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1
Department of Neuroscience,
Imaging and Clinical Sciences,
University “G. d’Annunzio”,
Chieti-­Pescara, Italy
2
Institute of Neurology,
Department of Applied Clinical
Sciences and Biotechnology,
University of L’Aquila, L’Aquila,
Italy
3
Department of Neurology,
Graduate School of Medicine,
Chiba University, Chiba, Japan
Correspondence to
Professor Antonino Uncini,
Neuroscience and Imaging,
University “G. d’Annunzio”
Chieti-­Pescar, Chieti 66100,
Italy; ​uncini@​unich.i​ t
Received 9 October 2019
Revised 17 December 2019
Accepted 18 December 2019
© Author(s) (or their
employer(s)) 2020. No
commercial re-­use. See rights
and permissions. Published
by BMJ.
To cite: Uncini A, Notturno F,
Kuwabara S. J Neurol
Neurosurg Psychiatry Epub
ahead of print: [please
include Day Month Year].
doi:10.1136/jnnp-2019-
321890
Review
Hyper-­reflexia in Guillain-­Barré syndrome:
systematic review
Antonino Uncini  ‍ ‍,1 Francesca Notturno,2 Satoshi Kuwabara  ‍ ‍3
Abstract
Areflexia or hyporeflexia is a mandatory clinical criterion
for the diagnosis of Guillain-­Barré syndrome (GBS). A
systematic review of the literature from 1 January 1993
to 30 August 2019 revealed 44 sufficiently detailed
patients with GBS and hyper-­reflexia, along with one we
describe. 73.3% of patients were from Japan, 6.7% from
the USA, 6.7% from India, 4.4% from Italy, 4.4% from
Turkey, 2.2% from Switzerland and 2.2% from Slovenia,
suggesting a considerable geographical variation. Hyper-­
reflexia was more frequently associated with antecedent
diarrhoea (56%) than upper respiratory tract infection
(22.2%) and the electrodiagnosis of acute motor
axonal neuropathy (56%) than acute inflammatory
demyelinating polyneuropathy (4.4%). Antiganglioside
antibodies were positive in 89.7% of patients. Hyper-­
reflexia was generalised in 90.7% of patients and
associated with reflex spread in half; it was present from
the early progressive phase in 86.7% and disappeared in
a few weeks or persisted until 18 months. Ankle clonus
or Babinski signs were rarely reported (6.7%); spasticity
never developed. 53.3% of patients could walk unaided
at nadir, none needed mechanical ventilation or died.
92.9% of patients with limb weakness were able to walk
unaided within 6 months. Electrophysiological studies
showed high soleus maximal H-­reflex amplitude to
maximal compound muscle action potential amplitude
ratio, suggestive of spinal motoneuron hyperexcitability,
and increased central conduction time, suggestive of
corticospinal tract involvement, although a structural
damage was never demonstrated by MRI. Hyper-­reflexia
is not inconsistent with the GBS diagnosis and should
not delay treatment. All GBS variants and subtypes can
present with hyper-­reflexia, and this eventuality should
be mentioned in future diagnostic criteria for GBS.
Introduction
Progressive motor weakness of more than one limb
and universal areflexia or hyporeflexia are the clin-
ical diagnostic criteria of Guillain-­Barré syndrome
(GBS) proposed in 1978 and confirmed in 1981
and 1990.1–3 Even in the more recently proposed
case definitions of GBS and Miller-­Fisher syndrome
(MFS), all the three levels of diagnostic certainty
include decreased or absent deep tendon reflexes.4
In 1993, McKhan and collaborators outlined the
acute motor axonal neuropathy (AMAN) subtype
of GBS and remarked that some patients, areflexic
in the progressive phase of the disease, showed
during the early recovery a reappearance of deep
tendon reflexes (DTRs) while muscles were still
weak.5 Moreover, a mild degree of hyper-­reflexia
Uncini A, et al. J Neurol Neurosurg Psychiatry 2020;0:1–7. doi:10.1136/jnnp-2019-321890
Neuromuscular
was present in about half patients examined up to
1 year after the disease onset.5 Interestingly enough,
in the same year, because of the areflexia/hypore-
flexia criterion, three North American men who
presented, after a gastrointestinal illness, with pure
motor axonal neuropathy and normal or brisk DTRs
were thought not to be affected by GBS and were
not treated.6 Since then, patients with preserved or
even hyperactive reflexes, which could be otherwise
classified as GBS, have been repeatedly described,
but the topic of hyper-­reflexia in GBS remains quite
controversial. Indeed, these observations raised
Enseignement Superieur (ABES). Protected by copyright.
issues on diagnosis and classification and call into
question the areflexia/hyporeflexia requisite. The
aims of this paper were not only to describe an addi-
tional representative patient but also to systemati-
cally review, for the first time, the characteristics of
the reported patients with GBS with hyper-­reflexia
and to discuss the possible pathophysiology.
Case report
A 48-­year-­old Italian man presented with a 3-­day
history of acute, progressive lower limb weakness
and gait unsteadiness, following an upper respira-
tory tract infection (URTI). Neurological exam-
ination revealed proximal and distal weaknesses of
the lower limbs, with a Medical Research Council
(MRC) score of 4/5 in the quadriceps femoris, ilio-
psoas and tibialis anterior muscles bilaterally. The
patient had ataxic gait, impairment of deep sensa-
tion at the lower limbs and hyperactive DTRs at four
limbs with abnormal reflex spread (finger flexions
after tendon tapping of the biceps brachii and thigh
adduction after patella tendon tapping), and bilat-
eral unsustained ankle clonus but no Babinski sign
or increased muscle tone. Cerebrospinal fluid (CSF)
examination, performed on day 4, revealed normal
cell count and proteins. MRI of the brain, cervical
and thoracic spinal cord was normal. Nerve conduc-
tion studies performed on day 6 showed normal
distal motor latencies and motor conduction veloc-
ities with slightly reduced distal compound muscle
action potential (CMAP) amplitude of the right
peroneal nerve (table 1). Sensory conductions and
sensory nerve action potential amplitude (SNAP)
amplitudes were normal. The study of H-­ reflex
recorded in the prone position and relaxed state
from the soleus muscles after stimulation of the
tibial nerve at the popliteal fossa showed a high (0.8
bilaterally) H:M ratio, defined as maximal peak-­
to-­peak H-­ reflex amplitude to maximal CMAP
amplitude. Although the patient showed weakness
restricted to the lower limbs, generalised hyper-­
reflexia, normal CSF examination and practically
1
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Neuromuscular
also examined. Full-­text papers in English were independently
Table 1  Serial motor and sensory nerve conductions
analysed by two authors (AU and FN) and those reporting suffi-
Day 6 Day 14 Day 60 Control ciently detailed information, according to a predefined list of 20
Motor items (the headings of tables 1 and 2 of online supplementary file
 Tibial nerve (left) 1), were selected. Data were extracted from reports according
  
DML (ms) 5.3 8 6.3 <6 to a template from one author (FN), and a second author (AU)
  
CV (m/s) 49.7 40.6 44.2 >40 checked the accuracy of extracted data. Some missing informa-
  
dCMAP (mV) 8.0 8.1 13.0 >6 tion was acquired by directly contacting the authors. Duplicated
 Peroneal nerve (right) reports were identified by author names and patient character-
  
DML (ms) 5.3 5.1 4.7 <5.8 istics; the data of patients were eventually integrated and the
  
CV (m/s) 40.9 46.4 46.1 >40
duplicates were eliminated. This systematic review was made
following, when applicable, the Preferred Reporting Items for
  
dCMAP (mV) 2.9 2.7 6.0 >3
Systematic Reviews and Meta-­Analyses statement.9
 Peroneal nerve (left)
  
DML (ms) 5.6 5.5 5.7 <5.8
  
CV (m/s) 44.5 42.0 46.5 >40
Results
  
dCMAP (mV) 3.6 3.4 6.1 >3 A total of 22 papers reporting patients with GBS with hyper-­
Sensory reflexia were identified. Two reports describing 24 patients were
 Sural nerve (left) excluded because of coexisting disorders, such as transverse
  
SNAP (µV) 7.8 6.0 10.0 >4 myelitis, which could explain by themselves hyper-­reflexia. Four
  
CV (m/s) 40.0 41.0 42.0 >40 reports with 31 patients were discarded because of insufficient
 Median nerve (right) or low-­quality information. Finally, 17 papers (eight single case

Enseignement Superieur (ABES). Protected by copyright.

SNAP (µV)
   7.8 6.0 10.0
CV (m/s)
   40.0 41.0 42.0
CV, conduction velocity; dCMAP, distal compound muscle action potential
amplitude; DML, distal motor latency; SNAP, sensory nerve action potential
amplitude.
normal nerve conduction studies, a tentative diagnosis of GBS
was made and the patient was treated with intravenous immu-
noglobulins (IVIGs) (0.4 g/kg/day for 5 days). In the meanwhile,
serum IgG anti-­GM2 antibodies were found. A follow-­up study
performed on day 14 confirmed the slightly reduced peroneal
CMAP amplitude with additionally a 133% prolongation of the
left tibial nerve distal motor latency (table 1). These alterations
did not fulfil the demyelinating nor axonal diagnostic criteria
for GBS.7 The patient was discharged, and in the following
weeks, there was a progressive improvement. At 2 months, he
had fully recovered and DTRs were normal. A third electrodi-
agnostic study showed normal distal motor latencies and motor
conduction velocities. However, distal CMAP amplitude of the
peroneal and tibial nerves increased at 162%–201%, without
CMAP temporal dispersion, compared with the first examina-
tion (table 1). Sensory conduction velocities were normal and
the median SNAP amplitude increased at 146%. The patient
was finally diagnosed with a mild sensorimotor paraparetic form
of GBS not electrophysiologically classifiable at the first two
studies. However, the greater than 150% increase in the distal
CMAP amplitude of peroneal and tibial nerves without temporal
dispersion at the third study indicated a reversible conduction
failure in motor nerve fibres.7 8 The observation of this patient
stimulated a systematic review of hyper-­reflexia in GBS.
>12 reports) describing, after adjusting for duplication, a total of 44
>48 patients were in included the review, together with the case we
report. The demographic data and the clinical, laboratory and
imaging features of the 45 patients are detailed in online supple-
mentary tables 1 and 2 and are summarised in table 2. Because
of the characteristics of the reports, the low number of patients,
and the variability in the reported features and measures, we
describe the studies and summarise their results qualitatively and
quantitatively rather than by a meta-­analysis approach.
Frequency and geographical distribution of reported hyper-
reflexic GBS
In the first report, 48% of 25 Chinese patients with AMAN
followed up for 1 year showed a mild degree of hyper-­reflexia
with abnormal reflex spread; however, detailed information
on the individual subjects was missing.5 In Japan, 13% of 54
consecutive patients with GBS and 26% of patients with AMAN
developed hyper-­reflexia and reflex spread in the early recovery
phase.10 In a study of 213 patients with GBS from three hospi-
tals in Japan and Italy, 7% had exaggerated DTRs throughout
the disease course, and in the recently published results of the
International Guillain-­ Barré Syndrome Outcome Study on
regional variation, only 1.7% of 920 patients had hyper-­reflexia
at least of the lower limbs.11 12 The reports included in this
review are single cases or small series, and it is difficult to estab-
lish the overall frequency of hyper-­reflexia in GBS. Regarding
the geographical distribution, of 45 patients, 33 (73.3%) were
from Japan; 4 (8.9%) were from Europe; 3 (6.7%) were from
the USA; 3 (6.7%) were from India; and 2 (4.4%) were from
Turkey (table 2).

Methods
We performed a PubMed search to identify papers reporting
patients with GBS with hyper-­reflexia from 1 January 1993 (the
year of description of AMAN with hyper-­reflexia) to 30 July 2019
using the following terms: “Guillain-­Barré syndrome”, “Miller
Fisher syndrome”, “acute inflammatory demyelinating polyneu-
ropathy”, “acute motor axonal neuropathy”, “acute motor and
sensory axonal neuropathy” combined with “hyperreflexia”,
“brisk tendon reflexes”, “hyperactive tendon reflexes” and
“exaggerated tendon reflexes”. Reference lists of articles were
2 Uncini A, et al. J Neurol Neurosurg Psychiatry 2020;0:1–7. doi:10.1136/jnnp-2019-321890
Preceding infection
An infection preceding the disease was reported in 35/45 (77.8%)
patients. Diarrhoea or gastroenteritis was reported in 25 (56%)
patients and Campylobacter jejuni infection was demonstrated
in 14/14 patients by isolation from stool or serological evidence.
Sore throat or an URTI was described in 10 (22.2%) patients.
No infective antecedent was reported in 9 (20%) patients, and in
the remaining patient, GBS was preceded by a not better speci-
fied headache.
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Neuromuscular
Limb weakness and functional disability
Table 2  Demographic, geographical, clinical and laboratory features
Limb weakness was present in 36/45 (80%) patients and was
of 45 Guillain-­Barré patients with hyper-­reflexia
usually mild to moderate. Weakness generally involved all four
n (%) limbs being limited to upper or lower limbs in only three patients
Patients (n) 45 (8.3%). Strength was assessed according to the MRC scale in
Country 15/36 (41.7%) patients and was scored grade 2 or less in in some
 Japan 33/45 (73.3) muscles of six (16.7%) patients. Disability at nadir of the disease
 USA 3/45 (6.7) was assessed or inferred from clinical data by Hughes’ scale in
 India 3/45 (6.7) 30/45 (66.7%) patients.13 Four patients (13.3%) had grade 1; 12
 Italy 2/45 (4.4) (40%) had grade 2; 11 (36.7%) had grade 3; and only 3 (10%)
 Turkey 2/45 (4.4) were confined to the bed or chair bound (grade 4). None of
 Switzerland 1/45 (2.2) patients required assisted ventilation or died (grades 5 and 6).
 Slovenia 1/45 (2.2)
Age (years), median (range) 34 (12–70) Cranial nerve palsy
Gender, male:female 28 (62.2):17(37.8) Cranial nerves were involved in 17/45 (37.8%) patients. Eight
Preceding infection (17.8%) presented with external ophthalmoplegia (seven
 Diarrhoea or gastroenteritis 25/45 (56.0) without limb muscle weakness); one had minimal ophthalmo-
 URTI 10/45 (22.2) paresis, bilateral facial palsy and neck muscles weakness. Other
 None 9/45 (20.0) cranial nerves were involved in 10/45 (22.2%) patients, in 7
Neurological findings patients (15.6%), the VII nerve was affected (in four bilaterally).
 External ophthamoplegia 8/45 (17.8) Two patients (4.4%) showed bulbar weakness and two (4.4%)
developed bilateral papillitis.

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 Facial palsy 7/45 (15.6)
 Bulbar palsy 2/45 (4.4)
 Papillitis 2/45 (4.4) Sensory involvement and ataxia
 Limb weakness 36/45 (80.0) Twelve out of 45 (26.7%) patients showed some sensory involve-
 Weakness limited to ULs or LLs 3/36 (8.3) ment and 8 (17.8%) had ataxia.
 Sensory disturbance 12/45 (26.7)
 Ataxia 8/45 (17.8) Characteristics of hyper-reflexia and associated signs
Hughes’ disability score at nadir Reflexes were variously described as brisk, hyperactive and
 Not reported or not deducible 15/45 (33.3) exaggerated but not formally graded.14 Hyper-­reflexia in patient
 Grade 1 4/30 (13.3) 16 (summarised in online supplementary tables 1 and 2) is
 Grade 2 12/30 (40.0) shown in the online supplementary video file. The extension
 Grade 3 11/30 (36.7) of hyper-­reflexia was not specified in 2/45 patients. In 39/43
 Grade 4 3/30 (10.0) (90.7%) patients, hyper-­reflexia was generalised at four limbs
Electrodiagnosis except in 1 patient in whom ankle jerks were absent. Hyper-­
 AMAN 25/45 (56.0) reflexia was restricted to the biceps and knee jerks bilaterally in
 AMSAN 2/45 (4.4) one (2.3%) patient and was limited to the lower limbs in three
 AIDP 2/45 (4.4) (6.9%) patients. Regarding the time course, hyper-­reflexia was
 Unclassifiable 6/45 (13.3) reported to be already present in the acute progressive phase in
 Normal 10/45 (22.2) 39/45 (86.7%) patients and was reported in the early recovery
 CSF phase (weeks 3–4) in 43/43 (100%) patients. The follow-­up was
 Not done or not individually specified 20/45 (44.4) not described in 26/45 (57.8%) patients. Hyper-­ reflexia was
 Increased protein 18/25 (72.0) reported to disappear in 5/19 (26.3%) patients from 6 weeks to
 Pleocytosis 0/25 (0.0) 12 months after onset and to persist, although often reduced, in
Antiganglioside antibodies 14 (73.7%) patients from 6 weeks to 18 months. Reflex spread
 Not done 6/45 (13.3) (or irradiation) was not mentioned in 25/45 (55.5%) patients;
 Positive for at least one antibody 35/39 (89.7) when reported, it was present in 11/20 (55%) patients. The
MRI search for ankle clonus was mentioned in 20/45 (44.4%) patients
 Not done 26/45 (57.8) and it was found in only 1 patient (5%). A bilateral Babinski sign
 Negative 19/19 (100) was described in 2/45 (4.4%) patients and an unilateral tendency
Treatment to big toe extension in another one. The search of the Hoffman’s
 Not reported or not done 11/45 (24.4) sign was mentioned in 12/45 (26.7%) patients and was reported
 IVIG or PE 30/34 (88.2) to be positive in 75%.
 IVIG and IVMP 3/34 (8.8)
 IVMP 1/34 (2.9) Electrophysiology
Outcome in patients with limb weakness Twenty-­ seven out of 45 (60 %) patients showed an axonal
 Not reported 8/36 (22.2) pattern that in 25 patients was restricted to motor fibres (the
 Able to walk unaided at 3 months 16/28 (57.1) AMAN pattern) and in 2 involved motor and sensory fibres (the
 Able to walk unaided at 6 months 26/28 (92.9) acute motor and sensory axonal neuropathypattern).15 16 In five
AIDP, acute inflammatory demyelinating polyneuropathy; AMAN, acute motor axonal patients, all with antiganglioside antibodies, reversible conduc-
neuropathy; AMSAN, acute motor and sensory axonal neuropathy; CSF, cerebrospinal fluid; tion failure was demonstrated at follow-­up studies. Reversible
IVIG, intravenous immunoglobulin; IVMP, intravenous methylprednisolone; PE, plasma
conduction failure is characterised by an abnormal CMAP
exchange; URTI, upper respiratory tract infection.
amplitude reduction and conduction slowing that promptly
Uncini A, et al. J Neurol Neurosurg Psychiatry 2020;0:1–7. doi:10.1136/jnnp-2019-321890 3

Neuromuscular
Figure 1  Left: patient 16 (online supplementary tables 1 and 2), soleus
H-­reflexes recorded on days 8 and 350 from disease onset. On day 8
(A), the H:M ratio. On day 350 (B), the patient was still hyper-­reflexic.
CMAP and H-­reflex amplitudes were higher and the H:M ratio was still
0.69. Lower traces: superimposed responses. Right: patient 7 (online
supplementary tables 1 and 2), H-­reflexes recorded in the abductor pollicis
brevis muscle on day 55 from onset. Lower traces: superimposed responses.
Reproduced from Kuwabara et al.10 20 CMAP; H:M, maximal H-­reflex
amplitude to maximal compound muscle action potential amplitude.
recover at serial studies without the development of excessive
temporal dispersion.7 8 Reversible conduction failure is thought
to be caused by antiganglioside antibodies and complement-­
mediated attack at the node of Ranvier, inducing a transient
dysfunction of excitability not progressing to axonal degenera-
tion.17 Only two patients (4.4%) were reported to have demy-
elinating features.10 18 Six patients (13.3%) had abnormal nerve
conductions but were unclassifiable, not fulfilling the commonly
employed electrodiagnostic criteria.7 In one of these unclassi-
fiable patients, serial recordings showed reversible conduction
failure, although CMAP amplitudes were in the normal range
in the initial study. In 10 (22.2%) patients, limb nerve conduc-
tions were normal; 7 patients had ophthalmoplegia but not limb
weakness; 3 patients had bilateral facial weakness associated in 2
patients with neck weakness.
An H-­reflex study was performed in nine patients with GBS
with hyper-­ reflexia: seven AMAN, one acute inflammatory
demyelinating polyneuropathy (AIDP) and in the case we report.
There is a considerably interindividual variability in absolute H
reflex amplitude and H:M ratio. However, in seven patients
with hyper-­reflexic GBS, the mean soleus H:M ratio was higher
than normal controls, and it was greater than 0.7 in another
patient and in the one we report (figure 1).10 19 20 Moreover,
H-­reflex was tested in muscles, from which cannot be normally
demonstrated in seven patients and recorded in the abductor
pollicis brevis in four patients and in the abductor hallucis in
three patients (figure 1).10
Oshima and coworkers showed in 13 patients (six with
AMAN and seven with acute ataxia and ophthalmoplegia) a
prolongation of the central conduction time to distal upper limb
muscles obtained by subtracting (F+M–1)/2 from the latency
of the motor evoked potential by transcranial magnetic stimu-
lation.21 22 Central conduction time improved 2–3 weeks after
treatment.
CSF examination
CSF examination was not done or not reported in 10/45 (22.2%)
patients. In 10 other (22.2%) patients, the CSF protein concen-
tration was reported as mean values, and it was not possible to
4 Uncini A, et al. J Neurol Neurosurg Psychiatry 2020;0:1–7. doi:10.1136/jnnp-2019-321890
J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2019-321890 on 14 January 2020. Downloaded from http://jnnp.bmj.com/ on January 15, 2020 at Agence Bibliographique de l
assess in how many subjects it was effectively increased. In the
remaining 25 patients, proteins were augmented in 18 patients
(72%) and normal in 7 patients (3 in the first week of disease).
None of 35 patients showed pleocytosis (≥50 leucocytes).4
Antiganglioside antibodies
Antibodies to gangliosides were not searched in 6/45 (13.3%)
patients. Although not all antibodies were systematically looked
for in the different reports, at least one antiganglioside antibody
was found in 35/39 (89.7%) patients. Antibodies to GM1 were
present in 18/35 (51.4%), antibodies to GD1a and GalNAc-­
GD1a in 12/35 (34.3%), antibodies to GQ1b in 6 (17.1%)
patients (all with ophthalmoplegia) and antibodies to GT1a
in 3/45 (6.7%) (one patient could be classified as pharingeal–
cervical–brachial subtype and one as bilateral facial weakness
and paresthesias subtype).
MRI
MRI was performed in 19/45 (42.2%) patients. Brain MRI in 2
patients, spine MRI in 2 patients, and brain and spine MRI in 15
patients were all negative.
Enseignement Superieur (ABES). Protected by copyright.
Cinical classification
The GBS framework has become increasingly complex in the
past 35 years, and different clinical variants and subtypes have
been described.23 The 45 patients, leaving aside hyper-­reflexia,
could be classified according to a recently proposed clinical diag-
nostic classification as follows: 34 (75.5%) as classical GBS, 2
(4.4 %) as acute facial diplegia with paresthesias and 1 (2.2%)
as pharyngeal–cervical–brachial subtype; 1 (2.2%) could fit
into the paraparetic form; and 7 (15.5%) could be diagnosed
as MFS.22–26
Treatment and outcome
In 5/45 (11.1%) patients, treatment was not reported.20 25 Six
patients (13.3%) were not treated: two because hyper-­reflexia
was thought to preclude the GBS diagnosis and four because the
patients were able to walk unaided.6 10
Thirty out of the remaining 34 patients (88.2%) were treated
with IVIG or plasma exchange; 3 (8.8%) received combined
courses of IVIG and intravenous methylprednisolone; 1 (2.9%)
was treated only with intravenous methylprednisolone. A
follow-­up or outcome was reported, although in different ways,
in 39 out of 45 (86.7%) patients. Significant improvement was
reported in 12/20 patients (60%) in a time interval from 2 weeks
to 3 months from onset; complete recovery was reported in
26/28 patients (92.8 %) within an interval from 6 weeks to 8
months. Six adjunctive patients were reported to be able to walk
at 6 months, whereas one patient showed only a slight improve-
ment at 9 months after onset.11 27 Overall, in patients presenting
with limb weakness, follow-­up was available in 28/36 (77.8%)
patients: 16/28 (57.1%) patients were able to walk unaided at
3 months and further 10 (35.7%) at 6 months.
Discussion
Features of patients with hyper-reflexic GBS
By reviewing the literature, it is evident that hyper-­reflexia in
GBS is not so frequent worldwide as early reported in China
and Japan.5,10 Most of the cases analysed in this review are
from Japan, suggesting a considerable geographical variation.
The high frequency in Far East countries may be related to the
greater incidence of the AMAN subtype. Overall, in the rest of
the world, GBS with hyper-­reflexia seems to be quite rare.

A preceding infection was reported in more than three-­
quarters of patients and diarrhoea in more than half. Of patients
with GBS with hyper-­reflexia, 56% had AMAN and 76% carried
anti-­GM1-­GD1a or -GalNAc-­GD1a antibodies that are usually
associated with this subtype.11 The clinical manifestations seem
similar to those of the other patients with AMAN without
hyper-­reflexia, namely, less frequent cranial and less sensory
nerve involvement compared with AIDP.10 11 Only two patients
were classified, on the basis of electrophysiological findings, as
AIDP. It has been reported that patients with antiganglioside
antibodies, finally diagnosed as AMAN with reversible conduc-
tion failure after serial studies, showed in the early disease stage
conduction block and conduction slowing, and could be there-
fore fallaciously classified as AIDP.11 28 It is also possible that in
some patients, the damage caused by antiganglioside antibodies
at the nodal region involves extensively the paranodes inducing
electrophysiological alterations, fulfilling even the more strin-
gent demyelinating criteria configuring a grey diagnostic zone
between axonal GBS with reversible conduction failure (RCF)
and AIDP.7 The seven patients classified as acute ataxia and
ophthalmoplegia (five with anti-­ GQ1b antibodies) could be
considered MFS with hyper-­reflexia instead of areflexia. The
presence of hyper-­ reflexia without hypersomnolence is not
sufficient, in our opinion, to classify these patients as Bickerstaff
brainstem encephalitis, which is currently thought to belong to
the MFS spectrum.23 At last, hyper-­reflexia has been described in
all GBS subtypes, including facial diplegia with paresthesias, the
pharyngeal–cervical-­brachial and the paraparetic form.
Hyper-­reflexia was initially reported to be present in the early
recovery phase.5 10 This review shows that hyper-­reflexia can be
already present, in the majority of patients, in the acute progres-
sive phase making even more problematic the diagnosis. Hyper-­
reflexia can disappear but persists, although often decreased,
in the majority of patients even after the complete recovery of
muscle strength and normalisation of CMAP amplitudes.20
Regarding disability, 53.3% of hyper-­reflexic patients could
walk independently at nadir; none of the patients needed
mechanical ventilation or died. These findings are similar to
those reported in 23 patients with GBS with preserved or exag-
gerated reflexes showing significantly less disability than 190
patients with GBS and reduced or absent DTRs.11
Outcome is also favourable; about 93% of hyper-­ reflexic
patients with limb weakness were able to walk unaided within
6 months and almost all reported patients completely recovered
within 8 months.
Differential diagnosis with acute transverse myelitis and with
rare patients with coexisting GBS and transverse myelitis may be
difficult above all in patients presenting with hyper-­reflexia in
the early progressive phase.29 A sensory level and early urinary
retention suggest a myelopathy; abnormal nerve conductions are
helpful in the diagnosis of GBS, while MRI is essential to demon-
strate an acute myelopathy. A higher suspicion index is necessary
in patients with hyper-­reflexia, ophthalmoplegia and ataxia that
may have normal limb nerve conductions.
Finally, some nosological considerations should be taken into
account. Given the areflexia/hyporeflexia criterion, should we
rule out that the reviewed patients have GBS? All the authors,
except Jackson and coworkers,6 agree that these patients do have
GBS. Some authors propose that patients with hyper-­reflexia
should be considered as a separate GBS variant.18 21 30 Anyway,
as all GBS subtypes and MFS can present with hyper-­reflexia,
we think that neurologists should be aware that some patients
with GBS and MFS can present with hyper-­reflexia, and this
possibility should be mentioned in the upcoming EFNS/PNS
Uncini A, et al. J Neurol Neurosurg Psychiatry 2020;0:1–7. doi:10.1136/jnnp-2019-321890
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Neuromuscular
(European Federation of Neurological Societies and Peripheral
Nerve Society) diagnostic criteria.
Pathophysiology of hyper-reflexia
DTRs rely on relatively synchronised volleys of impulses and
are more dependent on normal sensory than motor nerve fibres.
Therefore, a motor axonal disorder as AMAN, not involving the
sensory afferent arc of the stretch reflex, is expected, if affecting
only a fraction of axons, to preserve tendon jerks more than a
demyelinating disorder, as AIDP, desynchronising both sensory
and motor volleys. Mild to moderate weakness can also explain
the preservation or early reappearance of DTRs. Dutch patients
with pure motor GBS maintained tendon reflexes down to an
MRC scale score of 3/5.31 Moreover, reflex activity is known to
be more powerful, in some instances, than the voluntary drive
so to break through a peripheral paresis. Impaired upward gaze
with preservation of Bell’s phenomenon has been described in
oculomotor nerve palsy; in myasthenia gravis, impaired volun-
tary eye adduction with the preservation of reflex convergence
is not uncommon, and it has long been known that DTRs are
normal or even brisk in spite of weakness.32 33
Enseignement Superieur (ABES). Protected by copyright.
The above-­mentioned observations could account for the pres-
ervation or earlier reappearance of tendon reflexes in GBS, but
hyper-­reflexia cannot be simply imputable to mild weakness as
DTRs were brisk in three patients with AMAN in whom muscle
strength was graded 0–2 in the distal lower limb muscles.27 30
Hyper-­reflexia and reflex spread are considered signs of upper
motoneuron or corticospinal tract lesion.34 35 Only a few studies
attempted to elucidate the pathophysiology of hyper-­ reflexia
in GBS. A high soleus H:M ratio that correlates with hyper-­
reflexia and the recording of H reflex in muscles where it is not
normally elicitable (ie, considered a pathological sign) have been
reported.10 20 36 These findings indicate a lower motoneuron
hyperexcitability and have been interpreted as a possible conse-
quence of the dysfunction of spinal inhibitory interneurons.10
Oshima and coworkers showed in six patients with hyper-­
reflexia and AMAN and in seven patients with hyper-­reflexia,
ophthalmoplegia and ataxia a prolongation of central conduc-
tion time.21 22 These findings, although a structural damage was
never demonstrated by MRI, suggested a functional involvement
of the corticospinal tract. An involvement of corticospinal tracts
can also increase the excitability of motoneurons by reducing
presynaptic inhibition at Ia fibre–α motoneuron synapsis and by
increased axonal sprouting of the terminal Ia fibres.37
Hyper-­ reflexia is occasionally seen also in chronic motor
neuropathy associated with conduction block and high-­titre anti-­
GM1 antibody.38 39 Sera from patients with motor neuropathy
and anti-­GM1 antibody immunostained the bovine spinal grey
matter and isolated spinal motoneurons, and anti-­GM1 serum
injected in the subarachnoid space caused damage of nerve roots
and spinal cord.40 41 It is conceivable that, in some patients with
GBS, the spinal root inflammation may disrupt the blood–central
nervous system barrier and allow antiganglioside antibodies to
access neural structures and networks in the anterior horns, as
the corticospinal terminals and the intramedullary collateral
branches to the inhibitory interneurons, increasing lower moto-
neuron excitability and finally inducing hyper-­reflexia. Although
the Babinski sign, as part of a disinhibited flexion reflex circuitry,
has also been rarely reported, increased muscle tone never devel-
ops,differentiating hyper-­reflexia in GBS from the consequence
of classical upper motor neuron or corticospinal tract lesion.
Finally, it is well known that DTRs are influenced by volition
(reinforcement manoeuvres) and brisk reflexes, even with some
5

Neuromuscular
spread to other synergistic muscles and a few beats of clonus,
can be seen in anxious subjects and hyperthyroidism.42 Thus, it
cannot be completely excluded that in a few patients, the combi-
nation of situational anxiety, because of the disease, and mild
weakness might account for hyper-­reflexia. However, this does
not explain the persistence of increased DTRs in some patients
until 18 months after the disease onset.
In future studies, the application of appropriate specific
neurophysiological tests studying the spinal circuits may help to
dissect and understand the fine mechanisms at the basis of hyper-­
reflexia in patients with GBS.43
Limitations
Limitations of this review are the restriction to English language
publications and the non-­uniformity, in the considered studies,
of the reported findings and measurements that made it possible
to evaluate some features only in subgroups of patients.
Conclusions
►► Some patients, with otherwise typical GBS variants and
subtypes, present with hyper-­reflexia.
►► Hyper-­
reflexia is mostly associated with antecedent diar-
rhoea, the AMAN subtype and antiganglioside antibodies, but
all GBS subtypes and MFS may present with hyper-­reflexia.
►► Hyper-­reflexia is typically generalised, usually present from
the early progressive phase, it may disappear in a few weeks
or may persist.
►► Hyper-­ reflexia is associated with less peak disability and
favourable outcome.
►► Infective antecedent and detection of antiganglioside anti-
bodies help to suggest the GBS diagnosis.
►► Abnormal nerve conductions are usually helpful in the diag-
nosis of GBS, while MRI is essential to exclude an acute
myelopathy.
►► A higher suspicion index is necessary in patients with hyper-­
reflexia, ophthalmoplegia and ataxia that may have normal
limb nerve conductions.
►► Hyper-­ reflexia can be the expression of antiganglioside
antibody-­mediated damage of the neural networks and corti-
cospinal tract terminals in the spinal anterior horns.
►► The presence of hyper-­ reflexia in an appropriate clin-
ical setting suggestive of GBS should not induce delay in
treatment.
►► Hyper-­reflexia should not be considered inconsistent with
the diagnosis of GBS, and the possibility that some patients
with GBS present with hyper-­reflexia should be mentioned
in the upcoming EFNS/PNS diagnostic criteria.
Contributors  AU conceived the review, searched the literature and wrote the
first draft. FN followed up the reported patient and searched the literature. SK
contributed with the electrophysiological figure and the video. All authors critically
revised all the versions of the manuscript.
Funding  The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-­for-­profit sectors.
Competing interests  None declared.
Patient consent for publication  Obtained.
Provenance and peer review  Commissioned; externally peer reviewed.
ORCID iDs
Antonino Uncini http://​orcid.​org/0​ 000-​0002-​8131-​8912
Satoshi Kuwabara http://​orcid.​org/0​ 000-​0002-​4716-​8578
6 Uncini A, et al. J Neurol Neurosurg Psychiatry 2020;0:1–7. doi:10.1136/jnnp-2019-321890
J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2019-321890 on 14 January 2020. Downloaded from http://jnnp.bmj.com/ on January 15, 2020 at Agence Bibliographique de l
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