Clinical Neurophysiology xxx (2015) xxx–xxx

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Clinical Neurophysiology
journal homepage: www.elsevier.com/locate/clinph

Ultrasound and electrophysiologic findings in patients with

Guillain–Barré syndrome at disease onset and over a period of six
months
Alexander Grimm a,b,⇑, Bernhard F. Décard a, Axel Schramm c, Anne-Katrin Pröbstel a, Maria Rasenack a,
Hubertus Axer d,1, Peter Fuhr a,1
a
Department of Neurology, Basel University Hospital, Basel, Switzerland
b
Department of Neurology, University of Tuebingen, Tuebingen, Germany
c
Department of Neurology, Erlangen University Hospital, Erlangen, Germany
d
Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany

a r t i c l e i n f o h i g h l i g h t s

Article history:
 Enlarged cervical spinal and peripheral nerves detected by ultrasound might be an early marker for
Accepted 15 June 2015
Available online xxxx
Guillain–Barré syndrome (GBS).
 Vagus enlargement occurs in patients with GBS, predominantly in those with autonomic

Keywords:
dysregulation.
Nerve ultrasonography  Vagus nerve and spinal nerves normalize after six months, while the peripheral nerves remain
Immune-mediated neuropathy enlarged.
Spinal nerves
Vagus nerve
Guillain–Barré syndrome a b s t r a c t
Objective: To investigate cross-sectional areas (CSAs) of several peripheral nerves including the vagus nerve
and the diameter of spinal nerves as measured by nerve ultrasound (NUS) and nerve conduction studies
(NCS) in Guillain–Barré syndrome (GBS) patients over at least six months compared to healthy controls.
Methods: NUS and/or NCS of several nerves, the vagus nerve, and the 5th/6th cervical spinal nerves were
performed in patients with GBS at days 2–3 after symptom onset, at days 10–14 after immunoglobulin ther-
apy and after six months compared to healthy controls.
Results: 27 GBS-patients and 31 controls were included. Using NUS significant enlargement was found in all
measured nerves (P < 0.001), except the sural nerve (P = 0.086) compared to the controls at onset. The vagus
(median 3.0 mm2 vs. 2.0 mm2, P < 0.0001) and the cervical spinal nerves were significantly enlarged (med-
ian 3.5/4.0 mm vs. 2.6/3.2 mm, p < 0.0001), the vagus most obviously in patients with autonomic dysregu-
lation (AD, 4.0 mm2). Six months later, NCS showed persisting pathology in CMAP-amplitudes with
amelioration of F-wave pathology. NUS showed restitution in the spinal nerves (median 2.6/3.2 mm) and
the vagus (median 2.0 mm2) in all patients excluding the vagus in those with persistent AD (median
4.0 mm2). The peripheral nerves did not change significantly (P > 0.05).
Conclusion: Ultrasonographic detection of cervical spinal nerve enlargement supports the diagnosis of GBS
in the early phase. Its regression may be a good parameter for the clinical restitution over time. Vagus
enlargement may be a risk marker for development of AD.
Significance: Ultrasound is a reliable diagnostic follow-up tool in early GBS.
Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights
reserved.

Abbreviations: AD, autonomic dysregulation/dysfunction; AIDP, acute inflammatory demyelinating polyradiculoneuropathy; AM(S)AN, acute motor (and sensory) axonal
neuropathy; AUC, area under the curve; C5/C6, cervical spinal nerve 5/6; CIDP, chronic inflammatory demyelinating polyneuropathy; CMAP, compound muscle action
potential; CSA, cross-sectional area; CSF, cerebrospinal fluid; CV, conduction velocity; dmL, distal motor latency; GBS, Guillain–Barré syndrome; ms, millisecond; m/s, meter
per second; mV, millivolt; NCS, nerve conduction studies; NUS, nerve ultrasound; SNAP, sensory nerve action potential.
⇑ Corresponding author at: Department of Neurology, Basel University Hospital, Petersgraben 4, 4031 Basel, Switzerland. Tel.: +41 61 5565130.
E-mail address: alexander.grimm@usb.ch (A. Grimm).
1
Contributed equally.

http://dx.doi.org/10.1016/j.clinph.2015.06.032
1388-2457/Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Grimm A et al. Ultrasound and electrophysiologic findings in patients with Guillain–Barré syndrome at disease onset and
over a period of six months. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.06.032
2 A. Grimm et al. / Clinical Neurophysiology xxx (2015) xxx–xxx
1. Introduction
Diagnosis of Guillain–Barré syndrome (GBS) is based on typical
history, clinical examination, and electrophysiological studies
(Asbury and Cornblath, 1990; Fokke et al., 2014; Hadden et al.,
1998; Hughes and Cornblath, 2005; van den Berg et al., 2014)
while serologic findings usually are available later and serve for
corroboration. Many variants of GBS exist, e.g. the Miller Fisher
syndrome with ataxia, areflexia, and oculomotor dysfunction
(Hughes and Cornblath, 2005). The most common types are the
acute inflammatory demyelinating polyradiculoneuropathy
(AIDP) and the acute motor axonal neuropathy (AMAN).
Autonomic dysregulation (AD) is most dangerous in the early stage
of the disease. Reduced heart rate reactions to Valsalva and deep
breathing as well as blood pressure measurements are suitable
methods to diagnose AD. However, no clear prognostic markers
exist so far to predict AD.
The value of nerve ultrasonography (NUS) in immune-mediated
polyneuropathies is well described (Beekman et al., 2005; Gallardo
et al., 2015; Grimm et al., 2014a,b,c; Hobson-Webb and Cartwright,
2014; Kerasnoudis et al., 2013, 2014a,b; Padua et al., 2012, 2014;
Scheidl et al., 2012, 2014; Zaidman et al., 2009, 2013, 2014).
In post-GBS patients patchy and slight enlargements have been
reported (Kerasnoudis et al., 2013; Zaidman et al., 2009, 2013),
whereas in acute stage cervical spinal nerve enlargement and
hypertrophy of the vagus are probably the most obvious findings
(Gallardo et al., 2014; Grimm et al., 2014d). However, only little
is known about the course of nerve morphology from onset until
clinical recovery. Therefore, aim of this study is to describe the
time course of NUS changes in correlation to nerve conduction
studies (NCS) and clinical course.
2. Methods
2.1. Subjects
Between August 2013 and December 2014, all consecutive
patients suffering from acute AIDP or AM(S)AN, presenting at par-
ticipating hospitals were included in this study. Inclusion criterion
was the diagnosis of acute onset polyneuropathy fulfilling the pub-
lished diagnostic criteria for GBS (Asbury and Cornblath, 1990;
Cornblath et al., 1988; Fokke et al., 2014; Hadden et al., 1998;
Hughes and Cornblath, 2005; van den Berg et al., 2014).
Exclusion criterion was symptom onset >three days before screen-
ing. Patients were screened within the first two days of hospitaliza-
tion. All patients were examined clinically by at least one board
certified neurologist, by nerve ultrasonography, and NCS as
described below in the first three days of symptom onset and after
six months. Ultrasound and NCS routines were standardized over
all visits. NUS only was performed 10–14 days after immunoglob-
ulin therapy. Laboratory analysis including anti-ganglioside anti-
bodies and CSF analysis were performed in the acute phase.
Disability was classified using the Hughes-Score (Hughes and
Cornblath, 2005; Hughes et al., 1978) ranging from 0 (normal) to
6 (death). In addition to reported or clinically evaluated symptoms
(sweating problems, orthostatic dysregulation, sexual dysfunction)
AD was evaluated using 24-h heart rate monitoring and blood
pressure measurements five times daily for at least the first seven
days of acute hospitalization. In cases of autonomic symptoms the
monitoring was performed until amelioration of symptoms. After
six months the AD was evaluated by a standardized questionnaire
including symptoms for sweating problems, orthostatic intoler-
ance, cardiac arrhythmias, and sexual dysfunction. In addition, a
healthy control group consisting of medical staff and patients
without neuromuscular disorders was examined using the same
Please cite this article in press as: Grimm A et al. Ultrasound and electrophysiologic findings in patients with Guillain–Barré syndrome at disease onset and
over a period of six months. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.06.032
ultrasonography and electrophysiology protocol. The study was
registered with the German clinical trial register
(DRKS-ID00006140) and approved by the local ethics committee
(No. 3663-01/13 and EKZN 2014-230). Informed consent was
obtained from all patients and controls.
2.2. Ultrasonography
Ultrasonography of different nerves was performed using a high
frequency 14 MHz probe real-time broadband linear array scanner
(ZONARE Ultrasound systems, Uk Ltd. and Aplio 300 Ultrasound
System, Toshiba medical systems, Japan). Each nerve was scanned
in axial plane, and the cross-sectional area (CSA) was measured at
standardized anatomical points as described (Grimm et al.,
2014a,b,d), in brief: vagus nerve in carotid sheath; median nerve
in upper arm, elbow, forearm; ulnar nerve in upper arm and fore-
arm; tibial nerve in poplitea and ankle; peroneal nerve in popliteal
fossa, and sural nerve in the calf. In addition, the diameter of the
ventral branch of the 5th and the 6th cervical spinal nerve was
measured in longitudinal scan, after leaving the intervertebral
foramen and the processus transversus, when turning into the
straight course. All measurements were done on the right side
due to the symmetric clinical presentation. Analysis of data from
ultrasonography was performed both online and offline.
Approximately 40 min were needed for a complete ultrasonic
examination.
2.3. Nerve conduction studies
NCS were performed in the corresponding nerves using a stan-
dard electro-neurophysiologic device (Synergy 15.0, VIASYS
Healthcare UK Ltd.). Measurements were performed as described
in literature (Preston and Shapiro, 2013). Motor nerve conduction
studies (NCS) were carried out on the right median, ulnar, tibial
and peroneal nerves. Distal motor latency (dmL), nerve conduction
velocity (CV) and compound muscle action potential (CMAP)
amplitude measurements were undertaken as well as measure-
ments of the mean F-M-latencies of 16 F-wave responses
(F-wave latency–dmL). Similarly, sensory nerve action potential
(SNAP) amplitude and CV measurements were carried out on the
right median, the right ulnar and the sural nerves by averaging
of at least 10 responses.
2.4. Statistics
For statistical analysis, we used IBM SPSS Statistics, version 19
(Chicago, IL). Mann–Whitney-test was used for evaluating differ-
ences concerning epidemiological data (age, gender, height and
weight). Median values of NCS and CSA data were evaluated.
Mann–Whitney-test with Bonferroni correction was used to detect
differences of nerve CSAs and NCS between patients and controls
and between patients at different time points. Pearson correlation
coefficients were calculated to quantify correlations between NCS,
ultrasonographic findings, clinical course, and laboratory findings.
Chi-square-test with Fisher’s exact test was used for comparing the
frequency of pathological nerve or spinal nerve enlargement and
F-waves in acute and post-GBS patients compared to controls.
Receiver operating characteristic (ROC) curve analysis was used
to define cut-off values for several ultrasound measurement points
to differentiate acute GBS from controls. For all tests, a two-sided
P-value <0.05 was considered to be statistically significant.
3. Results
27 patients with GBS and 31 controls were included in the
study. Baseline characteristics of the patients and the healthy
 A. Grimm et al. / Clinical Neurophysiology xxx (2015) xxx–xxx
Table 1
Baseline characteristics of the study population.
N 27 (AIDP 25, AM(S)AN 2)
Mean age in years ± SD
Men: women
Height in cm
Weight in kg
Onset
Hughes-Score (HS) at onset and after six months (Hughes et al., 1978)
Abbreviations: AM(S)AN = acute motor (and sensory) axonal neuropathy, cm = centimeter; HS = Hughes-Score (after six months); GBS = Guillain–Barré syndrome;
kg = kilogram; SD = standard deviation.
Significance was set at P < 0.05 and shown in bold print.
controls are shown in Table 1. Some patients and controls of this
study were already described in a former study conducted in the
acute phase of GBS (Grimm et al., 2014d). 25 patients fulfilled
the electrophysiological criteria for a demyelinating polyneuropa-
thy (Hadden et al., 1998), two patients had signs of a severe axonal
neuropathy with typical clinical onset of a GBS, and elevated CSF
protein and thus were diagnosed as AMAN, and acute motor and
sensory axonal neuropathy (AMSAN) respectively (Asbury and
Cornblath, 1990; Fokke et al., 2014; Hadden et al., 1998; Hughes
and Cornblath, 2005; van den Berg et al., 2014). At onset, 16
patients were severely impaired from neuropathy according to a
Hughes-Score P3 (Hughes et al., 1978). Seven patients had AD
according to monitoring results and reported symptoms, e.g.
orthostatic intolerance, missing heart rate response to exercise,
and sweating problems. All patients were treated with 0.4 g/kg
bodyweight immunoglobulins for 5 days.
3.1. Onset period days 2–3
Table 2 shows motor NCS of the median and tibial nerve in the
acute phase of the disease. Results of the NCS of the other nerves
are not shown in this table but were used for diagnosis of GBS
according to the literature (Asbury and Cornblath, 1990;
Cornblath et al., 1988; Hadden et al., 1998; Hughes and
Cornblath, 2005). Overall the median values of the NCS of the med-
ian nerve are within the reported ranges in literature (Preston and
Shapiro, 2013), the nerve involvement differed interindividually
(median nerve: CV reduced in 12 patients out of 27, CMAP reduced
10/27, dmL prolonged 13/27, temporal dispersion 4/27, F-wave
pathology 19/27; tibial nerve: CV 14/27; CMAP amplitude 20/27;
dmL 19/27, temporal dispersion 6/27, F-wave pathology 23/27).
Ulnar and median nerve SNAPs were absent in 10 patients while
sural nerve SNAP was absent in only three patients – reflecting
sural sparing (Derksen et al., 2014). We orientated on boundary
values of literature and our laboratories (Preston and Shapiro,
2013).
Median ultrasonic CSA measurements of the GBS patients were
enlarged compared to the controls in all nerves (Fig. 1, black and
light gray box plots; Mann–Whitney-test, P < 0.001⁄) except the
sural nerve, which was only enlarged by trend in GBS. The spinal
nerves and the vagus nerve were significantly enlarged compared
to the controls (Fig. 1, Mann–Whitney-test with Bonferroni correc-
tion P < 0.0001⁄⁄). Based on ROC curve analysis boundary values for
the spinal nerves (2.9 mm and 3.8 mm) and the vagus (3.0 mm2)
could be defined to reliably differentiate GBS from controls with
high sensitivity and specificity (Fig. 2A and B). In contrast, CSA of
Please cite this article in press as: Grimm A et al. Ultrasound and electrophysiologic findings in patients with Guillain–Barré syndrome at disease onset and
over a period of six months. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.06.032
3
GBS Control Mann–Whitney-test
31
57.1 ± 18.0 47.5 ± 17.9 P = 0.018
16:11 16:15 P = 0.492
175.7 ± 9.4 174.8 ± 5.9 P = 0.790
77.7 ± 19.6 68.0 ± 17.9 P = 0.187
Pure sensory n = 18
Sensorimotor n = 6
Cranial nerve n = 3
HS 0 n = 0 (n = 4)
HS 1 n = 3 (n = 13)
HS 2 n = 8 (n = 3)
HS 3 n = 8 (n = 1)
HS 4 n = 8 (n = 0)
peripheral nerves revealed lower potential to differentiate GBS
from controls (e.g. tibial nerve, Fig. 2C) and the sural nerve was
not suitable for diagnosing GBS (Fig. 2C). Fig. 3 gives an example
of the enlarged vagus nerve and the spinal nerve C6 compared to
a healthy control.
Median values of the vagus differed significantly between those
patients with and those without AD (Fig. 1, dark gray and black
filled box plots, P < 0.001).
No correlation between CSA of several nerves and disability
Hughes-Score or different NCS data (CMAP, dmL or CV) were found.
Additionally, no differences of CSA measurements were detected
between certain subtypes of GBS, e.g. patients with and without
cranial nerve involvement, or with and without anti-ganglioside
antibodies. Pearson correlation was significant between the CSF
protein level and the diameter of C6 (0.458, P = 0.028) and slightly
missed significance between the CSF protein and the diameter of
C5 (0.468, P = 0.068).
3.2. Days 10–14 after therapy
NCS were not done at this time point. Mean CSA values were
almost identical compared to onset examination (Fig. 4). Ten
patients worsened clinically (P1 point in the Hughes Score)
between onset and this time point and showed an increase of nerve
CSAs, but no significant correlation between clinical worsening and
increased nerve enlargement was found.
3.3. Six months later
Follow-up examination was performed in 21 patients. Two
patients denied follow-up, three were not available anymore due
to migration, one patient died from suicide.
All patients recovered well during the six months period. Clinical
disability, evaluated with the Hughes score improved significantly in
all patients (Table 1, Mann–Whitney-test p < 0.001). Thirteen
patients showed only subtle symptoms such as sensory deficits, gait
disturbances, or discreet paresis in follow-up. Four patients com-
plained still about remarkable AD, such as sweating problems, sex-
ual dysfunctions and ongoing orthostatic dysregulation.
Electrophysiological findings are given in Table 2; in summary they
show improved motor conduction properties in arm (e.g. only 2 out
of 21 patients with reduced CV in median nerve) and leg nerves (e.g.
4 out of 21 with reduced CV in tibial nerve). However, median and
tibial CMAP amplitudes were still markedly reduced in some
patients (4 out of 21 in median and 9 out of 21 in tibial nerve).
The median follow-up ultrasonic measurements are shown in
Fig. 1. No significant differences of the CSA values of the peripheral
4 A. Grimm et al. / Clinical Neurophysiology xxx (2015) xxx–xxx

Table 2
Nerve conduction studies at onset and after six months.

Median (range) Control Acute GBS Post-GBS Mann–Whitney-test Mann–Whitney-test Mann–Whitney-test

after six with Bonferroni acute- with Bonferroni with Bonferroni acute-
months GBS/controls post-GBS /controls GBS/post-GBS
Motor CV median nerve 51.0 (49.0–61.0) 47.0 (26.0–59.0) 49.0 (34.0–65.0) P = 0.015 P = 0.107 P = 0.707
(m/s)
CMAP amplitude median 11.9 (5.0–18.0) 5.6 (0.6–12.0) 6.5 (0.5–11.0) P < 0.001 P = 0.023 P = 0.176
nerve (mV)
Distal motor latency 4.0 (2.9–4.2) 4.6 (3.3–13.2) 4.0 (2.6–8.0) P = 0.015 P = 0.163 P = 0.437
median nerve(ms)
Median F-wave latency (ms) 26.5 (25.0–32.5) 31.6 (28.0–41.0) 29.0 (24.0–53.0) P = 0.008 P = 0.213 P = 0.063
Absent n=0 n = 10 n=2 P < 0.001 P = 0.345 P = 0.006
Motor CV tibial nerve (m/s) 44.5 (41.0–47.0) 39.0 (32.0–48.0) 41.0 (29.0–52.0) P < 0.001 P = 0.272 P = 0.221
CMAP amplitude tibial 13.1 (7.4–24.0) 2.0 (0.0–15.0) 7.0 (0.2–18.0) P < 0.001 P = 0.003 P = 0.045
nerve (mV)
Distal motor latency tibial 4.5 (3.1–6.8) 6.0 (4.0–20.0) 4.8 (3.7–11.0) P = 0.003 P = 0.145 P = 0.233
nerve(ms)
Tibial nerve F-wave latency 53.0 (43.0–61.4) 60.0 (48.3–87.0) 55.0 (45.0–76.2) P = 0.054 P = 0.126 P = 0.396
(ms) Absent n=0 n = 13 n=3 P < 0.001 P = 0.677 P < 0.001

Abbreviations: GBS = Guillain–Barré syndrome; CV = conduction velocity, CMAP = composed motor action potential, ms = millisecond, mV = milli volt, m/s = meter per second.
Significance was set P < 0.05. Significant differences are shown in bold print.

Fig. 1. Median ultrasound values. Median values of the peripheral nerve measurements in acute GBS (black box plots), after six months (dark gray box plots) and controls
(light gray box plots). Differences between vagus nerve with (AD+) and without autonomic dysregulation (AD ) at onset (acute) and after six months are shown in filled, dark
gray, black, light gray and gray box plots. The vagus box plots are showing the complete CSA range. * = P < 0.001; ** = P < 0.0001. CSA = cross-sectional area.

nerves could be measured in the follow-up group compared to the
onset values (Mann–Whitney-test with Bonferroni correction,
P > 0.05, Fig. 1). With regard to the intraindividual course in the
peripheral nerves, no trend could be evaluated. In comparison to
the control group the CSAs were still increased in median nerve
and tibial nerves (Mann–Whitney-test with Bonferroni correction,
P < 0.001⁄).
In contrast, vagus nerve CSA as well as the 5th/6th cervical
spinal nerve diameters significantly decreased over the six months
period (Fig. 4) and finally reached almost normal values again in
each patient (Fig. 1). The intraindividual course revealed reduction
of diameter of cervical spinal nerves in most patients. In the vagus,
however, CSA enlargement persisted in those patients with persist-
ing AD compared to those without (4 out of 7, P < 0.001⁄ Fig. 1 –
light gray and gray filled box plots).
Chi square test revealed differences in the frequency of cervical
spinal nerve enlargement between GBS at onset and GBS after six
months as well as controls concerning the 5th and the 6th spinal
nerve (C5; v2 = 28.663, df 3, p < 0.001 and C6; v2=16.300, df 3,
p = 0.001). Furthermore, Chi square test revealed a decrease of
the number of pathologic F-waves of median and ulnar nerve (pro-
longed latency or reduced persistency <50%) over the six months
period (v2 = 21.064, df2, p < 0.0001). Overall, 75% of patients
showed congruent results in F-waves and cervical spinal nerves
(either both qualities with pathology or both qualities normal).
In acute GBS this concordance was 73.9%, after six months it was
76.5%.
4. Discussion
The current study shows, that ultrasonic enlargement of the
peripheral nerves, the cervical spinal nerves as well as the vagus
occurs in the very early stage of GBS, most prominently in the

Please cite this article in press as: Grimm A et al. Ultrasound and electrophysiologic findings in patients with Guillain–Barré syndrome at disease onset and
over a period of six months. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.06.032
 A. Grimm et al. / Clinical Neurophysiology xxx (2015) xxx–xxx 5

Fig. 2. ROC curve analysis of boundary values. ROC curve analysis of the cervical spinal nerves (A), the vagus (B), the tibial nerve in the ankle and the sural nerve (C). The
spinal nerves and the vagus show significant differences with high sensitivity and specificity and boundary values can be defined, while the differences are less obvious for
the tibial nerve. The sural nerve has no power to differentiate between GBS and controls. AUC = area under the curve.

Fig. 3. Ultrasound of the vagus and the 6th cervical spinal nerve in a patient and a healthy control. The ultrasound image shows the vagus nerve and the cervical spinal nerves
enlarged in a patient with acute GBS (A) compared to a healthy control (B). The cross sectional area of the vagus nerve (next to the carotid artery marked with a star) is 4 mm2
in the patient (A1) and 1 mm2 in the control (B1). The C6 diameter, measured after leaving the processus transversus is 4.9–6.4 mm, the CSA is 17 mm2 in the patient (A2 and
A3) and 3.6 mm/8 mm2 in the control (B2 and B3). The CSA of the 5th cervical nerve is not enlarged (7 vs. 8 mm2 A and B3).

Fig. 4. Ultrasound follow-up values. Median CSA follow-up values of the vagus and median diameter of the C5 and C6 nerves in acute GBS (days 2–3), two weeks after
immunoglobulins and after six months. The median values including the range are shown for the onset and the sixth month follow-up. Significant decrease is found in the
vagus and the 5th and 6th spinal nerves (Mann–Whitney-test with Bonferroni correction <0.001, bold print).

Please cite this article in press as: Grimm A et al. Ultrasound and electrophysiologic findings in patients with Guillain–Barré syndrome at disease onset and
over a period of six months. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.06.032
6 A. Grimm et al. / Clinical Neurophysiology xxx (2015) xxx–xxx
spinal nerves and the vagus and may, therefore, serve as an early
diagnostic indicator of GBS. However, while spinal nerve enlarge-
ment and vagus nerve hypertrophy regress consistently over six
months, enlargement in many peripheral nerves persists even after
six months – independently from clinical improvement. The vagus
enlargement persists in patients with ongoing autonomic deficits.
Enlargement of the cervical spinal nerves, peripheral as well as
the vagus nerves has already been demonstrated by ultrasound in
acute and in chronic stage of GBS (Gallardo et al., 2014; Grimm
et al., 2014d; Zaidman et al., 2009, 2013). Nevertheless, nerve
enlargement in GBS is not as prominent as in chronic inflammatory
demyelinating polyradiculoneuropathy (CIDP) (Kerasnoudis et al.,
2013, 2014a,b; Zaidman and Pestronk, 2014) with a variable distri-
bution. However, to the best of our knowledge, the present study is
the first to report on long-term course of ultrasound changes in
GBS.
4.1. Findings at baseline in cross-sectional comparison
In our study population, the median values of the NCS data were
significantly changed compared to the controls. However, the val-
ues are still in the range of reported reference values (Preston and
Shapiro, 2013), due to the interindividual involvement of nerves in
this early stage of GBS (Albertí et al., 2011). With regard on ultra-
sound, all sensorimotor nerves were significantly enlarged in the
first three days of symptom onset, although frequency and extent
of morphological changes varied inter- and intraindividually. The
morphology of the purely sensory sural nerve was not significantly
altered, which could be the ultrasonic correlate of the electrophys-
iological finding of ‘‘sural sparing’’ (Derksen et al., 2014).
Additionally, the cervical spinal nerves and/or the vagus nerve
showed extensive enlargement in almost all GBS patients in the
very early phase (Fig. 3). The amount of cervical spinal nerve
enlargement correlated significantly with the CSF protein level in
the spinal nerve C6 and only slightly missed significance in the
spinal nerve C5. Similar correlations have been described previ-
ously (Grimm et al., 2014d; Kerasnoudis et al., 2014c). The vagus
nerve enlargement was most pronounced in cases of AD and might
therefore serve as early risk marker (Fig. 1).
Based on ROC curve analysis boundary values could be defined
to differentiate GBS from controls with high sensitivity and speci-
ficity using ultrasonic measurements of the diameter of the spinal
nerves and the CSA of the vagus (Fig. 2A and B). In contrast, CSA of
the peripheral nerves revealed not to be a suitable diagnostic crite-
rion (Fig. 2C). The age difference between patients and controls is a
limitation of the present study; however, we estimate this factor to
be of minor influence (Boehm et al., 2014).
4.2. Longitudinal observations
About two weeks after immunoglobulin therapy no significant
changes in the ultrasound data were seen in comparison to the
baseline data. Six months later most patients had clinically recov-
ered well and showed only slight residual symptoms with regard
to disability (Hughes Score). Ultrasonic enlargement of the periph-
eral nerves did not change remarkably within six months in spite
of good electrophysiological and clinical recovery. In contrast, cer-
vical spinal nerves and vagus nerve were almost back to normal
within six months (Fig. 4). Nevertheless, in the patients with ongo-
ing AD the vagus was still significantly enlarged (Fig. 1).
Most peripheral nerves electrophysiologically recovered well
except for reduced CMAP amplitudes (9 out of 21 patients in tibial
nerve), which depend more on axonal regeneration and accord-
ingly need more time to recover. No correlations could be ascer-
tained between ultrasound measurements and CV, CMAP, and
dmL over six months. Similar findings were already described for
Please cite this article in press as: Grimm A et al. Ultrasound and electrophysiologic findings in patients with Guillain–Barré syndrome at disease onset and
over a period of six months. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.06.032
CIDP and post-GBS patients (Kerasnoudis et al., 2013, 2014a).
However, pathologic F-wave-responses decreased significantly
over six months. The concordance to ultrasonic spinal nerve
enlargement – with similar amelioration – was 75%. Although,
the ulnar and median F-waves do not have relation to the 5th
and the 6th cervical spinal nerves, the significant correlation
between pathology and normalization of both qualities is remark-
able as both represent the proximal accentuation of GBS onset and
recovery. The negative correlation of NCS and NUS in the periph-
eral nerves is interesting, as it contrasts the findings, reported in
hereditary neuropathies (Schreiber et al., 2013). NUS reveals mor-
phological aspects, such as the epineurium, fascicles, echogenicity,
vascularization, whereas the electrophysiology represents the
nerve functionality and excitability. Therefore, the combination
of both could have a synergistic effect in the diagnosis and obser-
vation of inflammatory neuropathies.
The origin of the focal nerve enlargement in acute GBS remains
unclear, but it might be the ultrasonic correlation of focal inflam-
matory edematous demyelination with swelling of the nerve
sheaths as reported in histopathology (Gallardo et al., 2014;
Grimm et al., 2014d). Nerve echo intensity seems not to be altered
in contrast to descriptions in CIDP (Goedee et al., 2014; Padua
et al., 2012). The persistent nerve hypertrophy in the peripheral
nerves might be a consequence of ongoing slight inflammation
with edema and/or remyelination processes (Asbury et al., 1969).
Nevertheless, nerve hypertrophy seems to persist even after longer
time (Kerasnoudis et al., 2013, 2014a; Zaidman et al., 2009), and as
our study shows no correlation with clinical improvement over
time, ultrasound of peripheral nerves with its intra- and interindi-
vidual heterogeneity is not suitable to evaluate therapeutic effects
or serve as a prognostic marker. In contrast, the prominent
enlargement of vagus nerve and spinal nerves in the acute GBS
and its normalization within six months might serve as prognostic
marker for good recovery. The dichotomy of hypertrophy of the
spinal nerves and the vagus nerve in the acute phase and its reduc-
tion over time and persisting hypertrophy in peripheral nerves (as
well as the regression of F-wave pathology in NCS) points to an
outstanding role of the very proximal nerve segments in acute
GBS (Albertí et al., 2011; Asbury et al., 1969). The apparent differ-
ences of persisting hypertrophy between the spinal nerves/the
vagus and the peripheral nerve segments might be a consequence
of hypertrophic remyelination in the peripheral nerve segments. A
second way of nerve hypertrophy might be the (secondary) axonal
damage and Wallerian degeneration in peripheral nerve segments
(persisting CMAP amplitude reduction in our study population).
Axonopathy might lead to fascicular, hypertrophy – a remodeling
cascade, which was already discussed in sarcoid neuropathy
(Kerasnoudis et al., 2014d) – and might be another way of nerve
hypertrophy next to remyelination (Palumbo et al., 2002), edema
and inflammation (Grimm et al., 2014b and d).
The persistence of vagus hypertrophy in patients still complain-
ing about autonomic deficits is remarkable and might be a conse-
quence of ongoing inflammation or – as suggested in peripheral
nerves – Wallerian degeneration. Nevertheless, the number of
patients with AD was small and autonomic symptoms were only
evaluated with clinical examination, heart rate, blood pressure
monitoring, as well as history and not by specific tests
(Flachenecker et al., 1997), and therefore, results have to be inter-
preted cautiously. Standardized functional testing of parasympa-
thetic and sympathetic nerve function should be used in a longer
follow-up and multicentre study. As limitation, we must consider
that only two patients suffering from axonal variant of GBS were
included in this study and therefore a reliable comparison of
AM(S)AN and AIDP patients was not possible. Another limitation
was the short observation time as well as the long interval
between the screening visit and the follow-up visit; thus, we
 A. Grimm et al. / Clinical Neurophysiology xxx (2015) xxx–xxx
cannot predict based on our findings, whether ultrasound amelio-
ration in the spinal nerves and the vagus occurs prior to clinical
improvement or vice versa. Finally, no patients with bad recovery
could have been included in this study and therefore the findings
must be interpreted carefully. In addition, clinical outcome mea-
sures, such as the Hughes-Score, the inflammatory Rush built dis-
ability score (Draak et al., 2014) can reliably quantify clinical
outcome and therefore the use of ultrasound and NCS in
follow-up might be restricted. However, persisting spinal nerve
or vagus enlargement as well as progressing peripheral nerve
enlargement in cases of incomplete recovery could facilitate the
decision for further therapeutic or diagnostic procedures.
Therefore, large multicentre studies with short observation inter-
vals are necessary to further observe the development of nerve
enlargement in GBS.
5. Conclusion
Although enlargement of peripheral nerves may be less pro-
nounced than in CIDP and no significant changes have been found
over a follow-up period of half a year, the ultrasonic detection of
cervical spinal nerves and vagus enlargement supports the diagno-
sis of GBS in the early phase. The regression of this enlargement is
remarkable, but must be proven in patients with worse recovery to
serve as candidate prognostic marker. Moreover, detection of
vagus nerve hypertrophy in early GBS may be a potential risk mar-
ker for the development of autonomic dysregulation.
Conflict of interest
The authors report no competing interests.
References
Albertí MA, Alentorn A, Martínez-Yelamos S, Martínez-Matos JA, Povedano M,
Montero J, et al. Very early electrodiagnostic findings in Guillain–Barré
syndrome. J Peripher Nerv Syst 2011;16:136–42.
Asbury AK, Cornblath DR. Assessment of current diagnostic criteria for Guillain–
Barré syndrome. Ann Neurol 1990;27(Suppl):21–4.
Asbury AK, Arnason BG, Adams RD. The inflammatory lesion in idiopathic
polyneuritis. Its role in pathogenesis. Medicine (Baltimore) 1969
May;48(3):173–215.
Beekman R, van den Berg LH, Franssen H, Visser LH, van Asseldonk JT, Wokke JH.
Ultrasonography shows extensive nerve enlargements in multifocal motor
neuropathy. Neurology 2005;65(305):307.
Boehm J, Scheidl E, Bereczki D, Schelle T, Aranyi Z. High-resolution ultrasonography
of peripheral nerves: measurements on 14 nerve segments in 56 healthy
subjects and reliability assessments. Ultraschall Med 2014;35:459–67.
Cornblath DR, Mellits ED, Griffin JW, McKhann GM, Albers JW, Miller RG, et al.
Motor conduction studies in Guillain–Barré syndrome: description and
prognostic value. Ann Neurol 1988;23:354–9.
Derksen A, Ritter C, Athar P, Kieseier BC, Mancias P, Hartung HP, et al. Sural sparing
pattern discriminates Guillain–Barré syndrome from its mimics. Muscle Nerve
2014;50:780–4.
Draak TH, Vanhoutte EK, van Nes SI, Gorson KC, Van der Pol WL, Notermans NC,
et al. PeriNomS Study Group. Changing outcome in inflammatory neuropathies:
Rasch-comparative responsiveness. Neurology 2014;83:2124–32.
Flachenecker P, Wermuth P, Hartung HP, Reiners K. Quantitative assessment of
cardiovascular autonomic function in Guillain–Barre syndrome. Ann Neurol
1997;42:171–9.
Fokke C, van den Berg B, Drenthen J, Walgaard C, van Doorn PA, Jacobs BC. Diagnosis
of Guillain Barré syndrome and validation of Brighton criteria. Brain
2014;137:33–43.
Gallardo E, Sedano MJ, Orizaola P, Sánchez-Juan P, González-Suárez A, García A,
et al. Spinal nerve involvement in early Guillain–Barré syndrome: a clinico-
Please cite this article in press as: Grimm A et al. Ultrasound and electrophysiologic findings in patients with Guillain–Barré syndrome at disease onset and
over a period of six months. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.06.032
7
electrophysiological, ultrasonographic and pathological study. Clin
Neurophysiol 2014;126:810–9.
Gallardo E, Noto Y, Simon NG. Ultrasound in the diagnosis of peripheral
neuropathy: structure meets function in the neuromuscular clinic. J. Neurol.
Neurosurg. Psychiatry 2015. http://dx.doi.org/10.1136/jnnp-2014-309599. pii:
jnnp-2014-309599.
Goedee HS, Brekelmans GJ, Visser LH. Multifocal enlargement and increased
vascularization of peripheral nerves detected by sonography in CIDP: a pilot
study. Clin Neurophysiol 2014;125:154–9.
Grimm A, Heiling B, Schumacher U, Witte OW, Axer H. Ultrasound differentiation of
axonal and demyelinating neuropathies. Muscle Nerve 2014a;50:976–83.
Grimm A, Décard BF, Bischof A, Axer H. Ultrasound of the peripheral nerves in
systemic vasculitic neuropathies. J Neurol Sci 2014b;347:44–9.
Grimm A, Thomaser AL, Peters N, Fuhr P. Vagal hypertrophy in immune-mediated
neuropathy visualised with high-resolution ultrasound (HR-US). J. Neurol.
Neurosurg. Psychiatry 2014. http://dx.doi.org/10.1136/jnnp-2014-308271. pii:
jnnp-2014-308271.
Grimm A, Decard B, Axer H. Ultrasonography of the peripheral nerve system in the
early stage of Guillain–Barré syndrome. J Peripher Nerv Syst 2014d;19:234–41.
Hadden RD, Cornblath DR, Hughes RA, Zielasek J, Hartung HP, Toyka KV, et al.
Electrophysiological classification of Guillain–Barré syndrome: clinical
associations and outcome. Plasma Exchange/Sandoglobulin Guillain–Barré
syndrome trial group. Ann Neurol 1998;44:780–8.
Hobson-Webb LD, Cartwright MS. Nerve ultrasound in CIDP: poly-parameters for
polyneuropathies. Clin Neurophysiol 2014;125:3–4.
Hughes RA, Cornblath DR. Guillain–Barré syndrome. Lancet 2005;366:1653–66.
Hughes RA, Newsom-Davis JM, Perkin GD, Pierce JM. Controlled trial prednisolone
in acute polyneuropathy. Lancet 1978;2:750–3.
Kerasnoudis A, Pitarokoili K, Behrendt V, Gold R, Yoon MS. Correlation of nerve
ultrasound, electrophysiological, and clinical findings in post Guillain–Barré
syndrome. J Peripher Nerv Syst 2013;18:232–40.
Kerasnoudis A, Pitarokoili K, Behrendt V, Gold R, Yoon MS. Correlation of nerve
ultrasound, electrophysiological and clinical findings in chronic inflammatory
demyelinating polyneuropathy. J Neuroimaging 2014. http://dx.doi.org/
10.1111/jon.12079.
Kerasnoudis A, Pitarokoili K, Behrendt V, Gold R, Yoon MS. Nerve ultrasound score
in distinguishing chronic from acute inflammatory demyelinating
polyneuropathy. Clin Neurophysiol 2014b;125:635–41.
Kerasnoudis A, Pitarokoili K, Behrendt V, Gold R, Yoon MS. Increased cerebrospinal
fluid protein and motor conduction studies as prognostic markers of outcome
and nerve ultrasound changes in Guillain–Barré syndrome. J Neurol Sci
2014c;340:37–43.
Kerasnoudis A, Woitalla D, Gold R, Pitarokoili K, Yoon MS. Sarcoid neuropathy:
correlation of nerve ultrasound, electrophysiological and clinical findings. J
Neurol Sci 2014d;347:129–36.
Padua L, Martinoli C, Pazzaglia C, Lucchetta M, Granata G, Erra C, et al. Intra- and
internerve cross-sectional area variability: new ultrasound measures. Muscle
Nerve 2012;45:730–3.
Padua L, Granata G, Sabatelli M, Inghilleri M, Lucchetta M, Luigetti M, et al.
Heterogeneity of root and nerve ultrasound pattern in CIDP patients. Clin
Neurophysiol 2014;125:160–5.
Palumbo C, Massa R, Panico MB, Di Muzio A, Sinibaldi P, Bernardi G, et al. Peripheral
nerve extracellular matrix remodeling in Charcot–Marie–Tooth type I disease.
Acta Neuropathol 2002;104:287–96.
Preston D, Shapiro B. Electromyography and neuromuscular disorders, clinical-
electrophysiological correlations. New York: Elsevier Saunders; 2013. 664p.
Scheidl E, Böhm J, Simó M, Rózsa C, Bereznai B, Kovács T, et al. Ultrasonography of
MADSAM neuropathy: focal nerve enlargements at sites of existing and
resolved conduction blocks. Neuromuscul Disord 2012;22:627–31.
Scheidl E, Böhm J, Simó M, Bereznai B, Bereczki D, Arányi Z. Different patterns of
nerve enlargement in polyneuropathy subtypes as detected by
ultrasonography. Ultrasound Med Biol 2014;40:1138–45.
Schreiber S, Oldag A, Kornblum C, Kollewe K, Kropf S, Schoenfeld A, et al.
Sonography of the median nerve in CMT1A, CMT2A, CMTX, and HNPP. Muscle
Nerve 2013;47:385–95.
van den Berg B, Walgaard C, Drenthen J, Fokke C, Jacobs BC, van Doorn PA. Guillain–
Barré syndrome: pathogenesis, diagnosis, treatment and prognosis. Nat Rev
Neurol 2014;10:469–82.
Zaidman CM, Pestronk A. Nerve size in chronic inflammatory demyelinating
neuropathy varies with disease activity and therapy response over time: a
retrospective ultrasound study. Muscle Nerve 2014;50:733–8.
Zaidman CM, Al-Lozi M, Pestronk A. Peripheral nerve size in normals and patients
with polyneuropathy: an ultrasound study. Muscle Nerve 2009;40:960–6.
Zaidman CM, Harms MB, Pestronk A. Ultrasound of inherited vs. acquired
demyelinating polyneuropathies. J Neurol 2013;260:3115–21.