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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 ultrasonography and electrophysiology protocol. The study was


registered with the German clinical trial register
Diagnosis of Guillain–Barré syndrome (GBS) is based on typical (DRKS-ID00006140) and approved by the local ethics committee
history, clinical examination, and electrophysiological studies (No. 3663-01/13 and EKZN 2014-230). Informed consent was
(Asbury and Cornblath, 1990; Fokke et al., 2014; Hadden et al., obtained from all patients and controls.
1998; Hughes and Cornblath, 2005; van den Berg et al., 2014)
while serologic findings usually are available later and serve for 2.2. Ultrasonography
corroboration. Many variants of GBS exist, e.g. the Miller Fisher
syndrome with ataxia, areflexia, and oculomotor dysfunction Ultrasonography of different nerves was performed using a high
(Hughes and Cornblath, 2005). The most common types are the frequency 14 MHz probe real-time broadband linear array scanner
acute inflammatory demyelinating polyradiculoneuropathy (ZONARE Ultrasound systems, Uk Ltd. and Aplio 300 Ultrasound
(AIDP) and the acute motor axonal neuropathy (AMAN). System, Toshiba medical systems, Japan). Each nerve was scanned
Autonomic dysregulation (AD) is most dangerous in the early stage in axial plane, and the cross-sectional area (CSA) was measured at
of the disease. Reduced heart rate reactions to Valsalva and deep standardized anatomical points as described (Grimm et al.,
breathing as well as blood pressure measurements are suitable 2014a,b,d), in brief: vagus nerve in carotid sheath; median nerve
methods to diagnose AD. However, no clear prognostic markers in upper arm, elbow, forearm; ulnar nerve in upper arm and fore-
exist so far to predict AD. arm; tibial nerve in poplitea and ankle; peroneal nerve in popliteal
The value of nerve ultrasonography (NUS) in immune-mediated fossa, and sural nerve in the calf. In addition, the diameter of the
polyneuropathies is well described (Beekman et al., 2005; Gallardo ventral branch of the 5th and the 6th cervical spinal nerve was
et al., 2015; Grimm et al., 2014a,b,c; Hobson-Webb and Cartwright, measured in longitudinal scan, after leaving the intervertebral
2014; Kerasnoudis et al., 2013, 2014a,b; Padua et al., 2012, 2014; foramen and the processus transversus, when turning into the
Scheidl et al., 2012, 2014; Zaidman et al., 2009, 2013, 2014). straight course. All measurements were done on the right side
In post-GBS patients patchy and slight enlargements have been due to the symmetric clinical presentation. Analysis of data from
reported (Kerasnoudis et al., 2013; Zaidman et al., 2009, 2013), ultrasonography was performed both online and offline.
whereas in acute stage cervical spinal nerve enlargement and Approximately 40 min were needed for a complete ultrasonic
hypertrophy of the vagus are probably the most obvious findings examination.
(Gallardo et al., 2014; Grimm et al., 2014d). However, only little
is known about the course of nerve morphology from onset until 2.3. Nerve conduction studies
clinical recovery. Therefore, aim of this study is to describe the
time course of NUS changes in correlation to nerve conduction NCS were performed in the corresponding nerves using a stan-
studies (NCS) and clinical course. 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
2. Methods studies (NCS) were carried out on the right median, ulnar, tibial
and peroneal nerves. Distal motor latency (dmL), nerve conduction
2.1. Subjects velocity (CV) and compound muscle action potential (CMAP)
amplitude measurements were undertaken as well as measure-
Between August 2013 and December 2014, all consecutive ments of the mean F-M-latencies of 16 F-wave responses
patients suffering from acute AIDP or AM(S)AN, presenting at par- (F-wave latency–dmL). Similarly, sensory nerve action potential
ticipating hospitals were included in this study. Inclusion criterion (SNAP) amplitude and CV measurements were carried out on the
was the diagnosis of acute onset polyneuropathy fulfilling the pub- right median, the right ulnar and the sural nerves by averaging
lished diagnostic criteria for GBS (Asbury and Cornblath, 1990; of at least 10 responses.
Cornblath et al., 1988; Fokke et al., 2014; Hadden et al., 1998;
Hughes and Cornblath, 2005; van den Berg et al., 2014). 2.4. Statistics
Exclusion criterion was symptom onset >three days before screen-
ing. Patients were screened within the first two days of hospitaliza- For statistical analysis, we used IBM SPSS Statistics, version 19
tion. All patients were examined clinically by at least one board (Chicago, IL). Mann–Whitney-test was used for evaluating differ-
certified neurologist, by nerve ultrasonography, and NCS as ences concerning epidemiological data (age, gender, height and
described below in the first three days of symptom onset and after weight). Median values of NCS and CSA data were evaluated.
six months. Ultrasound and NCS routines were standardized over Mann–Whitney-test with Bonferroni correction was used to detect
all visits. NUS only was performed 10–14 days after immunoglob- differences of nerve CSAs and NCS between patients and controls
ulin therapy. Laboratory analysis including anti-ganglioside anti- and between patients at different time points. Pearson correlation
bodies and CSF analysis were performed in the acute phase. coefficients were calculated to quantify correlations between NCS,
Disability was classified using the Hughes-Score (Hughes and ultrasonographic findings, clinical course, and laboratory findings.
Cornblath, 2005; Hughes et al., 1978) ranging from 0 (normal) to Chi-square-test with Fisher’s exact test was used for comparing the
6 (death). In addition to reported or clinically evaluated symptoms frequency of pathological nerve or spinal nerve enlargement and
(sweating problems, orthostatic dysregulation, sexual dysfunction) F-waves in acute and post-GBS patients compared to controls.
AD was evaluated using 24-h heart rate monitoring and blood Receiver operating characteristic (ROC) curve analysis was used
pressure measurements five times daily for at least the first seven to define cut-off values for several ultrasound measurement points
days of acute hospitalization. In cases of autonomic symptoms the to differentiate acute GBS from controls. For all tests, a two-sided
monitoring was performed until amelioration of symptoms. After P-value <0.05 was considered to be statistically significant.
six months the AD was evaluated by a standardized questionnaire
including symptoms for sweating problems, orthostatic intoler- 3. Results
ance, cardiac arrhythmias, and sexual dysfunction. In addition, a
healthy control group consisting of medical staff and patients 27 patients with GBS and 31 controls were included in the
without neuromuscular disorders was examined using the same study. Baseline characteristics of the patients and the healthy

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 3

Table 1
Baseline characteristics of the study population.

GBS Control Mann–Whitney-test


N 27 (AIDP 25, AM(S)AN 2) 31
Mean age in years ± SD 57.1 ± 18.0 47.5 ± 17.9 P = 0.018
Men: women 16:11 16:15 P = 0.492
Height in cm 175.7 ± 9.4 174.8 ± 5.9 P = 0.790
Weight in kg 77.7 ± 19.6 68.0 ± 17.9 P = 0.187
Onset Pure sensory n = 18
Sensorimotor n = 6
Cranial nerve n = 3
Hughes-Score (HS) at onset and after six months (Hughes et al., 1978) 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)

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 peripheral nerves revealed lower potential to differentiate GBS
study were already described in a former study conducted in the from controls (e.g. tibial nerve, Fig. 2C) and the sural nerve was
acute phase of GBS (Grimm et al., 2014d). 25 patients fulfilled not suitable for diagnosing GBS (Fig. 2C). Fig. 3 gives an example
the electrophysiological criteria for a demyelinating polyneuropa- of the enlarged vagus nerve and the spinal nerve C6 compared to
thy (Hadden et al., 1998), two patients had signs of a severe axonal a healthy control.
neuropathy with typical clinical onset of a GBS, and elevated CSF Median values of the vagus differed significantly between those
protein and thus were diagnosed as AMAN, and acute motor and patients with and those without AD (Fig. 1, dark gray and black
sensory axonal neuropathy (AMSAN) respectively (Asbury and filled box plots, P < 0.001).
Cornblath, 1990; Fokke et al., 2014; Hadden et al., 1998; Hughes No correlation between CSA of several nerves and disability
and Cornblath, 2005; van den Berg et al., 2014). At onset, 16 Hughes-Score or different NCS data (CMAP, dmL or CV) were found.
patients were severely impaired from neuropathy according to a Additionally, no differences of CSA measurements were detected
Hughes-Score P3 (Hughes et al., 1978). Seven patients had AD between certain subtypes of GBS, e.g. patients with and without
according to monitoring results and reported symptoms, e.g. cranial nerve involvement, or with and without anti-ganglioside
orthostatic intolerance, missing heart rate response to exercise, antibodies. Pearson correlation was significant between the CSF
and sweating problems. All patients were treated with 0.4 g/kg protein level and the diameter of C6 (0.458, P = 0.028) and slightly
bodyweight immunoglobulins for 5 days. missed significance between the CSF protein and the diameter of
C5 (0.468, P = 0.068).

3.1. Onset period days 2–3 3.2. Days 10–14 after therapy

Table 2 shows motor NCS of the median and tibial nerve in the NCS were not done at this time point. Mean CSA values were
acute phase of the disease. Results of the NCS of the other nerves almost identical compared to onset examination (Fig. 4). Ten
are not shown in this table but were used for diagnosis of GBS patients worsened clinically (P1 point in the Hughes Score)
according to the literature (Asbury and Cornblath, 1990; between onset and this time point and showed an increase of nerve
Cornblath et al., 1988; Hadden et al., 1998; Hughes and CSAs, but no significant correlation between clinical worsening and
Cornblath, 2005). Overall the median values of the NCS of the med- increased nerve enlargement was found.
ian nerve are within the reported ranges in literature (Preston and
Shapiro, 2013), the nerve involvement differed interindividually 3.3. Six months later
(median nerve: CV reduced in 12 patients out of 27, CMAP reduced
10/27, dmL prolonged 13/27, temporal dispersion 4/27, F-wave Follow-up examination was performed in 21 patients. Two
pathology 19/27; tibial nerve: CV 14/27; CMAP amplitude 20/27; patients denied follow-up, three were not available anymore due
dmL 19/27, temporal dispersion 6/27, F-wave pathology 23/27). to migration, one patient died from suicide.
Ulnar and median nerve SNAPs were absent in 10 patients while All patients recovered well during the six months period. Clinical
sural nerve SNAP was absent in only three patients – reflecting disability, evaluated with the Hughes score improved significantly in
sural sparing (Derksen et al., 2014). We orientated on boundary all patients (Table 1, Mann–Whitney-test p < 0.001). Thirteen
values of literature and our laboratories (Preston and Shapiro, patients showed only subtle symptoms such as sensory deficits, gait
2013). disturbances, or discreet paresis in follow-up. Four patients com-
Median ultrasonic CSA measurements of the GBS patients were plained still about remarkable AD, such as sweating problems, sex-
enlarged compared to the controls in all nerves (Fig. 1, black and ual dysfunctions and ongoing orthostatic dysregulation.
light gray box plots; Mann–Whitney-test, P < 0.001⁄) except the Electrophysiological findings are given in Table 2; in summary they
sural nerve, which was only enlarged by trend in GBS. The spinal show improved motor conduction properties in arm (e.g. only 2 out
nerves and the vagus nerve were significantly enlarged compared of 21 patients with reduced CV in median nerve) and leg nerves (e.g.
to the controls (Fig. 1, Mann–Whitney-test with Bonferroni correc- 4 out of 21 with reduced CV in tibial nerve). However, median and
tion P < 0.0001⁄⁄). Based on ROC curve analysis boundary values for tibial CMAP amplitudes were still markedly reduced in some
the spinal nerves (2.9 mm and 3.8 mm) and the vagus (3.0 mm2) patients (4 out of 21 in median and 9 out of 21 in tibial nerve).
could be defined to reliably differentiate GBS from controls with The median follow-up ultrasonic measurements are shown in
high sensitivity and specificity (Fig. 2A and B). In contrast, CSA of Fig. 1. No significant differences of the CSA values of the peripheral

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
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 months as well as controls concerning the 5th and the 6th spinal
onset values (Mann–Whitney-test with Bonferroni correction, nerve (C5; v2 = 28.663, df 3, p < 0.001 and C6; v2=16.300, df 3,
P > 0.05, Fig. 1). With regard to the intraindividual course in the p = 0.001). Furthermore, Chi square test revealed a decrease of
peripheral nerves, no trend could be evaluated. In comparison to the number of pathologic F-waves of median and ulnar nerve (pro-
the control group the CSAs were still increased in median nerve longed latency or reduced persistency <50%) over the six months
and tibial nerves (Mann–Whitney-test with Bonferroni correction, period (v2 = 21.064, df2, p < 0.0001). Overall, 75% of patients
P < 0.001⁄). showed congruent results in F-waves and cervical spinal nerves
In contrast, vagus nerve CSA as well as the 5th/6th cervical (either both qualities with pathology or both qualities normal).
spinal nerve diameters significantly decreased over the six months In acute GBS this concordance was 73.9%, after six months it was
period (Fig. 4) and finally reached almost normal values again in 76.5%.
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- 4. Discussion
ing AD compared to those without (4 out of 7, P < 0.001⁄ Fig. 1 –
light gray and gray filled box plots). The current study shows, that ultrasonic enlargement of the
Chi square test revealed differences in the frequency of cervical peripheral nerves, the cervical spinal nerves as well as the vagus
spinal nerve enlargement between GBS at onset and GBS after six 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 CIDP and post-GBS patients (Kerasnoudis et al., 2013, 2014a).
diagnostic indicator of GBS. However, while spinal nerve enlarge- However, pathologic F-wave-responses decreased significantly
ment and vagus nerve hypertrophy regress consistently over six over six months. The concordance to ultrasonic spinal nerve
months, enlargement in many peripheral nerves persists even after enlargement – with similar amelioration – was 75%. Although,
six months – independently from clinical improvement. The vagus the ulnar and median F-waves do not have relation to the 5th
enlargement persists in patients with ongoing autonomic deficits. and the 6th cervical spinal nerves, the significant correlation
Enlargement of the cervical spinal nerves, peripheral as well as between pathology and normalization of both qualities is remark-
the vagus nerves has already been demonstrated by ultrasound in able as both represent the proximal accentuation of GBS onset and
acute and in chronic stage of GBS (Gallardo et al., 2014; Grimm recovery. The negative correlation of NCS and NUS in the periph-
et al., 2014d; Zaidman et al., 2009, 2013). Nevertheless, nerve eral nerves is interesting, as it contrasts the findings, reported in
enlargement in GBS is not as prominent as in chronic inflammatory hereditary neuropathies (Schreiber et al., 2013). NUS reveals mor-
demyelinating polyradiculoneuropathy (CIDP) (Kerasnoudis et al., phological aspects, such as the epineurium, fascicles, echogenicity,
2013, 2014a,b; Zaidman and Pestronk, 2014) with a variable distri- vascularization, whereas the electrophysiology represents the
bution. However, to the best of our knowledge, the present study is nerve functionality and excitability. Therefore, the combination
the first to report on long-term course of ultrasound changes in of both could have a synergistic effect in the diagnosis and obser-
GBS. vation of inflammatory neuropathies.
The origin of the focal nerve enlargement in acute GBS remains
4.1. Findings at baseline in cross-sectional comparison unclear, but it might be the ultrasonic correlation of focal inflam-
matory edematous demyelination with swelling of the nerve
In our study population, the median values of the NCS data were sheaths as reported in histopathology (Gallardo et al., 2014;
significantly changed compared to the controls. However, the val- Grimm et al., 2014d). Nerve echo intensity seems not to be altered
ues are still in the range of reported reference values (Preston and in contrast to descriptions in CIDP (Goedee et al., 2014; Padua
Shapiro, 2013), due to the interindividual involvement of nerves in et al., 2012). The persistent nerve hypertrophy in the peripheral
this early stage of GBS (Albertí et al., 2011). With regard on ultra- nerves might be a consequence of ongoing slight inflammation
sound, all sensorimotor nerves were significantly enlarged in the with edema and/or remyelination processes (Asbury et al., 1969).
first three days of symptom onset, although frequency and extent Nevertheless, nerve hypertrophy seems to persist even after longer
of morphological changes varied inter- and intraindividually. The time (Kerasnoudis et al., 2013, 2014a; Zaidman et al., 2009), and as
morphology of the purely sensory sural nerve was not significantly our study shows no correlation with clinical improvement over
altered, which could be the ultrasonic correlate of the electrophys- time, ultrasound of peripheral nerves with its intra- and interindi-
iological finding of ‘‘sural sparing’’ (Derksen et al., 2014). vidual heterogeneity is not suitable to evaluate therapeutic effects
Additionally, the cervical spinal nerves and/or the vagus nerve or serve as a prognostic marker. In contrast, the prominent
showed extensive enlargement in almost all GBS patients in the enlargement of vagus nerve and spinal nerves in the acute GBS
very early phase (Fig. 3). The amount of cervical spinal nerve and its normalization within six months might serve as prognostic
enlargement correlated significantly with the CSF protein level in marker for good recovery. The dichotomy of hypertrophy of the
the spinal nerve C6 and only slightly missed significance in the spinal nerves and the vagus nerve in the acute phase and its reduc-
spinal nerve C5. Similar correlations have been described previ- tion over time and persisting hypertrophy in peripheral nerves (as
ously (Grimm et al., 2014d; Kerasnoudis et al., 2014c). The vagus well as the regression of F-wave pathology in NCS) points to an
nerve enlargement was most pronounced in cases of AD and might outstanding role of the very proximal nerve segments in acute
therefore serve as early risk marker (Fig. 1). GBS (Albertí et al., 2011; Asbury et al., 1969). The apparent differ-
Based on ROC curve analysis boundary values could be defined ences of persisting hypertrophy between the spinal nerves/the
to differentiate GBS from controls with high sensitivity and speci- vagus and the peripheral nerve segments might be a consequence
ficity using ultrasonic measurements of the diameter of the spinal of hypertrophic remyelination in the peripheral nerve segments. A
nerves and the CSA of the vagus (Fig. 2A and B). In contrast, CSA of second way of nerve hypertrophy might be the (secondary) axonal
the peripheral nerves revealed not to be a suitable diagnostic crite- damage and Wallerian degeneration in peripheral nerve segments
rion (Fig. 2C). The age difference between patients and controls is a (persisting CMAP amplitude reduction in our study population).
limitation of the present study; however, we estimate this factor to Axonopathy might lead to fascicular, hypertrophy – a remodeling
be of minor influence (Boehm et al., 2014). cascade, which was already discussed in sarcoid neuropathy
(Kerasnoudis et al., 2014d) – and might be another way of nerve
4.2. Longitudinal observations hypertrophy next to remyelination (Palumbo et al., 2002), edema
and inflammation (Grimm et al., 2014b and d).
About two weeks after immunoglobulin therapy no significant The persistence of vagus hypertrophy in patients still complain-
changes in the ultrasound data were seen in comparison to the ing about autonomic deficits is remarkable and might be a conse-
baseline data. Six months later most patients had clinically recov- quence of ongoing inflammation or – as suggested in peripheral
ered well and showed only slight residual symptoms with regard nerves – Wallerian degeneration. Nevertheless, the number of
to disability (Hughes Score). Ultrasonic enlargement of the periph- patients with AD was small and autonomic symptoms were only
eral nerves did not change remarkably within six months in spite evaluated with clinical examination, heart rate, blood pressure
of good electrophysiological and clinical recovery. In contrast, cer- monitoring, as well as history and not by specific tests
vical spinal nerves and vagus nerve were almost back to normal (Flachenecker et al., 1997), and therefore, results have to be inter-
within six months (Fig. 4). Nevertheless, in the patients with ongo- preted cautiously. Standardized functional testing of parasympa-
ing AD the vagus was still significantly enlarged (Fig. 1). thetic and sympathetic nerve function should be used in a longer
Most peripheral nerves electrophysiologically recovered well follow-up and multicentre study. As limitation, we must consider
except for reduced CMAP amplitudes (9 out of 21 patients in tibial that only two patients suffering from axonal variant of GBS were
nerve), which depend more on axonal regeneration and accord- included in this study and therefore a reliable comparison of
ingly need more time to recover. No correlations could be ascer- AM(S)AN and AIDP patients was not possible. Another limitation
tained between ultrasound measurements and CV, CMAP, and was the short observation time as well as the long interval
dmL over six months. Similar findings were already described for between the screening visit and the follow-up visit; thus, we

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 7

cannot predict based on our findings, whether ultrasound amelio- electrophysiological, ultrasonographic and pathological study. Clin
Neurophysiol 2014;126:810–9.
ration in the spinal nerves and the vagus occurs prior to clinical
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Conflict of interest 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
The authors report no competing interests. and nerve ultrasound changes in Guillain–Barré syndrome. J Neurol Sci
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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