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Guillain-Barré syndrome in children – High occurrence of Miller Fisher syndrome in East Asian region

Open AccessPublished:July 26, 2022DOI:https://doi.org/10.1016/j.braindev.2022.07.003

      Abstract

      Background

      Guillain-Barré syndrome (GBS) is a rare acquired immune-mediated polyneuropathy. Updated population-based data concerning paediatric GBS is needed.

      Methods

      Paediatric patients aged below 18 years diagnosed with GBS between 2009 and 2018 in all 11 paediatric departments in Hong Kong were identified from the Hong Kong Hospital Authority Clinical Data Analysis and Reporting System. The collected data from medical health records were reviewed by paediatric neurologist from each department. Estimated incidence of paediatric GBS was calculated. We also compared our findings with other paediatric GBS studies in Asia.

      Results

      63 subjects of paediatric GBS were identified, giving an estimated annual incidence of 0.62 per 100,000 population. Half of the subjects had acute inflammatory demyelinating polyneuropathy (AIDP) (n = 31; 49.2%), one quarter had Miller Fisher Syndrome (MFS) (n = 16; 25.4%), one-fifth had axonal types of GBS (n = 12; 19.0%), and four were unclassified. Paediatric subjects with axonal subtypes of GBS compared to the other 2 subtypes, had significantly higher intensive care unit (ICU) admission rates (p = 0.001) and longest length of stay (p = 0.009). With immunomodulating therapy, complete recovery was highest in those with MFS (100%), followed by AIDP (87.1%) and axonal GBS (75%). Our study also confirms a higher MFS rate for paediatric GBS in East Asia region and our study has the highest MFS rate (25.4%).

      Conclusion

      Our population-based 10-year paediatric GBS study provides updated evidence on estimated incidence, healthcare burden and motor outcome of each subtype of paediatric GBS and confirmed a higher occurrence of paediatric MFS in East Asia.

      Abbreviations:

      GBS (Guillain-Barré syndrome), AIDP (acute inflammatory demyelinating polyneuropathy), AMAN (acute motor axonal neuropathy), AMSAN (acute motor and sensory axonal polyneuropathy), MFS (Miller Fisher syndrome), HA (Hospital Authority), CDARS (Clinical Data Analysis and Reporting System), CSF (cerebrospinal fluid), NCS (nerve conduction study), CMAP (compound muscle action potential), SNAP (sensory nerve action potential), LOS (length of stay)

      Keywords

      1. Introduction

      Guillain-Barré syndrome (GBS) is a rare, acquired auto-immune disorder with different clinical and electrophysiological subtypes. Often preceded by antecedent infection or vaccination, it is characterised by acute inflammation and damage to peripheral nerves, nerve roots and sometimes cranial nerves. Classically, it presents as rapidly progressive, ascending flaccid paralysis with diminished or absent reflexes [
      • Chung A.
      • Deimling M.
      Guillain-Barre Syndrome.
      ].
      There are four clinical variants of GBS: acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), and Miller Fisher syndrome (MFS). Their relative distribution is subjected to regional variation. AIDP is the predominant GBS subtype in Europe and North America, Oceania and Middle East [
      • Shahrizaila N.
      • Lehmann H.C.
      • Kuwabara S.
      Guillain-Barre syndrome.
      ], and also in Asia [
      • Shahrizaila N.
      • Lehmann H.C.
      • Kuwabara S.
      Guillain-Barre syndrome.
      ,
      • Hui A.C.
      • Chow K.M.
      • Tang A.S.
      • Fu M.
      • Kay R.
      • Wong K.S.
      Electrophysiological, clinical and epidemiological study of Guillain-Barre Syndrome in Hong Kong Chinese.
      ,
      • Ma Y.M.
      • Liu T.K.
      • Wong V.
      Guillain-Barre syndrome in southern Chinese children: 32 year experience in Hong Kong.
      ,
      • Doets A.Y.
      • Verboon C.
      • van den Berg B.
      • Harbo T.
      • Cornblath D.R.
      • Willison H.J.
      • et al.
      Regional variation of Guillain-Barre syndrome.
      ,
      • Lyu R.K.
      • Tang L.M.
      • Cheng S.Y.
      • Hsu W.C.
      • Chen S.T.
      Guillain-Barre syndrome in Taiwan: a clinical study of 167 patients.
      ,
      • Mitsui Y.
      • Kusunoki S.
      • Arimura K.
      • Kaji R.
      • Kanda T.
      • Kuwabara S.
      • et al.
      A multicentre prospective study of Guillain-Barre syndrome in Japan: a focus on the incidence of subtypes.
      ], and has a demyelinating pattern of motor and sensory nerves in electrophysiological studies. AMAN was previously thought to be the most prevalent subtype amongst Chinese population and was once called the Chinese paralytic syndrome [
      • McKhann G.M.
      • Cornblath D.R.
      • Ho T.
      • Griffin J.W.
      • Li C.Y.
      • Bai A.Y.
      • et al.
      Clinical and electrophysiological aspects of acute paralytic disease of children and young adults in northern China.
      ]. However, later studies have shown that AMAN is not only common in east Asia [
      • Lee J.H.
      • Sung I.Y.
      • Rew I.S.
      Clinical presentation and prognosis of childhood Guillain-Barre syndrome.
      ,
      • Nagasawa K.
      • Kuwabara S.
      • Misawa S.
      • Fujii K.
      • Tanabe Y.
      • Yuki N.
      • et al.
      Electrophysiological subtypes and prognosis of childhood Guillain-Barre syndrome in Japan.
      ,
      • Luo H.Y.
      • Li X.J.
      • Cheng M.
      • Wang J.
      • Xie L.L.
      • Yao Z.X.
      • et al.
      Clinical characteristics of children with Guillain-Barre syndrome and factors associated with disease severity.
      ], but also in India [
      • Yadav S.
      • Jain P.
      • Sharma S.
      • Kumar V.
      • Aneja S.
      Guillain-Barre syndrome in North Indian children: Clinical and serial electrophysiological features.
      ,
      • Kannan M.A.
      • Ch R.K.
      • Jabeen S.A.
      • Mridula K.R.
      • Rao P.
      • Borgohain R.
      Clinical, electrophysiological subtypes and antiganglioside antibodies in childhood Guillain-Barre syndrome.
      ] and Bangladesh [
      • Shahrizaila N.
      • Lehmann H.C.
      • Kuwabara S.
      Guillain-Barre syndrome.
      ]. AMSAN resembles AMAN but has an additional sensory component. Whilst MFS is rare amongst Caucasians, it is more common in Asia [
      • Doets A.Y.
      • Verboon C.
      • van den Berg B.
      • Harbo T.
      • Cornblath D.R.
      • Willison H.J.
      • et al.
      Regional variation of Guillain-Barre syndrome.
      ], and has been reported to constitute up to 20–26% of the GBS cases in Taiwan [
      • Lyu R.K.
      • Tang L.M.
      • Cheng S.Y.
      • Hsu W.C.
      • Chen S.T.
      Guillain-Barre syndrome in Taiwan: a clinical study of 167 patients.
      ] and Japan [
      • Mitsui Y.
      • Kusunoki S.
      • Arimura K.
      • Kaji R.
      • Kanda T.
      • Kuwabara S.
      • et al.
      A multicentre prospective study of Guillain-Barre syndrome in Japan: a focus on the incidence of subtypes.
      ] in their adult patients respectively. MFS/GBS overlapping syndrome is also more common in Asia with incidence rate close to that of classical MFS [
      • Doets A.Y.
      • Verboon C.
      • van den Berg B.
      • Harbo T.
      • Cornblath D.R.
      • Willison H.J.
      • et al.
      Regional variation of Guillain-Barre syndrome.
      ,
      • Tan C.Y.
      • Razali S.N.O.
      • Goh K.J.
      • Shahrizaila N.
      Determining the utility of the Guillain-Barre syndrome classification criteria.
      ].
      The incidence of paediatric GBS is likewise subjected to considerable regional variation. The global incidence rate of GBS is estimated to be 0.34–1.34 per 100,000 people per year in children aged 0–15 years [
      • McGrogan A.
      • Madle G.C.
      • Seaman H.E.
      • de Vries C.S.
      The epidemiology of Guillain-Barre syndrome worldwide. A systematic literature review.
      ]. Another global study showed the paediatric estimated incidence rate of GBS were 0.62 and 0.75 per 100,000 people per year for age group 0–9 years and 10–19 years respectively [
      • Sejvar J.J.
      • Baughman A.L.
      • Wise M.
      • Morgan O.W.
      Population incidence of Guillain-Barre syndrome: a systematic review and meta-analysis.
      ]. The regional estimated incidence could be as high as 1.7 per 100,000 people per year in Bangladesh [
      • Islam Z.
      • Jacobs B.C.
      • Islam M.B.
      • Mohammad Q.D.
      • Diorditsa S.
      • Endtz H.P.
      High incidence of Guillain-Barre syndrome in children, Bangladesh.
      ], or as low as 0.22–0.5 per 100,000 people per year in Northern China [
      • Chen Y.
      • Ma F.
      • Zhang J.
      • Chu X.
      • Xu Y.
      Population incidence of Guillain-Barre syndrome in parts of China: three large populations in Jiangsu province, 2008–2010.
      ].
      We performed a 10-year territory-wide retrospective study on Paediatric GBS with the aim to better understand the local incidence, presentation, treatment, and outcome relating to different GBS subtypes in Hong Kong. We have also performed a literature search to study how the local epidemiology of paediatric GBS compares with other Asian regions.

      2. Methods

      This is a retrospective study of paediatric subjects (<18 years old) with a confirmed diagnosis of GBS admitted to any of the 11 paediatric units of the public hospitals under the Hospital Authority of Hong Kong between 1st January 2009 and 31st December 2018 inclusive. Collectively, the Hospital Authority managed all the public hospitals in Hong Kong that covered more than 85% of all admissions within the whole Hong Kong territory. Moreover, almost all paediatric patients diagnosed with GBS in the private hospitals would be referred to the public hospitals for possible intensive care and rehabilitation care need, so our current study provided a highly representative cohort of paediatric GBS in our region. The Hospital Authority uses diagnostic coding, which contains mapped codes for ICD-10 available via the Clinical Data Analysis and Reporting System (CDARS). All admissions within public hospitals under the Hospital Authority with a specific diagnosis are searchable via the CDARS using ICD-10 codes. Admissions coded with G61.0 Guillain-Barré syndrome (GBS) in subjects aged <18 years inclusive on the day of admissions were retrieved. Duplicated entries due to repeated admissions or patients being transferred to other hospitals were checked and excluded. Children with other confirmed causes including acute flaccid paralysis, chronic inflammatory demyelinating polyneuropathy and doubtful diagnosis were also excluded from this study.
      Systemic evaluation of each patient’s past clinical summaries from the electronic medical health records were performed by a paediatric neurologist from each participating hospital when collecting the acquired data. Information on individual subjects’ clinical presentation, blood and cerebrospinal fluid (CSF) investigation results, nerve conduction study findings, treatments administered, need for paediatric intensive care admission and ventilation use, and the functional outcome, were collected and analysed. The functional outcome was categorized as (1) able to run; (2) able to walk independently but unable to run; (3) able to walk with support; (4) need wheelchair use. The diagnosis of paediatric GBS in Hong Kong is based on clinical history, physical examination, and the supporting investigations including CSF examinations and electrodiagnostic studies. We have further categorised our cohort using the Brighton Collaboration Diagnostic Criteria for Guillain Barre syndrome (GBS) and Miller Fisher syndrome (MFS) into different level of diagnostic certainty [
      • Roodbol J.
      • de Wit M.Y.
      • van den Berg B.
      • Kahlmann V.
      • Drenthen J.
      • Catsman-Berrevoets C.E.
      • et al.
      Diagnosis of Guillain-Barre syndrome in children and validation of the Brighton criteria.
      ,
      • Sejvar J.J.
      • Kohl K.S.
      • Gidudu J.
      • Amato A.
      • Bakshi N.
      • Baxter R.
      • et al.
      Guillain-Barre syndrome and Fisher syndrome: case definitions and guidelines for collection, analysis, and presentation of immunization safety data.
      ]. Those with MFS presentation and limb weakness were classified as MFS/GBS overlapping syndrome and evaluated according to the Brighton Collaboration Diagnostic Criteria for GBS.
      For the nerve conduction studies (NCS), age-specific reference values were taken into account, especially in the younger pre-adolescent children. The electrophysiological diagnostic criteria adopted to determine the demyelinating sensorimotor polyneuropathy (AIDP subtype), included non-uniform slowing of the conduction velocities of both motor and sensory nerves, prolongation of distal motor latencies, increased F-wave latencies, dispersion of proximally evoked compound motor action potentials, and conduction block. The presence of typical ‘sural sparing patterns’ with normal sural sensory nerve action potentials, while the median and ulnar sensory nerve action potentials are decreased or absent, was also taken into consideration [
      • Sejvar J.J.
      • Kohl K.S.
      • Gidudu J.
      • Amato A.
      • Bakshi N.
      • Baxter R.
      • et al.
      Guillain-Barre syndrome and Fisher syndrome: case definitions and guidelines for collection, analysis, and presentation of immunization safety data.
      ,
      • Hughes R.A.
      • Cornblath D.R.
      Guillain-Barre syndrome.
      ,
      • Willison H.J.
      • Jacobs B.C.
      • van Doorn P.A.
      Guillain-Barre syndrome.
      ]. The electrophysiological diagnostic criteria adopted for axonal motor and sensorimotor polyneuropathy (AMAN and AMSAN subtypes) included profound reductions in the compound muscle action potentials (CMAPs) ± sensory nerve action potentials (SNAPs) with relatively preserved conduction velocities. Reversible transient motor nerve conduction block might be observed [
      • Sejvar J.J.
      • Kohl K.S.
      • Gidudu J.
      • Amato A.
      • Bakshi N.
      • Baxter R.
      • et al.
      Guillain-Barre syndrome and Fisher syndrome: case definitions and guidelines for collection, analysis, and presentation of immunization safety data.
      ,
      • Hughes R.A.
      • Cornblath D.R.
      Guillain-Barre syndrome.
      ,
      • Willison H.J.
      • Jacobs B.C.
      • van Doorn P.A.
      Guillain-Barre syndrome.
      ]. Hadden et al. electrodiagnostic criteria for GBS was generally adopted [
      • Hadden R.D.
      • Cornblath D.R.
      • Hughes R.A.
      • Zielasek J.
      • Hartung H.P.
      • Toyka K.V.
      • et al.
      Electrophysiological classification of Guillain-Barre syndrome: clinical associations and outcome. Plasma Exchange/Sandoglobulin Guillain-Barre Syndrome Trial Group.
      ]. If the NCS was normal or showed only abnormal late response in F-wave and Hoffman reflexes (H-reflexes), as may be the case early in the disease course, a follow-up study would be performed in the next week where feasible.
      Institutional Review Board approval from the Hong Kong West Cluster/University of Hong Kong board was granted (IRB number UW20-360).

      2.1 Statistical analysis

      The annual incidence of paediatric GBS was estimated using the number of cases in each year, divided by total population aged 0 to <18 years old in each year, using data obtained from the Census Department of Hong Kong [

      Census and Statistics Department TGotHKS. Population Census. 2009–2018.

      ]. The average incidence of GBS was then calculated using a 10-year average. A simple linear regression analysis of the trend of paediatric GBS incidence from 2009 to 2018 was performed. P-values for categorical comparisons between different subgroups of GBS was calculated using a Chi-Square test. Statistical significance is considered p < 0.05 in two tails. Post-test significance was further evaluated using 2 × 2 Chi-square test. Statistical analysis was performed with IBM SPSS Statistics 27.0 for Windows.

      2.2 Literature review

      We have also performed literature search with PubMed using search terms ‘Guillain-Barré syndrome’ and ‘children’, or ‘pediatric/paediatric’, with publication dates between 1 January 2000 and 31 December 2019 inclusive. Cohort studies of GBS from Asian regions including China, Taiwan, Korea, Japan, Thailand, India, Iran and Turkey were included for further analysis. Studies with overlapping adult cohorts with no specific paediatric patient data and single case reports were excluded.

      3. Results

      3.1 Case finding and epidemiology

      80 subjects from 11 hospitals were initially identified. Detailed evaluations of each subject’s clinical record were performed by a paediatric neurologist of each hospital. Those with overlapping records (n = 4), incomplete records (n = 4), and GBS-mimicking conditions (n = 9) were excluded. The diagnoses of excluded patients included chronic idiopathic demyelinating polyneuropathy, juvenile idiopathic arthritis, and generalized sensory neuropathy.
      A total of 63 subjects with confirmed diagnosis of GBS were included in this study for analysis. There were 34 male subjects, giving a male to female ratio of 1.2:1. The age of the subjects ranged from 0.75 to 17.9 years old. The mean duration of follow up was 26.4 months (median 22.5 months). All subjects with AMAN or AMSAN fulfilled level 1 of the Brighton Collaboration Diagnostic Criteria for GBS. Amongst subjects under AIDP subtype that responded promptly to IVIG, 25/31 (80%) fulfilled level 1 of the Brighton Collaboration Diagnostic Criteria for GBS, with 5/31 (22.6%) fulfilled level 2 of the diagnostic certainty with normal or no NCS but raised CSF protein, and 1/31 (3.2%) fulfilled level 3 of the diagnostic certainty [
      • Sejvar J.J.
      • Kohl K.S.
      • Gidudu J.
      • Amato A.
      • Bakshi N.
      • Baxter R.
      • et al.
      Guillain-Barre syndrome and Fisher syndrome: case definitions and guidelines for collection, analysis, and presentation of immunization safety data.
      ]. Half of the subjects (8/16; 50%) with classical MFS, had ophthalmoplegia, ataxia, and areflexia, while the other half (8/16; 50%), had MFS/GBS overlapping presentation. For those with classical MFS, 2/8 (25%) fulfilled level 1 of the Brighton Collaboration Diagnostic Criteria for MFS, and 6/8 (75%) fulfilled level 2 diagnostic certainty with either raised CSF protein or normal NCS. For those with MFS/GBS overlapping syndrome, adopting the Brighton Collaboration Diagnostic Criteria for GBS, 1/8 (12.5%) fulfilled level 1 diagnostic certainty, 6/8(75%) fulfilled level 2 diagnostic certainty with either abnormal NCS or raised CSF protein, and 1/8 (12.5%) fulfilled level 3 diagnostic certainty with normal NCS and CSF protein.
      The overall estimated annual incidence of paediatric GBS in Hong Kong from 2009 to 2018 was 0.62 per 100,000 population (Supplementary Table 1). The estimated annual incidence and distribution of cases by subtypes can be found in Fig. 1. Nearly-two-thirds of the subjects were admitted during the spring and summer months (Supplementary Table 2), the warmer seasons in Hong Kong.
      Figure thumbnail gr1
      Fig. 1Distribution of paediatric GBS cases by subtypes and year.

      3.2 Clinical characteristics and investigations

      Among the 63 subjects, half of the subjects had AIDP (n = 31; 49.2%), and one quarter had MFS (n = 16; 25.4%). One fifth of the subjects had axonal types of GBS (n = 12; 19.0%) including AMAN (n = 5; 7.9%) and AMSAN (n = 7; 11.1%). Of the four patients with unclassified subtype, one had Bickerstaff encephalitis, two had normal NCS (one had positive GQ1b antibody, one had elevated protein in cerebrospinal fluid), and one had a mixed axonal and demyelinating picture on NCS.
      The characteristics of the three subtypes of GBS is summarised in Table 1. The three subtypes shared similar age of onset and proportions of patients with prodromal illness, none of which involved vaccination. MFS had the highest percentage of cranial nerve involvement, lowest percentage of autonomic disturbance and best motor outcome. Whilst AIDP and MFS had comparable length of stay (LOS), intensive care unit (ICU) admission rate and need for ventilator support, the axonal types of GBS had significantly higher healthcare utilization rate.
      Table 1Comparison of clinical presentation, investigation result, treatment, healthcare utilization and outcome of different GBS subtypes.
      AIDPAMAN/AMSANMFSChi-Square Test

      (P value)
      Post-test significant findings

      (P value)
      Number of patients (n)311216
      AMAN:AMSAN5:7MFS: MFS/GBS Sx8:8
      Mean age of onset (range) years8.0 (1.9–17.4)11.4 (3.3–17.9)10.2 (2.9–17.6)
      Male to female ratio0.82 (14/17)1.4 (7/5)1.28 (9/7)0.6515
      Prodromal illness (n) (%)24 (77%)11 (92%)12 (75%)0.502
      Infective agents identified (n) (%)6 (19.4%)2 (16.7%)4 (25%)0.8466
      Cranial nerve involvement (n) (%)
      Cranial nerve dysfunction included: bulbar dysfunction/palsy, ptosis, external ophthalmoplegia.
      6 (19.4%)5 (41.7%)14 (87.5%)<0.001MFS vs AMAN/AMSAN (0.016)MFS vs AIDP

      (<0.001)
      Autonomic involvement (n) (%)
      Autonomic dysfunction included: urinary retention, hypertension, postural hypotension, bradycardia.
      5 (16.1%)5 (42%)1 (6.3%)0.0512
      Mean length of stay (range) days21.9 (3–68)61.5 (7–199)23.8 (7–104)0.009AMAN/AMSAN vs MFS (0.045)

      AMAN/AMSAN vs AIDP (0.008)
      Required PICU admission (n) (%)8 (25.8%)11 (91.7%)5 (31.3%)0.001AMAN/AMSAN vs AIDP (0.0001)

      AMAN/AMSAN vs MFS (0.002)
      Need for ventilator support (n) (%)2 (6.45%)4 (33.3%)2 (12.5%)0.0687
      Testing for AGA after 2015 (n) (%)10/14 (71.4%)6/8 (75%)8/8 (100%)0.2506
      Positive yield for AGA after 2015 (n) (%)1/10 (10%)1/6 (16.7%)7/8 (87.5%)0.002MFS vs AMAN/AMSAN (0.0256)MFS vs AIDP

      (0.0029)
      AGA findingsAnti-GD1b and anti- GM1Anti-GM1Anti-GQ1b (6/7); Anti-GQ1b and anti-GM1(1/7)
      NCS test (n) (%)28 (90.3%)12 (100%)12 (75%)0.77
      Positive yield for NCS test (n) (%)25/28 (89.3%)12/12 (100%)4/12 (33.3%)0.037MFS vs AMAN/AMSAN (0.027)MFS vs AIDP

      (<0.001)
      Testing for MRI spine (contrast) (n) (%)25 (80.6%)7 (58.3%)5 (31.3%)0.004
      Positive yield of MRI spine for those being tested (%)18/25 (72%)5 (71.4%)1/5 (20%)0.044AIDP vs AMAN/AMSAN (0.1459)AIDP vs MFS

      (0.0472)
      Conservative treatment (n) (%)2 (6.5%)0 (0%)1 (6.3%)0.6677
      1st line – IVIG (n) (%)29 (93.5%)12 (100%)15 (93.8%)0.6677
      2nd line – Plasmapheresis (n) (%)3 (9.7%)3 (25%)1 (6.3%)0.272
      Lost to follow up (n) (%)1 (3.2%)0 (0%)0 (0%)0.6317
      Complete motor recovery (n) (%)26 (83.9%)9 (75%)16 (100%)0.1337
      Incomplete motor recovery (n) (%)4 (12.9%)3 (25.0%)0 (0%)0.1246
      • Motor clumsiness (n) (%)
      4 (12.9%)2 (16.7%)0 (0%)
      • Wheelchair bound (n) (%)
      0 (0%)1 (8.3%)*0 (0%)0.2699
      Residual sensory symptoms (n) (%)0 (0%)1 (8.3%)3 (28.7%)0.0516
      Abbreviations: AIDP, acute inflammatory demyelinating polyneuropathy; AMAN, acute motor axonal neuropathy; AMSAN, acute motor and sensory axonal neuropathy; MFS, Miller Fisher syndrome; AGA, antiganglioside antibodies; IVIG, intravenous immunoglobulin; NCS, nerve conduction study; PICU, paediatric intensive care unit.
      *Declined second line therapy with plasmapheresis.
      P < 0.05 statistically significant.
      # Cranial nerve dysfunction included: bulbar dysfunction/palsy, ptosis, external ophthalmoplegia.
      @ Autonomic dysfunction included: urinary retention, hypertension, postural hypotension, bradycardia.
      Anti-ganglioside antibody testing and contrast MRI spine study were increasingly adopted to aid diagnostic evaluation during the study period. Anti-ganglioside antibody testing including both IgG and IgM of anti-GD1b, anti-GQ1b and anti-GM1. The panel was made available to all our public hospitals only from 2015 onward. The MFS subgroup had the highest testing rate (100%) for anti-gangliosides antibodies, and positive diagnostic rate (87.5%), all of which were for anti-GQ1b. The positive diagnostic rate was much lower in AIDP (10%) and axonal GBS (16.7%) subgroups. Anti-GM1 antibodies were found in all 3 subtypes, with one patient in each subtype. One patient from the MFS subtype was positive for both anti GQ1b and anti-GM1, whereas one patient from the AIDP subtype was positive for both anti-GM1 and anti-GD1b.

      3.3 Medical facilities usage, treatment and outcome

      No patient with paediatric GBS died during the study period. Overall, two-fifths of the patients (n = 26, 41.2%) required ICU stay, with one-third (n = 9, 34.6%) of them required ventilator support. The combined acute-and-rehabilitation-associated LOS ranged from 3 to 199 days, with a median LOS of 14 days.
      Among the three clinical subtypes, axonal GBS had the highest usage of medical facilities. 91.7% of patients with axonal GBS were admitted to the paediatric ICU (p = 0.001) with one-third required ventilator support, i.e. five times that of AIDP. The average LOS of axonal GBS patients was 61.5 days, nearly triple that of AIDP (21.9 days) (p = 0.009). All patients with axonal GBS required IVIG and 25% of them also required second-line therapy with plasmapheresis, as compared to 93% of patients with AIDP and MFS required IVIG and <10% of the patients in these 2 subgroups required plasmapheresis. Despite such aggressive treatments, the chance of complete motor recovery in subjects with axonal GBS was lower at 75%, compared to the 87.1% for AIDP and 100% in MFS. No paediatric patients in the AIDP subgroup required wheelchair use. For the child with axonal GBS that could not walk, the family refused plasmapheresis and subsequently defaulted follow-up as the family returned to mainland China in <6 months after onset of symptom, so the outcome in 1 year is not known.
      Patients with MFS/GBS overlapping syndrome also demonstrated significantly higher healthcare utilization rates compared to those with classical MFS. The LOS was nearly doubled amongst patients with MFS/GBS overlapping syndrome (average 31.6 days, compared to 16 days for pure MFS). Whereas 62.5% of the patients with MFS/GBS overlapping syndrome required ICU admission, all of those with pure MFS were managed in paediatric general ward (p = 0.025). The overall rate of complete recovery, however, was the same in both groups as of 100% (Table 2).
      Table 2Comparing the healthcare utilization of classical MFS and MFS/GBS overlapping syndrome.
      Classical MFSMFS/GBS overlapping syndromeP-value
      Mean, median length of stay (range) (days)16, 13 (7–35)31.6, 21 (11–104)0.196
      Required PICU admission (n) (%)0 (0%)5 (62.5%)0.0256*
      Need for ventilator support (n) (%)0 (0%)2/8 (25%)0.4667
      *P < 0.05 statistically significant.

      3.4 Literature review

      Sixty-three studies were obtained from PubMed search using the search terms ‘Guillain-Barré syndrome’ and ‘children’ or ‘paediatric/pediatric’ with a publication date between 1 January 2000 and 31 December 2019 inclusive. A total of thirteen cohort studies from Asian regions were identified. Two of the identified studies came from the same centre and the study with the shorter duration of study period was excluded. The relevant data is summarized in Supplementary Table 3 [
      • Lee J.H.
      • Sung I.Y.
      • Rew I.S.
      Clinical presentation and prognosis of childhood Guillain-Barre syndrome.
      ,
      • Nagasawa K.
      • Kuwabara S.
      • Misawa S.
      • Fujii K.
      • Tanabe Y.
      • Yuki N.
      • et al.
      Electrophysiological subtypes and prognosis of childhood Guillain-Barre syndrome in Japan.
      ,
      • Luo H.Y.
      • Li X.J.
      • Cheng M.
      • Wang J.
      • Xie L.L.
      • Yao Z.X.
      • et al.
      Clinical characteristics of children with Guillain-Barre syndrome and factors associated with disease severity.
      ,
      • Yadav S.
      • Jain P.
      • Sharma S.
      • Kumar V.
      • Aneja S.
      Guillain-Barre syndrome in North Indian children: Clinical and serial electrophysiological features.
      ,
      • Kannan M.A.
      • Ch R.K.
      • Jabeen S.A.
      • Mridula K.R.
      • Rao P.
      • Borgohain R.
      Clinical, electrophysiological subtypes and antiganglioside antibodies in childhood Guillain-Barre syndrome.
      ,
      • Lin J.J.
      • Hsia S.H.
      • Wang H.S.
      • Lyu R.K.
      • Chou M.L.
      • Hung P.C.
      • et al.
      Clinical variants of Guillain-Barre syndrome in children.
      ,
      • Wu X.
      • Shen D.
      • Li T.
      • Zhang B.
      • Li C.
      • Mao M.
      • et al.
      Distinct clinical characteristics of pediatric Guillain-Barre syndrome: A comparative study between children and adults in Northeast China.
      ,
      • Tang J.
      • Dai Y.
      • Li M.
      • Cheng M.
      • Hong S.
      • Jiang L.
      • et al.
      Guillain-Barre syndrome in Chinese children: a retrospective analysis.
      ,
      • Varkal M.A.
      • Uzunhan T.A.
      • Aydinli N.
      • Ekici B.
      • Caliskan M.
      • Ozmen M.
      Pediatric Guillain-Barre syndrome: indicators for a severe course.
      ,
      • Sen S.
      • Kumar A.
      • Roy B.
      Clinical outcome of Guillain-Barre Syndrome in 108 children.
      ,
      • Parveen A.
      • Khan S.A.
      • Talat S.
      • Hussain S.N.F.
      Comparison of the clinical outcomes of Guillain Barre syndrome based on electrophysiological subtypes in Pakistani children.
      ,
      • Sri-udomkajorn S.
      • Suwannachote S.
      Demographics, clinical features, outcome and prognostic factors of Guillain-Barre syndrome in Thai children.
      ,
      • Ashrafi M.R.
      • Mohammadalipoor A.
      • Naeini A.R.
      • Amanat M.
      • Tavasoli A.R.
      • Heidari M.
      • et al.
      Clinical characteristics and electrodiagnostic features of Guillain-Barre syndrome among the pediatric population.
      ].
      Overall, the proportion of children with prior infective symptoms within this study was comparable to that of neighbouring regions. The overall percentage of AIDP was also comparable to neighbouring regions (32–67.4%).
      However, the proportion of MFS cases in this series was highest (25%) in the Asia region, followed by the studies in Korea (12.5%) [
      • Lee J.H.
      • Sung I.Y.
      • Rew I.S.
      Clinical presentation and prognosis of childhood Guillain-Barre syndrome.
      ], Taiwan (9%) [
      • Lin J.J.
      • Hsia S.H.
      • Wang H.S.
      • Lyu R.K.
      • Chou M.L.
      • Hung P.C.
      • et al.
      Clinical variants of Guillain-Barre syndrome in children.
      ] and Pakistan (4.3%) [
      • Parveen A.
      • Khan S.A.
      • Talat S.
      • Hussain S.N.F.
      Comparison of the clinical outcomes of Guillain Barre syndrome based on electrophysiological subtypes in Pakistani children.
      ]. While AMAN is more common in Iran, India, Turkey, Japan and south-central China, AMSAN was found to be more common that AMAN in our study (10.9% vs 7.8%) and in Pakistan study (26.1% vs 17%) [
      • Parveen A.
      • Khan S.A.
      • Talat S.
      • Hussain S.N.F.
      Comparison of the clinical outcomes of Guillain Barre syndrome based on electrophysiological subtypes in Pakistani children.
      ].

      4. Discussion

      4.1 Estimated incidence of paediatric GBS is similar to neighbouring Asia regions and global studies

      Previous systematic reviews showed that the incidence of paediatric GBS ranges from 0.34 to 1.34 per 100,000 population [
      • McGrogan A.
      • Madle G.C.
      • Seaman H.E.
      • de Vries C.S.
      The epidemiology of Guillain-Barre syndrome worldwide. A systematic literature review.
      ]. In neighbouring East Asia regions, the GBS incidence ranges from 0.233 per 100,000 population in Beijing [
      • Zheng P.
      • Tian D.C.
      • Xiu Y.
      • Wang Y.
      • Shi F.D.
      Incidence of Guillain-Barre syndrome (GBS) in China: A national population-based study.
      ] to 0.66 per 100,000 population in Taiwan [
      • Hung K.L.
      • Wang H.S.
      • Liou W.Y.
      • Mak S.C.
      • Chi C.S.
      • Shen E.Y.
      • et al.
      Guillain-Barre syndrome in children: a cooperative study in Taiwan.
      ]. Our study showed an average incidence of 0.62 per 100,000 population. As such, the epidemiological findings of our current study in Hong Kong do not differ significantly with regional or worldwide data.

      4.2 MFS is more common in paediatric GBS study in East Asia compared to neighbouring Asia regions

      While MFS is infrequent in western part of the world accounting for 3–11% of GBS cases in adult patients [
      • Doets A.Y.
      • Verboon C.
      • van den Berg B.
      • Harbo T.
      • Cornblath D.R.
      • Willison H.J.
      • et al.
      Regional variation of Guillain-Barre syndrome.
      ,
      • Rees J.H.
      • Soudain S.E.
      • Gregson N.A.
      • Hughes R.A.
      Campylobacter jejuni infection and Guillain-Barre syndrome.
      ,
      • Lo Y.L.
      Clinical and immunological spectrum of the Miller Fisher syndrome.
      ], it is more frequent in the East Asia accounting for up to 18–26% of GBS cases in adult patients in Taiwan [
      • Lyu R.K.
      • Tang L.M.
      • Cheng S.Y.
      • Hsu W.C.
      • Chen S.T.
      Guillain-Barre syndrome in Taiwan: a clinical study of 167 patients.
      ,
      • Yuan C.L.
      • Wang Y.J.
      • Tsai C.P.
      Miller fisher syndrome: a hospital-based retrospective study.
      ] and in Japan [
      • Mitsui Y.
      • Kusunoki S.
      • Arimura K.
      • Kaji R.
      • Kanda T.
      • Kuwabara S.
      • et al.
      A multicentre prospective study of Guillain-Barre syndrome in Japan: a focus on the incidence of subtypes.
      ,
      • Mori M.
      • Kuwabara S.
      • Fukutake T.
      • Yuki N.
      • Hattori T.
      Clinical features and prognosis of Miller Fisher syndrome.
      ].
      Likewise, MFS is uncommon in paediatric GBS in Caucasian population and accounts for 2–6% of GBS cases in paediatric patients [
      • Estrade S.
      • Guiomard C.
      • Fabry V.
      • Baudou E.
      • Cances C.
      • Chaix Y.
      • et al.
      Prognostic factors for the sequelae and severity of Guillain-Barre syndrome in children.
      ,
      • Levison L.S.
      • Thomsen R.W.
      • Markvardsen L.K.
      • Christensen D.H.
      • Sindrup S.H.
      • Andersen H.
      Pediatric Guillain-Barre syndrome in a 30-year nationwide cohort.
      ]. Our literature review confirmed that MFS is more common in paediatric GBS in East Asia region among neighbouring Asian countries. In the Taiwan GBS study in children, MFS ranged from 6.8% [
      • Lyu R.K.
      • Tang L.M.
      • Cheng S.Y.
      • Hsu W.C.
      • Chen S.T.
      Guillain-Barre syndrome in Taiwan: a clinical study of 167 patients.
      ] to 9.3% [
      • Lin J.J.
      • Hsia S.H.
      • Wang H.S.
      • Lyu R.K.
      • Chou M.L.
      • Hung P.C.
      • et al.
      Clinical variants of Guillain-Barre syndrome in children.
      ]. In the South Korean paediatric GBS study, MFS accounted for up to 12.5% [
      • Lee J.H.
      • Sung I.Y.
      • Rew I.S.
      Clinical presentation and prognosis of childhood Guillain-Barre syndrome.
      ]. Our paediatric GBS study found the highest percentage of MFS up to 25.4%.
      The findings of half of our MFS paediatric patients had overlapping syndrome are comparable to previous reports where MFS/GBS overlapping syndrome accounted for 44% [
      • Doets A.Y.
      • Verboon C.
      • van den Berg B.
      • Harbo T.
      • Cornblath D.R.
      • Willison H.J.
      • et al.
      Regional variation of Guillain-Barre syndrome.
      ] and 49% [
      • Tan C.Y.
      • Razali S.N.O.
      • Goh K.J.
      • Shahrizaila N.
      Determining the utility of the Guillain-Barre syndrome classification criteria.
      ] of the MFS/GBS overlapping syndrome and classical MFS combined. Our paediatric patients with MFS/GBS overlapping syndrome also showed a higher healthcare burden as compared to those with classical MFS syndrome, with more patients required paediatric ICU admission and had a longer length of stay (Table 2). However, our patients with classical MFS and MFS/GBS overlapping syndrome had excellent clinical outcome with full motor recovery (Table 1).

      4.3 Higher healthcare burden in axonal GBS subtypes

      Amongst the three subtypes of paediatric GBS, the group with axonal types of GBS had the severest clinical presentation, highest rates of healthcare utilization (with longest LOS, highest rates of paediatric ICU admission and ventilator use), as well as lowest rates of complete recovery.
      To the contrary of a prior report on adult GBS patients with predominant AIDP subtype where demyelinating feature could be associated with respiratory failure [
      • Durand M.C.
      • Porcher R.
      • Orlikowski D.
      • Aboab J.
      • Devaux C.
      • Clair B.
      • et al.
      Clinical and electrophysiological predictors of respiratory failure in Guillain-Barre syndrome: a prospective study.
      ], our findings echo adult and paediatric GBS studies performed amongst populations with higher representation of non-AIDP subtypes [
      • Tekgul H.
      • Serdaroglu G.
      • Tutuncuoglu S.
      Outcome of axonal and demyelinating forms of Guillain-Barre syndrome in children.
      ,
      • Zhang G.
      • Li Q.
      • Zhang R.
      • Wei X.
      • Wang J.
      • Qin X.
      Subtypes and prognosis of Guillain-Barre syndrome in Southwest China.
      ] that axonal GBS subtype is associated with higher rates of healthcare utilization and respiratory care need. Children with axonal GBS subtype tended to recover more slowly than those with demyelinating subtype but after 1 year of follow-up, the motor recovery was impressed to be good in both subtypes [
      • Tekgul H.
      • Serdaroglu G.
      • Tutuncuoglu S.
      Outcome of axonal and demyelinating forms of Guillain-Barre syndrome in children.
      ].
      Children with axonal types of GBS should thus be managed with higher healthcare vigilance. Close clinical monitoring should be matched with appropriate counselling regarding possibility of deterioration, with timely initiation of second line therapy and ventilatory support. Rehabilitation should also be arranged early in the recovery phase. There should be cautious counselling regarding prognosis and duration of training required.

      4.4 Standard of care for patients with GBS

      In the past decade, there have been updates in the recommendations regarding the practices for investigations and management of GBS. Use of anti-ganglioside antibodies as diagnostic test has been increasingly adopted. GBS subtypes are often associated with specific panel of antiganglioside antibodies. For instance, patients with AMAN often have IgG antibodies to GM1, GD1a, GalNAc-GD1a, GA1, or LM1/GA1 complex [
      • Goodfellow J.A.
      • Willison H.J.
      Antiganglioside, antiganglioside-complex, and antiglycolipid-complex antibodies in immune-mediated neuropathies.
      ]. Patients with MFS have antibodies against GQ1b, which is expressed in the paranodal regions of extraocular motor nerves [
      • Chiba A.
      • Kusunoki S.
      • Obata H.
      • Machinami R.
      • Kanazawa I.
      Serum anti-GQ1b IgG antibody is associated with ophthalmoplegia in Miller Fisher syndrome and Guillain-Barre syndrome: clinical and immunohistochemical studies.
      ]. In addition, Gal-C and LM1 are expressed in myelin, and the antibodies to those antigens are associated with AIDP [
      • Kuwahara M.
      • Suzuki S.
      • Takada K.
      • Kusunoki S.
      Antibodies to LM1 and LM1-containing ganglioside complexes in Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy.
      ,
      • Samukawa M.
      • Hamada Y.
      • Kuwahara M.
      • Takada K.
      • Hirano M.
      • Mitsui Y.
      • et al.
      Clinical features in Guillain-Barre syndrome with anti-Gal-C antibody.
      ]. GD1b is expressed in the paranodal myelin, so anti-GD1b antibodies could mediate paranodal demyelination resulting in pathophysiological features of AIDP. In contrast, GM1 is localized at the nodes of Ranvier and anti-GM1 antibodies are associated with AMAN phenotype [
      • Kusunoki S.
      • Willison H.J.
      • Jacobs B.C.
      Antiglycolipid antibodies in Guillain-Barre and Fisher syndromes: discovery, current status and future perspective.
      ].
      In Hong Kong, antiganglioside antibodies were made available to all public hospitals from 2015 onward, after which a significant increase in anti-ganglioside antibodies testing rate was observed. However, only a limited panel of antiganglioside antibodies (anti-GD1b, anti-GQ1b, anti-GM1) were offered. Whilst this may explain the lower positive yield in our study, it should also be noted that the positive yield antiganglioside antibodies could be lower amongst paediatric GBS compared to adult GBS [
      • Schessl J.
      • Koga M.
      • Funakoshi K.
      • Kirschner J.
      • Muellges W.
      • Weishaupt A.
      • et al.
      Prospective study on anti-ganglioside antibodies in childhood Guillain-Barre syndrome.
      ].
      MRI spine with contrast has also become increasingly available in the past decade. Although MRI spine with contrast showing cauda equina enhancement is not necessary in diagnosing GBS, it is especially useful in excluding transverse myelitis, in supporting the diagnosis of GBS in the setting of initially normal conduction study findings, and in cases with atypical presentation such as MFS/GBS overlapping syndrome [
      • Wakerley B.R.
      • Uncini A.
      • Yuki N.
      • GBS-Classification-Group
      Guillain-Barre and Miller Fisher syndromes–new diagnostic classification.
      ]. In cases with pharyngeal-cervical-brachial weakness and suspected Bickerstaff encephalitis, extended imaging with MRI brain will have diagnostic value.
      For the prediction of respiratory risk, documentation of the conduction block with the use of proximal/distal CMAP of studied motor nerves and the serial monitoring of the forced vital capacity will be helpful as both were found to be associated with increased risk of need for ventilation support [
      • Durand M.C.
      • Porcher R.
      • Orlikowski D.
      • Aboab J.
      • Devaux C.
      • Clair B.
      • et al.
      Clinical and electrophysiological predictors of respiratory failure in Guillain-Barre syndrome: a prospective study.
      ].
      In terms of treatment, use of intravenous immunoglobulin (IVIG) early on in the disease course is now proven to be beneficial [
      • Hughes R.A.
      • Swan A.V.
      • van Doorn P.A.
      Intravenous immunoglobulin for Guillain-Barre syndrome.
      ]. Instead of reserving it for only the severe cases, guidelines now encourage earlier empirical use of IVIG when the duration of symptom is short and/or when there is symptom progression [
      • Korinthenberg R.
      • Trollmann R.
      • Felderhoff-Muser U.
      • Bernert G.
      • Hackenberg A.
      • Hufnagel M.
      • et al.
      Diagnosis and treatment of Guillain-Barre Syndrome in childhood and adolescence: an evidence- and consensus-based guideline.
      ]. This is reflected in the changes in clinical practice in the management of GBS in our locality, with the proportion of patients with GBS being treated with IVIG surging from 29% in 2010 [
      • Ma Y.M.
      • Liu T.K.
      • Wong V.
      Guillain-Barre syndrome in southern Chinese children: 32 year experience in Hong Kong.
      ] to 93.7% in this current study. Looking forward, new modalities of treatment for the severe spectrum of GBS are emerging, with use of monoclonal antibodies i.e. eculizumab [
      • Motamed-Gorji N.
      • Matin N.
      • Tabatabaie O.
      • Pavone P.
      • Romano C.
      • Falsaperla R.
      • et al.
      Biological drugs in Guillain-Barre syndrome: an update.
      ,
      • Liu S.
      • Dong C.
      • Ubogu E.E.
      Immunotherapy of Guillain-Barre syndrome.
      ] having been explored as third-line treatment for those with suboptimal response to IVIG and plasmapheresis.

      5. Limitations of the study

      There are a few limitations to this retrospective study. Although international guidelines were generally adhered to by all the paediatric neurology units participating this study, there is no consensus on the adoption of Brighton collaboration Diagnostic Criteria on the initial reporting of the GBS subtypes. Moreover, our study period started few years before the validated Brighton collaboration Diagnostic Criteria was established, so the diagnostic certainty of each GBS subtype in this study is assigned through retrospective data collection based on the record keeping. The confirmation of the electrophysiological subtypes by our paediatric neurologists adopted both the narrative approach together with the stated criteria as reference. However, as more than one references [
      • Kasinathan A.
      • Saini A.G.
      • Suthar R.
      • Saini L.
      • Sahu J.K.
      • Singhi P.
      • et al.
      Comparison of five different electrophysiological criteria for childhood Guillain Barre syndrome.
      ] for electrophysiological subtyping may be considered for patients in different hospitals during the study period, the current electrophysiological subtyping is not based on a single cut off criteria. Data on the GBS disability score (Hughes functional grading scales) was not included in the analysis of current study as this scale was not used for some of the patients in our study. There is a need to re-emphasize the use of GBS disability scores to document the outcome of paediatric patients with GBS on top of our current documentation using functional motor performance. Anti-ganglioside antibodies diagnostic tests were not routinely available to all public hospitals within the HA before 2015, which may affect the estimation of its testing rate at the early years of the study.

      6. Conclusion

      Our retrospective territory wide study over 10 years provided detailed estimated incidence rate, clinical presentation, healthcare utilization and motor outcome of different subtypes of paediatric GBS in Hong Kong. Our study showed that the most common paediatric GBS subtype is AIDP, followed by MFS and axonal type of GBS. Compared with other subtypes, patients with axonal types of GBS had the highest rate of PICU admission and ventilator use, and the longest LOS, so the highest healthcare burden. We also found a good overall prognosis and motor recovery for all GBS subtypes with immunomodulating therapy. Compared to neighbouring East Asian regions, we found a highest proportion of paediatric patients with MFS in our region, with half of the MFS group had MFS/GBS overlapping syndrome.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      We would like to thank Ms. Rachel BY Lee for her professional English editing support. We would also like to thank Mr. Wilfred Wong and Mr. Michael Yu for their help to identify all the paediatric GBS patients from the HA CDARS system of the stated study period, and Mr. Wilfred Wong for his advice on the statistical analysis. We also like to thank the Chief of Services of the Paediatric Departments of all the participating hospitals in supporting their Paediatric Neurology Teams in the participation of this paediatric GBS study to make this study successful.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Author contribution

      ATGC was responsible for manuscript preparation (original draft, revision), data collection, curation and analysis. RWKC, MLYY, ACLY, AKFL, SWYL, AMCL, STHF, KHM, CWLL were responsible for patient data collection and curation, manuscript review. MMY, CHK, KWT, CKM, SMT, EKCY, EF, SPW, KLK were responsible for data curation (supervisory), manuscript review. SHSC was responsible for study conceptualization and design, research team invitation, data collection, manuscript preparation (original draft, revision), supervision, project administration.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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