients, the intensity of pain was moderate to severe. Longitudinal analysis showed
high mean pain intensity scores during the entire follow-up. Pain occurred in the whole spectrum
of GBS. The mean pain intensity was predominantly high in patients with GBS (non-MFS), patients
with sensory disturbances, and severely affected patients. Only during later stages of disease,
severity of weakness and disability were significantly correlated with intensity of pain.

Conclusions: Pain is a common and often severe symptom in the whole spectrum of GBS (including
MFS, mildly affected, and pure motor patients). As it frequently occurs as the first symptom, but
may even last for at least 1 year, pain in GBS requires full attention. It is likely that sensory nerve
fiber involvement results in more severe pain. Neurology 2010;75:11
GLOSSARY
A-CIDP acute onset chronic inflammatory demyelinating polyneuropathy; AIDP acute inflammatory demyelinating polyneuropathy; AMAN acute motor axonal neuropathy; CMAP compound muscle action potential; DML distal motor
latency; FSS Fatigue Severity Scale; GBS Guillain-Barre
syndrome; GRAPH GBS Research about Pain and Heterogeneity; INCAT Inflammatory Neuropathy Cause and Treatment; IVIg IV immunoglobulin; MFS Miller Fisher syndrome;
mNCV motor nerve conduction velocity; MP methylprednisolone; NRS numerical rating scale; ODSS overall disability sumscore; SNAP sensory nerve action potential; sNCV sensory nerve conduction velocity.

Editorial, page XXX

Supplemental data at
www.neurology.org

Guillain-Barre syndrome (GBS) is an acute immune-mediated polyradiculoneuropathy comprising a broad spectrum of clinical variants.1 Pain is often overlooked because most attention is
given to progression of weakness. Various types of pain have been described in GBS.2 The
pathophysiology of pain is poorly understood. The reported frequency of pain in GBS is highly
variable, and most studies determined pain only in the acute phase of GBS (table e-1 on the
Neurology Web site at www.neurology.org).3-11 Two studies performed a longer follow-up and
reported a decrease of pain intensity in time, and one-third of patients may even have pain after
2 years.4,8 Previously we showed that the character of pain may change during the clinical
course of GBS.10 Pain has also been reported in patients with the Miller Fisher syndrome
(MFS), acute motor axonal neuropathy (AMAN), and even mild forms of GBS.12-14 Pain may
therefore be a severe and chronic problem in a considerable proportion of patients with GBS.
The frequency and nature of the pain in GBS, however, needs to be further defined. All
studies thus far conducted included only a relatively small number of cases with a limited set of
clinical, electrophysiologic, and serologic data. Moreover, neither the different types nor the
e-Pub ahead of print on September 22, 2010, at www.neurology.org.
From the Departments of Neurology (L.R., J.D., J.L.M.J, G.H.V., B.C.J., P.A.V.D.), Immunology (B.C.J.), and Epidemiology and Biostatistics
(W.H.), Erasmus MC, Rotterdam, the Netherlands.
Disclosure: Author disclosures are provided at the end of the article.
Copyright 2010 by AAN Enterprises, Inc.

different locations of pain were systematically

analyzed. Here we report a prospective study
defining the character, location, and intensity
of pain in GBS during a follow-up of 1 year.
In addition, detailed information regarding
the clinical, electrophysiologic, and serologic
phenotype was obtained to be able to relate
the pain to the spectrum of GBS variants.
METHODS Patients. A total of 170 patients fulfilling the
diagnostic criteria for GBS were prospectively included in the
GBS Research about Pain and Heterogeneity (GRAPH)
study.15,16 Exclusion criteria were age below 12 years and significant comorbidity with a worse prognosis (predicted survival less
than 1 year). Patients with Bickerstaff encephalitis and patients
who developed acute onset chronic inflammatory demyelinating
polyneuropathy (A-CIDP) were also excluded.

Study design. Patients were included in the GRAPH study in

55 participating Dutch centers between February 2005 and October 2008. The protocol was approved by the ethics committee
of the participating centers. Clinical data, biological materials,
and electrophysiologic data were collected systematically during
1-year follow-up, after obtaining written informed consent.
Questionnaires were filled in by the neurologist weekly during the hospital stay and once after 6 months. The first 3 weeks
after inclusion was determined as the acute phase, because all
included patients had their nadir of weakness within 3 weeks
after inclusion. When the patient was discharged from the hospital, additional questionnaires were filled in by the patient at 3, 6,
9, and 12 months after inclusion. If questionnaires or answers to
some questions appeared to be lacking after 1 week, our research
coordinator phoned the patients and asked them to complete
and return the questionnaires if possible. If the patient was not
able to fill in the questionnaires, we asked relatives for help.
Patients who sent back their questionnaires where some answers
were missing were not excluded from the analyses.

Questionnaires. Baseline characteristics and data about medical history were obtained. Medical history also included questions about the presence of chronic pain within 3 months before
onset of GBS. If so, we asked for the type of pain and the daily
use of analgesics. The first questionnaire also contained identical
questions about pain in the 2 weeks before onset of weakness and
pain since the onset of weakness. In all subsequent questionnaires, we asked about the presence of pain in the past week.
Data about location ([low] back, interscapular, neck, extremities,
and trunk) and type of pain (radicular pain, painful paresthesias
and dysesthesias, joint pain, muscle pain, meningism, and other
type of pain2) were also obtained. The reported pain had to be
new or different from the pain felt in medical history. Intensity
of pain was determined using an 11-point numerical rating scale
(NRS), in which 0 represents no pain and 10 represents extreme
pain.17 The character of pain was obtained based on the simplified version of the Dutch McGill Pain Questionnaire.18,19 The
mean NRS of the severest pain in the past week was questioned.
Additionally, pain intensity was classified into mild (NRS 0 4),
moderate (NRS 57), and severe pain (NRS 8 10).20,21 The use
of daily analgesics was obtained and categorized based on the
WHOs pain ladder into the following categories: none, paracetamol or nonsteroidal anti-inflammatory drugs, opioids, antidepressants, or anticonvulsants.
2

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October 19, 2010

Besides information about pain, neurologic symptoms and

signs, impairment scales (Medical Research Council sumscore,
ranging from 0 [quadriplegic] to 60 [normal strength],22 and
Inflammatory Neuropathy Cause and Treatment [INCAT] sensory sumscore23,24), and disability scales (GBS disability score,
ranging from 0 [no symptoms or signs] to 6 [dead],25 and overall
disability sumscore [ODSS], ranging from 0 [no signs of disability] to 12 [most severe disability score]24,26), treatment and course
of disease were obtained from the questionnaires filled in by the
neurologist during the hospital stay and after 6 months. Regarding the INCAT sensory sumscore, we used the pinprick sensation score and vibration sensation score without the 2-point
discrimination score, because this score was often missing.23,24
After hospital discharge, pain symptoms, Fatigue Severity
Scale (FSS, ranging from 1 [no signs of fatigue] to 7 [most disabling fatigue]),27,28 disability scales (GBS disability score,
ODSS), and course of disease were obtained from the questionnaires filled in by the patient.
Clinical autonomic functions were obtained over the last 7
days. Clinical autonomic dysfunction parameters were defined
prior to study onset: hypertension (systolic 140 and/or diastolic 90 mm Hg), hypotension (systolic 90 mm Hg), tachycardia (heart rate 100 bpm), bradycardia (heart rate 60
bpm), gastrointestinal dysfunction (diarrhea, constipation, or
incontinence), and bladder dysfunction (urine retention or
incontinence).
We defined patients as GBS (non-MFS) or MFS when they
fulfilled the diagnostic criteria.15,16 The pure motor variant was
defined as having GBS without sensory deficits (normal pinprick
and vibration sense). The GBS disability scale was used to indicate the severity of disease at nadir: mildly affected able to
walk unaided GBS disability score 2; severely affected
unable to walk unaided GBS disability score 3.

Preceding infections. Clinical manifestations of infections

within 3 weeks of onset of weakness were classified as influenza,
influenza-like illness or respiratory tract infection, and gastroenteritis or diarrhea when these met the criteria of the Centers of
Disease Control and Prevention definitions for nosocomial infections.29 Baseline serum samples were tested to determine recent infection with Campylobacter jejuni as described.30
Antiganglioside antibodies. Pretreatment sera obtained after inclusion were tested for the presence of immunoglobulin G
and immunoglobulin M antibodies against the gangliosides
GM1, GM2, GD1a, and GQ1b using ELISA as described.31,32
Electromyographic studies. Electrophysiologic investigations were scheduled within 3 weeks after inclusion. Investigations were executed according to local settings of the
participating hospitals. Age- and sex-matched reference values
were used.33 Electrophysiologic investigations were classified as
demyelinating, axonal, inexcitable, equivocal, or normal.34

Statistics. Percentages were compared between groups using

the 2 test or Fisher exact test if appropriate. Longitudinal analysis of pain intensity scores, allowing for occasional missing data
at some time points, was performed using repeated-measurement
analysis of variance in the total group and in subgroups using
data from 2 weeks before onset weakness, the acute phase (inclusion day, 1, 2, and 3 weeks after inclusion), and the chronic
phase (weeks 13, 26, 39, and 52 after inclusion). For the acute
phase, we used the weekly data from the questionnaires until 3
weeks, because all patients had their nadir within 3 weeks after
inclusion and after 3 weeks many patients had been discharged
from the hospital, resulting in too small number of patients. The

population of patients was divided into different subgroups, such

as GBS (non-MFS) or MFS, and by age (using the median value
as cutoff), sex, severity according to GBS disability scale (mildly

Table 1

Baseline and clinical characteristics, electrophysiologic

classification, infections, and antiganglioside antibodies in the
acute phase in 156 patientsa
Values

Baseline
Male, n (%)

95 (61)

Age, y, median (interquartile range)

50 (3563)

GBS (non-MFS), n (%)

138 (88)

MFS, n (%)

18 (12)

Acute phase, n (%)

or severely affected), sensory signs (pinprick and vibration sense),

being treated with IV immunoglobulin (IVIg) with or without
methylprednisolone (MP), electrophysiologic classification (demyelinating or axonal), and different infections. When there was
no significant difference in the profile of mean values of the pain
intensity score during the whole follow-up between the subgroups, we calculated the mean difference with 95% confidence
interval between the subgroups from time before weakness until
52 weeks. Correlation between impairment (Medical Research
Council sumscore, INCAT sensory sumscore), disability (GBS
disability score, ODSS), and fatigue (FSS) vs pain intensity
(NRS) was analyzed using Spearman rank correlation test (rs).
For the relation between fatigue (FSS) and pain intensity (NRS),
changes from the previous measurement were also evaluated using rs. All calculations were performed using SPSS for Windows
2000 (version 15.0, SPSS, Chicago). A 2-sided p value 0.05
was considered to be significant.

Signs and symptoms

Cranial nerve involvement (n 153)

81 (53)

Sensory symptoms (n 152)

132 (87)

Sensory disturbances (n 150)

98 (65)

Severity at nadir
Severely affected (unable to walk unaided)

126 (81)

Respiratory support

28 (18)

Autonomic functions
Tachycardia

60 (38)

Bradycardia

14 (9)

Hypertension

107 (69)

Hypotension

17 (11)

Gastrointestinal dysfunction

70 (45)

Bladder dysfunction

30 (19)

GBS medical treatment

IVIg only

91 (58)

IVIg methylprednisolone

39 (25)

None

26 (17)

Electrophysiologic classification (n 140)

Demyelinating

65 (46)

Axonal

8 (6)

Equivocal

61 (44)

Inexcitable

2 (1)

Normal

4 (3)

Infections
Clinical gastroenteritis/diarrhea (n 153)

52 (34)

Clinical respiratory tract infection/

influenza or influenza-like (n 152)

56 (37)

Positive Campylobacter jejuni serology (n 148)

33 (22)

Antiganglioside antibodies (n 148)

IgM reactivity against GM1, GM2, GD1a, GD1b, or GQ1b

24 (16)

IgG reactivity against GM1, GM2, GD1a, GD1b, or GQ1b

44 (30)

Abbreviations: GBS Guillain-Barr syndrome; Ig immunoglobulin; IVIg IV immunoglobulin; MFS Miller Fisher syndrome.
a
Given percentages are based on number of patients with returned, filled-in questionnaires, serum, or electrophysiologic data. When the number of patients differs from 156, it
is indicated in parentheses.
b
First 3 weeks after inclusion. Sensory disturbances abnormal vibration sense/pinprick;
Severely affected unable to walk unaided GBS disability scale 3.

RESULTS Patients. Between February 2005 and

October 2008, 170 patients with GBS were enrolled
in the GRAPH study. During follow-up, some patients turned out to have another diagnosis (n 3),
Bickerstaff encephalitis (n 2), an accompanying
myelitis (n 1), or A-CIDP (n 8).35 These 14
patients were excluded from the analysis. Of the remaining 156 patients (61% male), 138 (88%) fulfilled the diagnostic criteria for GBS (non-MFS) and
18 (12%) had MFS.15,16

Patient characteristics. Baseline and clinical characteristics, electrophysiologic classification, infections,

and results of laboratory tests in the acute phase are
listed in table 1. All patients had their nadir of weakness within 3 weeks after inclusion, and within 4
weeks after onset of weakness. At nadir, 81% of the
patients (83% of GBS [non-MFS] and 67% of MFS)
were unable to walk independently (severely affected). After 6 months, 11% of patients (12% of
GBS [non-MFS] and 6% of MFS) were still unable
to walk independently.
Pain. Prevalence, location, type, and intensity of pain
in the acute phase and during follow-up are listed in
table 2. A total of 22% of patients had chronic pain
in their medical history (mostly joint and backache,
both 35%; nearly half of them [47%] used daily analgesics). A total of 66% of patients (69% of GBS
[non-MFS] and 44% of MFS; p 0.05) had pain in
the acute phase. After the acute phase, the prevalence
of pain between GBS [non-MFS] and MFS was not
significantly different. A total of 36% of patients already had pain in the 2 weeks before the onset of
weakness (40% of GBS [non-MFS] and 6% of MFS;
p 0.01; median 5 days, interquartile range 113).
The prevalence of pain during the entire follow-up
was significantly higher in patients with sensory disturbances compared to patients with the clinical pure
motor form (t 0: 62% vs 43%; t 6 months: 56%
vs 34%; p 0.05). In the first 6 months, the prevaNeurology 75

October 19, 2010

Table 2

Presence, location, severity, and interpretation of pain in GBS (n 156) and the use of
daily analgesicsa

Pain, n/N (%)

Maximum 2 wk
before onset
of weakness

Acute
phaseb

13 wk

26 wk

39 wk

52 wk

54/151 (36)

100/152 (66)

84/148 (57)

74/150 (49)

58/148 (39)

55/146 (38)

Locations of pain,
n/n with pain (%)
Low back or back

19/54 (35)

50/100 (50)

26/84 (31)

31/74 (42)

22/58 (38)

20/55 (36)

Interscapular

15/54 (28)

34/100 (34)

24/84 (29)

18/74 (24)

18/58 (31)

18/55 (33)

Extremities

38/54 (70)

76/100 (76)

68/84 (81)

65/74 (88)

48/58 (83)

45/55 (82)

Neck

15/54 (28)

34/100 (34)

24/84 (29)

21/74 (28)

16/58 (28)

16/55 (29)

Trunk

6/54 (11)

12/100 (12)

14/84 (17)

9/74 (12)

10/58 (17)

10/55 (18)

Severity of pain,
n/n with pain (%)
NRS 14

8/54 (15)

9/100 (9)

19/84 (23)

17/74 (23)

17/58 (29)

16/55 (29)

NRS 57

25/54 (46)

36/100 (36)

30/84 (36)

28/74 (38)

22/58 (38)

20/55 (36)

NRS 810

21/54 (39)

50/100 (50)

28/84 (33)

26/74 (35)

18/58 (31)

19/55 (35)

Unknown

7/84 (8)

3/74 (4)

1/58 (2)

NE

5/74 (7)

NE

NE

5/100 (5)

Interpretation of pain,
n/n with pain (%)
Radicular pain

12/54 (22)

31/100 (31)

Meningism

1/54 (3)

4/100 (4)

NE

NE

NE

Painful paresthesias/
dysesthesias

16/54 (30)

43/100 (43)

NE

23/74 (31)

NE

NE

Muscle pain

28/54 (52)

62/100 (62)

NE

32/74 (43)

NE

NE

Arthralgia

3/54 (6)

14/100 (14)

NE

16/74 (22)

NE

NE

Unknown

4/54 (7)

7/100 (7)

NE

16/74 (22)

NE

NE

Use of daily
analgesics, n/n
with pain (%)
Nonopioids
(PCM, NSAID)

20/54 (37)

70/100 (70)

30/84 (36)

25/74 (34)

21/58 (36)

13/55 (24)

Opioids
(mildstrong)

5/54 (9)

39/100 (39)

13/84 (15)

11/74 (15)

7/58 (12)

4/55 (7)

Amitriptyline/
antiepileptic drugs

1/54 (2)

24/100 (24)

18/84 (21)

16/74 (22)

10/58 (17)

7/55 (13)

None

33/54 (61)

25/100 (25)

48/84 (57)

41/74 (55)

31/58 (53)

39/55 (71)

Abbreviations: GBS Guillain-Barr syndrome; NE not evaluated; NRS numerical rating scale; NSAID nonsteroidal
anti-inflammatory drug; PCM paracetamol.
a
The percentages for the location, severity, interpretation, and analgesic use are for patients with GBS who had pain at
that timepoint (n/n with pain). The interpretation about the nature of the pain is only filled in by the neurologist. Before
weakness maximum of 2 weeks before onset of weakness.
b
First 3 weeks after inclusion.

lence of pain in mildly and severely affected patients

was comparable; thereafter, the prevalence of pain
was significantly higher in the severely affected patients (t 39 weeks: 45% vs 17%, p 0.01; t 52
weeks: 42% vs 21%, p 0.05). For the entire group,
the prevalence of pain after 3, 6, and 9 months was
significantly higher in patients with pain in the acute
phase compared to patients without pain in the acute
phase ( p 0.05). There was no significant difference
in the prevalence of pain during the whole follow-up
between the patients with or without chronic pain in
medical history. From the patients having pain in the
4

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October 19, 2010

acute phase, 86% reported moderate to severe pain

despite using analgesics. Mean pain intensity is
shown in figure 1.
In the acute phase and during the entire period of
follow-up, pain was most frequently present in the
extremities. Low-back or back pain was notably
present in the acute phase. Often, the patient indicated different types of pain at more than 1 location
and the neurologist often indicated more than 1 interpretation (from the patients having pain, 61% reported pain at more than 1 location in the acute
phase and 51% after 6 months; 53% had more than

Figure 1

Mean pain intensity over time for the entire group of patients with Guillain-Barre
syndrome (GBS)

Mean pain intensity over time for the entire group (n 156). Data shown are means (SE) from analysis of variance. The
means are based on number of patients (indicated in parentheses) with returned questionnaires and filled in numerical
rating scale (NRS) score. Before weakness maximum of 2 weeks before onset of weakness.

1 interpretation for the pain in the acute phase and

31% after 6 months).
The mean pain intensity was higher in the acute
and follow-up phase in females and patients with
GBS (non-MFS), in patients with sensory disturbances, preceding gastroenteritis or diarrhea, and in
severely affected patients (figure 2). No association
was found between pain intensity and age, additional
treatment with MP, the presence of antigangliosides,
and demyelinating vs axonal GBS. When we excluded the patients with MFS to evaluate differences
in the mean pain intensity between subgroups, the
results were comparable (see figure 2 legend). Patients without pain before onset of weakness and patients without pain in the acute phase (n 43) had a
lower mean pain intensity in the beginning of the
follow-up (week 13: mean difference 1.4 [2.6,
0.2], p 0.05; week 26: mean difference 1.3
[2.6, 0.1], p 0.05) compared to patients with
pain during that period. This significant difference
disappeared after 26 weeks.
The correlation between disability, impairment,
and fatigue vs pain intensity is listed in table 3. Summarized, pain intensity is associated with level of
weakness, functional disability, and fatigue, not in
the acute but during later stages of GBS. Sensory
involvement is associated with the intensity of pain
during the acute and later stage of GBS.
This is the first large prospective
follow-up study on the different aspects of pain in
GBS in relation to the spectrum of GBS. As shown in
this study, pain appeared to be a very common symptom in the acute phase and during the later stage of
GBS and it also occurs in the whole spectrum of GBS
DISCUSSION

variants, like MFS, pure motor, and mildly affected

patients.
By far the most frequent location of pain during
the entire follow-up was in the extremities, followed
by low-back pain or back pain, and often more than
one location was indicated. In MFS, neck pain occurred most frequently in the acute phase and also
headache was regularly reported as other type of
pain, which is also described in another study.13 This
indicates that pain in GBS may affect various parts of
the body. Comparing GBS (non-MFS) with MFS,
the distribution of weakness seems to contribute
to the distribution of pain.
Despite the use of analgesics, nearly half of the
patients with pain reported moderate and one-third
even severe pain. This emphasizes the magnitude of
the clinical problem of pain in GBS. In a study in 55
patients with GBS, a similar mean pain intensity was
found in the acute phase, but a lower mean pain
intensity was found in the period until 24 weeks.8
We have asked for the presence of pain within 3
months before onset of weakness retrospectively,
therefore recall bias may have affected this part of the
results of our study. In the questionnaires, we emphasized that the reported pain during GBS had to
be new or different from the pain felt in medical
history. However, that it can be difficult for patients
to differentiate between preexistent and new pain.
To identify factors that are associated with pain,
we related pain to clinical features. As shown in this
study, pain intensity is associated with level of weakness, functional disability, and fatigue, not in the
acute but during later stages of GBS. Whether pain
causes part of disability or disability contributes to
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October 19, 2010

Figure 2

Mean pain intensity over time in Guillain-Barre

syndrome (GBS) subgroups

Data shown are means (SE) from analysis of variance. Mean differences (dotted minus solid line) in pain intensity (numerical rating scale [NRS]) with 95%
confidence interval and p value; from time before onset of weakness to 52 weeks after onset of weakness between the different groups are indicated. (A)
GBS (non-Miller Fisher syndrome [MFS]) (n 138) and MFS (n 18). (B) Weakness and sensory disturbances (n 98) and pure motor (n 52) (n 6
unknown). Same analysis without MFS: mean difference in pain intensity 0.9 (0.2, 1.7); p 0.05. (C) Gastroenteritis or diarrhea (n 52) and no gastroenteritis or diarrhea (n 101) (n 3 unknown). Same analysis without MFS: mean difference in pain intensity 0.8 (1.4, 0.1), p 0.05. (D) Respiratory
tract or influenza or influenza-like infection (n 56) and no respiratory tract or influenza or influenza-like infection (n 96) (n 4 unknown). Same analysis
without MFS: mean difference in pain intensity 0.4 (0.3, 1.1), p 0.23. (E) Severely affected at nadir (n 126) and mildly affected at nadir (n 30).
Same analysis without MFS: mean difference in pain intensity 1.1 (0.2, 1.9), p 0.05. (F) Female (n 61) and male (n 95). Same analysis without MFS:
mean difference in pain intensity 0.9 (0.3, 1.6), p 0.01.

pain cannot be concluded from our study. In another

follow-up study, no significant correlation between
disability and pain intensity was found.8 However,
several years after GBS, an interaction between fatigue, pain, and muscle weakness has been described.36 In this study, they found a higher risk of
pain and muscle weakness in individuals with pronounced fatigue. Both symptoms may influence each
other and need to be registered. Depression or anxiety may also influence pain in GBS. Depression or
anxiety was not specifically assessed in our study and
needs further attention in forthcoming studies. Our
results indicate that involvement of sensory nerves
plays a role in the occurrence and intensity of pain
during the acute and later stage of GBS. It has been
described that years after GBS, muscle aches and
cramps occur especially in patients with residual sensory disturbances.37 It was remarkable that in our
study patients with previous diarrhea had a signifi6

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October 19, 2010

cantly higher mean pain intensity score compared to

patients without diarrhea. The fact that in this study
the number of pure motor patients or severely affected patients was not significantly different in the
group with and without diarrhea does not explain the
difference. Possibly different immunologic factors
generated by an infection may play a role in pain.
The pathophysiology of pain in GBS is largely
unknown and this study indicates the complexity of
studying pain in GBS. Affected nerve roots may explain the occurrence of radicular nociceptive nerve
pain affecting the low back or back with radiation to
extremities or trunk.5 Inflammatory factors generating pain via the nervi nervorum may also play a role
in the pathophysiology of pain, but has not been
studied yet. In our study, the prevalence of back pain
was higher than the prevalence of radicular pain, indicating that other types of pain like muscle pain or
arthralgia possibly due to immobilization may also

Table 3

Correlations between disability, impairment, and fatigue in the chronic phase vs pain intensitya
t0

Week 13

Week 26

Week 39

Week 52

Muscle strength (MRC sumscore)

(n 131) 0.06

NE

(n 136) 0.25

NE

NE

Sensory involvement

(n 128) 0.28*

NE

(n 125) 0.41

NE

NE

Impairment

Disability
Disability (GBS disability score)

(n 138) 0.00

(n 141) 0.40

(n 147) 045

(n 146) 0.51

(n 146) 0.43

Disability score (ODSS score)

(n 135) 0.04

(n 140) 0.55

(n 147) 0.51

(n 147) 0.54

(n 143) 0.46

NE

(n 137) 0.43

(n 142) 0.52

(n 144) 0.51

(n 145) 0.37

Fatigue (FSS score)

Abbreviations: FSS Fatigue Severity Scale; GBS Guillain-Barr syndrome; MRC Medical Research Council; NE not
evaluated; ODSS overall disability sumscore.
a
Data given are Spearman correlation coefficients (rs) between disability, impairment, and fatigue vs pain intensity (NRS
score) for the entire group. For the relation between fatigue and pain intensity, changes from the previous measurement
were also evaluated (weeks 1326: rs 0.14; weeks 2639: rs 0.30; weeks 3952: rs 0.23).
*p 0.05.
p 0.01.
p 0.001.

contribute to back pain in GBS. Neuropathic pain

due to spontaneous or abnormal activity from large
myelinated sensory afferents may explain the occurrence of painful paraesthesias and dysesthesias in the
extremities. However, considering the high prevalence of pain in the extremities, other types of pain
also may play a role. Small nerve fibers can also be
affected in GBS.38 Affected small nerve fibers in GBS
may play a role in pain and autonomic dysfunction
and needs additional studies.
Nevertheless, 2 different combinations of pain
symptoms may be distinguished. One combination
starts before onset of weakness until hospital discharge, is mostly located in the extremities, and contains especially radicular pain, painful paresthesiae,
and muscle pain; the other combination is predominantly present after hospital discharge during rehabilitation, is also mostly located in the extremities,
and contains especially painful paresthesiae, muscle
pain, and arthralgia. The intensity of pain is severe
during the course of disease, but is most severe in the
acute phase. Pain symptoms are associated with sensory disturbances and severe pain symptoms later in
the stage of disease are associated with a higher level
of weakness and disability. Patients with acute pain
symptoms have a higher change on the occurrence of
the pain symptoms in the later stage.
In case reports, the analgesic effect of corticosteroids for lumbar and leg pain has been described.39,40
In this study there appeared to be no difference in
pain between patients treated with MP or not, which
is in line with a previous study on the additional
effect of MP in GBS.10
AUTHOR CONTRIBUTIONS
Statistical analysis was conducted by Dr. W.C.J. Hop and Dr. L. Ruts.

COINVESTIGATORS
The Dutch GBS Study Group (neurologists, including and assessing patients with GBS, who contributed to the study): L. Ruts, MD, and P.A.
van Doorn, PhD, MD (Erasmus MC, Rotterdam, n 33); A.J. van der
Kooi, PhD, MD (AMC, Amsterdam, n 10); G.W. van Dijk, PhD, MD
(Canisius-Wilhelmina, Nijmegen, n 10); H.A.W. Sinnige, MD
(Maasstad ZH, locatie Clara & Zuider, n 12); F.H. Vermeij, MD (SFG,
Rotterdam, n 10); U.A. Badrising, PhD, MD (Bethesda ZH, Middelharnis, n 8); I.N. van Schaik, PhD, MD (OLVG, Amsterdam, n 7);
J.C.B. Verhey, MD (Vlietland ZH, Schiedam, n 7); J.S. Straver, MD
(Hofpoort ZH, Woerden, n 6); W.H.J.P. Linssen, PhD, MD (Lucas
Andreas ZH, Amsterdam, n 5); E.G.J. Zandbergen, MD (ZH Rijnstate, Arnhem, n 4); M.C. de Rijk, PhD, MD (Catharina-ZH, Eindhoven, n 4); W.L. van der Pol, PhD, MD (UMCU, Utrecht, n 4);
J.P. Blankevoort, PhD, MD (Flevo ZH, Almere, n 3); D.G. Oenema,
MD (Wilhelmina ZH, Assen, n 3); B. Feenstra, MD (Lievensberg ZH,
Bergen op Zoom, n 3); D.J. Hofstee, MD (St. Jansdal ZH, Harderwijk, n 3); R. Beekman, PhD, MD (Atrium MC, Heerlen, n 3);
C.G. Faber, PhD, MD (UMCM, Maastricht, n 3); R.A.I.A.M.
Bernsen, PhD, MD (Jeroen Bosch ZH, Den Bosch, n 3); W.G.H.
Oerlemans, MD (Meander MC, Amersfoort, n 2); R.W.M. Keunen,
PhD, MD (HAGA ZH loc. Leyenburg, Den Haag, n 2); G.H.M.
Verheul, MD (Groene Hart ZH, Gouda, n 2); W. Snoek, PhD, MD
(Martini ZH, Groningen, n 2); T.C. van der Ree, MD (Westfries
Gasthuis, Hoorn, n 2); W.J. Schuiling, MD (MC Leeuwarden, Leeuwarden, n 2); J.L.M. Jongen (Ruwaard van Putten ZH, Spijkenisse,
n 2); Dr. L.H. Visser (Sint Elisabeth ZH, Tilburg, n 2); G.M.J.
Lassouw (VieCuri MC, Venlo, n 2); Dr. V.I.H. Kwa, PhD, MD (Slotervaart ZH, Amsterdam, n 1); J.A. Don, MD (Delfzicht ZH, Delfzijl,
n 1); M.J.B. Taphoorn, PhD, MD (HAGA ZH loc. Westeinde, Den
Haag, n 1); F. Visscher, MD (St. Oosterschelde ZH, Goes, n 1);
R.J.W. Witteveen, MD (Rijnland ZH, Leiderdorp, n 1); J.J.G.M. Verschuuren, PhD, MD (LUMC, Leiden, n 1); E.M. Leenders, MD (IJsselmeer ZH, Lelystad, n 1); P.H.M.F. van Domburg, PhD, MD
(Laurentius ZH, Roermond, n 1); D.M.H. Zuidgeest, MD (Ikazia ZH,
Rotterdam, n 1); H.J. Vroon, MD (Haven ZH, Rotterdam, n 1);
R.J. Groen, MD (Lange Land ZH, Zoetermeer, n 1).

ACKNOWLEDGMENT
The authors thank the patients for taking part in the study; the coinvestigators of the Dutch GBS Study Group listed in the appendix; Drs. K.
Kuitwaard, M.L. Kuijf, and S.I. van Nes, residents in Neurology (Erasmus MC, Rotterdam), and Dr. R. van Koniningsveld (currently working
in Elkerliek ziekenhuis, Helmond) for including patients; and A.P. TioNeurology 75

October 19, 2010

Gillen for determining the antiganglioside antibodies (Erasmus MC, Rotterdam) and M.M. de Kimpe, administrative coordinator, GRAPH study
(Erasmus MC, Rotterdam).

16.
17.

DISCLOSURE
Dr. Ruts reports no disclosures. Dr. Drenthen receives research support from
the Prinses Beatrix Fonds. Dr. Jongen has received speaker honoraria from
Pfizer Inc., Johnson & Johnson, and Boehringer Ingelheim; and has received
research support from the Dutch Ministry of Health. Dr. Hop and Dr. Visser
report no disclosures. Dr. Jacobs has received research support from the Netherlands Organization for Health Research and Development, Erasmus MC,
the Prinses Beatrix Fonds, and GBS-CIDP Foundation International. Prof.
Dr. van Doorn has served on scientific advisory boards for Octapharma AG
and Talecris Biotherapeutics; received a speaker honorarium from Baxter International Inc.; and serves on the editorial board of the Journal of the Peripheral Nervous System.

18.
19.

20.

21.

Received January 30, 2010. Accepted in final form June 29, 2010.
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