Abstract
We reported an association between SARS-CoV-2 infection and
Guillain-Barre´ syndrome (GBS). From 37 patients with GBS, Previous
SARS-CoV-2 infection clues, including fever, cough, and diarrhea were
recorded in 18 patients. Among them, SARS-CoV-2 IgG was detected in 7
patients, considered confirmed cases. SARS-CoV-2 PCR was positive in
just 1 patient. Consistent with previous studies, we found no increase
in patient recruitment during the pandemic compared to previous years,
however, our study indicated that SARS-CoV-2 is associated with poorer
outcomes. Studies with more sample size are required to determine if
there is a causative association or not.
Keywords: Guillain-Barre´ syndrome, SARS-CoV-2, Pediatric
Introduction
As previous reports of neurologic manifestations of coronaviruses, it
was expected that we would find these neurological disorders in the
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including
headache, seizures, cerebrovascular disorders and Guillain-Barre
Syndrome (GBS).(1)(2)
GBS is an immune-mediated peripheral neuropathy, typically characterized
by rapidly progressive bilateral and often symmetrical loss of sensory
and motor functions of the limbs. It might also involve respiratory or
cranial nerve-innervated muscles. (3) GBS is usually preceded by an
infection that often has been caused by Campylobacterjejuni or other bacterial or viral agents. (4) GBS has been
associated with respiratory viral pathogens such as human
coronaviruses(5); therefore, an outbreak of some viral infections may
lead to increased admission of GBS patients.
Based on clinical and electrophysiologic studies, GBS is divided into
several subtypes, including acute inflammatory demyelinating
polyradiculoneuropathy (AIDP), two axonal forms of GBS including acute
motor-sensory axonal neuropathy (AMSAN) and acute motor axonal
neuropathy (AMAN) and Miller Fisher syndrome (MFS).(6) Preceding
infections may result in special clinical and electrophysiological
subtypes of GBS.(7)
Recently, after the pandemic, there are some neurologic complications in
children, associated with the severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2). Of forty-nine adult patients with GBS, eight
(16%) had a confirmed and three (6%) a probable SARS-CoV-2 infection.
(7) A 6-year-old male ad been reported with a rapid progression axonal
GBS and positive SARS-CoV-2 infection. (8) SARS-CoV-2-GBS outcome is
worse compared to other GBS patients, and the prevalence/incidence of
GBS most likely increased since the outbreak of the pandemic. (9)
During the SARS-CoV-2 pandemic, we assumed that the incidence of GBS had
increased, and the subtypes may change, therefore, we set up a
prospective study for neurological manifestations of SARS-CoV-2
infections in the Children’s Medical Center (CMC), Tehran, which is one
of the largest referral pediatric centers in Iran. We report the
clinical finding, electrophysiological subtype, and disease course of
all GBS patients during the 17 months period of study.
Materials and methods
This prospective study was performed in Children Medical Center, Tehran,
Iran, from March 2020 to August 2021. All patients’ parents had assigned
the consent form. This study was approved by the Ethics Committee of
Tehran University of Medical Sciences, (Ethic code: IR.TUMS.VCR.REC.
1399.326)
All admitted children that fulfill the diagnostic criteria for GBS
(National Institute of Neurological Disorders and Stroke) enrolled
during the study period.(8) Exclusion criteria for this study were as
follows: other neurological diseases, which could affect brain function,
sequelae neurologic deficits that could affect the evaluation of GBS
severity.
Demographic data, associated symptoms, GBS severity according to
disability scores (1) on admission and discharge time, clinical and
electrophysiologic features, SARS-CoV-2 status, and other important data
were recorded in a structured questionnaire. All patients with GBS
underwent standard treatment by IVIG as indicated. Data analyzed with
suitable statistical methods.
Clinical suspicion of SARS-CoV-2 infection, laboratory, radiological,
and serological evidence recorded for all patients.
Reverse-transcription polymerase chain reaction (RT-PCR) of
nasopharyngeal swab specimen and serum antibodies (IgM and IgG) were
requested for all patients. Patients with positive SARS-CoV-2 PCR or
antibodies defined as confirmed SARS-CoV-2 cases and those with clinical
symptoms including fever, diarrhea, and upper respiratory complaints or
imaging finding in favor of SARS-CoV-2 or contact with confirmed
SARS-CoV-2 cases before neurologic signs considered as probable
SARS-CoV-2 cases.(9)
Results
Of 37 patients with GBS, 28 were male and 9 were female. The mean age
was 8.19±3.49 years, ranging from 2.5 to 15 years. The frequency of
previous SARS-CoV-2 infection clues, including fever, cough, and
diarrhea was 48%. SARS-CoV-2 PCR or antibodies was detected in 7
patients (19%), considered as confirmed cases. Among them, SARS-CoV-2
PCR was positive in just 1 patient. The overall frequency of confirmed
plus probable SARS-CoV-2 in GBS patients was 60 % (N=22). The median
time from the onset of infection to neurological symptoms was 11.25±8.44
days (ranging from 2 to 30 days). Demographic data and clinical findings
according to SARS-Cov-2 infection status are noted in table1.
All patients underwent electrophysiological examination and acute axonal
type motor polyneuropathy was the most prevalent type in both SARS-CoV-2
positive and negative patients. The second frequent type was acute
segmental demyelinating motor polyradiculoneuropathy. The disability
scale in most of the patients on admission and on discharge was 3 in
43.2% and 54.1%, respectively.
AMAN was the most frequent subtype of GBS in all our patients (65%),
apart from SARS-CoV-2 infection status. The second frequent subtype was
AIDP (32%) and the AMSAN subtype was detected in just one SARS-CoV-2
infection-negative patient. These findings were not significantly
different between SARS-CoV-2 infection positive and negative cases.
GBS disability scale 4 ≤ of 6 and at presentation, in confirmed patients
with SARS-CoV-2 infection was 57%, in comparison to 20% in SARS-CoV-2
infection negative patients, with was statistically significant. GBS
disability scale (DS) on admission was 5 out of 6. One patient was an
obese 8-year-old boy with a history of fever 14 days before weakness
onset SARS-CoV-2 IgG was positive. During 24 hours of lower limb
weakness, the ascending process involved the respiratory system and he
was intubated for about 2 weeks and then underwent tracheostomy for 2
months later. Another patient was a 15-year-old girl with a history of
lupus erythematous and URI symptoms around 3 weeks before weakness,
however, SARS-CoV-2 antibodies or PCR was negative. She had ascending
weakness and diplopia, after one week of the disease, she underwent
intubation for 3 weeks and then tracheostomy for 1.5 months later. Both
patients had refractory hypertension and tachycardia. Treatment was
challenging and they received IVIG. After 4 weeks of treatment, they
received high dose of methylprednisolone, due to poor response to IVIG.
Electrophysiology study was in favor of acute motor axonal neuropathy in
both of them. They had the longest hospital admission time which was
around 90 and 60 days, respectively.
The mean of hospital admission time, among confirmed SARS-CoV-2
infection patients, was 19.7 days, and among confirmed plus probable
SARS-CoV-2 infection was 11.8 days. These amounts are significantly
higher than 5.5 days in SARS-CoV-2 infection-negative patients
(p-value<0.05). Hospital stay was longer in around 8-year-old
patients, with a mean of 20 days. Acute axonal type motor polyneuropathy
was associated with the longest admission time (mean 11.78±20.32 days,
ranging from 4 to 89 days). This variable was longer in SARS-CoV-2
positive in comparison to those with negative SARS-CoV-2.
Discussion
In a study of 81 patients, most patients were diagnosed with AIDP. Three
of the patients died at the end of the first month. Three patients had
recurrent GBS. 74 patients received IVIG while eight patients were
treated with plasma exchange after IVIG because of ineffective
treatment. 7 of the patients were followed without treatment. (4)
Among 49 children with GBS, rapid progression to maximum paralysis was
seen in the male gender, while the older age group in pediatrics is
expected to endure residual paralysis at 60 days after disease onset.
Patients in colder seasons were more likely to have residual paralysis
too, compared to warmer seasons. (5)
Among 30 children with GBS diagnosis, in Iran, 12 participants were
diagnosed with acute inflammatory demyelinating polyradiculoneuropathy
and 18 patients were diagnosed with acute motor axonal neuropathy.(6)
GBS is usually preceded by an infectious viral or bacterial process (4).
Here, we investigated the association between SARS-CoV-2 and GBS in
children. We performed a study from March 2014 to 2017, in a tertiary
children’s hospital that enrolled 69 children with GBS. The prevalence
of GBS in the new study, during the SARS-CoV-2 pandemic, is higher,
however, this difference is not statistically valuable.
The male to female ratio in our study was 3.1, and among confirmed
cases, this ratio was 2.5. in a study by M. Ashrafi et al. (10), in
2008, in Iran, this ratio was 1.05, which may reflect the higher male
involvement during SARS-CoV-2 pandemic.
The frequency (60%) of a preceding SARS-CoV-2 infection track(confirmed
plus probable cases) in our study population was higher than estimates
in a multicenter study by Luijten LWG, et al.(11) on adults with GBS,
which was 22%. This may reflect the higher incidence of SARS-CoV-2
infection in Iran, during that time, which was about 1 million in 80
million population according to an official report of the ministry of
health and medical education of Iran.
Disability scale 4 ≤ of 6 and at presentation, in confirmed patients
with SARS-CoV-2 infection was 57%, in comparison to 20% in SARS-CoV-2
infection negative patients, with was statistically significant. Just
as, we had one intubated patient in confirmed and one in probable cases.
These findings along with the longest hospital admission time in
SARS-CoV-2 infection patients may reflect a poorer prognosis among
SARS-CoV-2 infection patients.
AMAN was the most frequent subtype of GBS in all our patients (65%),
apart from SARS-CoV-2 infection status. This finding\sout, is
concordant with a study of M. Ashrafi et al.(12), in Iran and different
from studies of other countries, with AIDP predominance.(13) The second
frequent subtype was AIDP (32%) and AMSAN was detected in just one
SARS-CoV-2 infection negative patient. These findings were not
significantly different between SARS-CoV-2 infection positive and
negative cases.
Conclusion
Consistent with previous studies, we found no increase in GBS patient
recruitment during the pandemic compared to previous years, however, our
study indicated that SARS-CoV-2 is associated with poorer outcomes.
Studies with more sample size are required to determine if there is a
causative association or not.