Guillain-Barré syndrome (GBS) is the most common immune-mediated polyradiculoneuropathy and it is also the most commonly reported severe adverse event following immunization in adults. To evaluate the results of clinical and laboratory features of GBS after vaccination in Korea, we analyzed the claims-based data from 2002 to 2014 using materials collected for the Advisory Committee Vaccination Injury Compensation (ACVIC) meeting including, clinical features, nerve conduction studies (NCSs), cerebrospinal fluid (CSF) profiles, treatment, and outcomes. Forty-eight compensated GBS cases (median age, 15 years; interquartile range [IQR], 13–51; male:female ratio, 1:1) of 68 suspected GBS were found following immunization and all of them with influenza immunizations with either monovalent (n = 35) or trivalent (n = 13). Among them, 30 cases fulfilled the Brighton criteria level 1–3 (62.5%). The median duration between the onset of symptoms to nadir, duration of the nadir, and total admission period were 3 (IQR, 2–7 days), 2 (IQR, 1–5 days), and 14 (IQR, 6–33 days) days, respectively. The most frequently reported symptom was quadriparesis which was present in 36 cases (75%) at nadir. CSF examination revealed albuminocytologic dissociation in 25.0% and NCS was abnormal in 61.8%. After treatment, most of them showed improvement. Clinical features were similar to typical post-infectious GBS and there were both demyelinating and axonal forms suggesting heterogeneous pathogenic mechanism. In order to improve the diagnostic certainty of post-vaccination GBS, careful documentation of clinical features and timely diagnostic work-up with follow-up studies are needed.
Guillain-Barré syndrome (GBS) is an acute or subacute peripheral polyneuropathy, which is accompanied by symmetric flaccid paralysis of the extremities, sensory abnormalities, and cranial nerve palsy. Although the pathogenesis of the GBS has not been clearly elucidated, recent immunological evidence has supported a mechanism of autoimmune damage (
Although GBS is the most common severe AEFI in adults (
Although there have also been similar local studies (
As a part of the National Immunization Program (NIP), the Advisory Committee Vaccination Injury Compensation (ACVIC) has been operating since 1995 to provide compensation for AEFI (
Demographic characteristics such as age and sex, underlying diseases, previous infection status, as well as CSF, nerve conduction studies (NCSs), and magnetic resonance imaging (MRI) test results, treatment methods, and prognosis, were verified using the epidemiological data collected for the vaccination compensation committee. Neurological test findings included motor weakness, sensory symptoms, cranial nerve involvement, ataxia, deep tendon reflex (DTR), autonomic dysfunction, and mechanical ventilation were analyzed at the first hospital visit (entry) and when clinical symptoms were most severe (nadir). Motor weakness was assessed based on the GBS disability score (GDS), and the time of the highest score on GDS was defined as the nadir.
The date of symptom presentation was defined as the time at which motor weakness in the extremities or cranial-nerve-innervated muscle occurred, or sensory abnormalities presented bilaterally. On this basis, the time from vaccination to the onset of symptoms, time from the onset of symptoms to nadir, the time from nadir to the start of recovery, and the time from the onset of symptoms to the first CSF and NCS, were all measured in days. The time of start of recovery refers to the time when motor weakness improvement or GDS score changes were first detected. Cases were divided into 2 groups according to age; young age group (≤ 19 years) and adult group (≥ 20 years). Outcome at discharge was classified into 3 status: full recovery, recovered with neurologic sequelae, and death according to whether accompanied by neurological symptoms.
Results of the NCS were classified as normal and abnormal. And abnormal NCS parameters were analyzed. Cases where CSF and NCS results could not be verified were treated as cases with missing values. All cases were classified for certainty of diagnosis from level 1 to 4, according to the Brighton criteria (
A definition of various parameters was presented. 1) Brighton criteria: patients were classified between level 1 (highest certainty of diagnosis) and 4 (lowest certainty of diagnosis) according to 7 criteria; bilateral flaccid paralysis of the extremities, abnormal DTR in extremities with paralysis, monophasic progression within 12 hours to 28 days of symptoms, < 50 cells/µL on CSF analysis, abnormally high protein concentration in CSF, subtype consistent with GBS on NCS, and a lack of other causes for weakness (
Statistical analysis was performed using SPSS statistics software, version 19.0 (SPSS Inc., Chicago, IL, USA). Categorical variables were presented as percentages, and continuous variables were presented as the mean and standard deviation (SD), or as the median and interquartile range (IQR) when they did not follow a normal distribution. The Mann-Whitney test and the χ2 test or Fisher's exact test for non-normal distributions were used to compare the size of continuous variables and the distribution of categorical variables between groups, respectively. A logistic regression analysis was used to verify the odds ratios (ORs) for categorical variables. Two-tailed tests were used and a
Since the data for this study were collected in accordance with Article 2 (Scope of Human Research), Section 2, Clause 1 of the Enforcement Rule of Biosafety and Ethics Act, it did not require separate approval by Institutional Review Board.
Basic characteristics are displayed in
Demography | No. of patients (%) |
---|---|
Gender | |
Male | 24 (50.0) |
Female | 24 (50.0) |
Age, yr | |
Median (IQR) | 15 (13–51) |
0–19 | 32 (66.6) |
20–59 | 7 (14.6) |
≥ 60 | 9 (18.8) |
Brighton criteria | |
Level 1 | 9 (18.8) |
Level 2 | 20 (41.7) |
Level 3 | 1 (2.1) |
Level 4 | 18 (37.4) |
History of disease | |
Diabetes mellitus | 2 (4.2) |
Hypertension | 4 (8.4) |
Cardiopulmonary disease* | 7 (14.6) |
Malignancy | 1 (2.1) |
Antecedent infection | |
Upper respiratory infection | 5 (10.4) |
GI tract infection | 1 (2.1) |
Tsutsugamushi | 1 (2.1) |
History of vaccination | |
Influenza (monovalent/trivalent) | 48 (35/13) |
Vaccination other than influenza | 0 |
Diagnostic test | |
CSF | 40 (83.3) |
NCS | 42 (87.5) |
MRI | 38 (79.2) |
Treatment | |
IVIG × 1 | 25 (52.0) |
IVIG × 2 | 1 (2.1) |
Steroid | 5 (10.4) |
IVIG + steroid or PE | 8 (16.7) |
No treatment | 9 (18.8) |
Symptom fluctuations | |
Monophasic | 39 (81.3) |
Treatment related fluctuation | 9 (18.7) |
Outcome at the discharge | |
Full recovery | 8 (16.8) |
Recovered with neurologic sequelae | 39 (81.1) |
Death | 1 (2.1) |
GBS = Guillain-Barré syndrome, IQR = interquartile range, GI = gastrointestinal, CSF = cerebrospinal fluid, NCS = nerve conduction study, MRI = magnetic resonance imaging, IVIG = intravenous immunoglobulin, PE = plasma exchange.
*Includes asthma, tuberculosis, and angina.
The times from vaccination to onset of symptoms are shown in
The relationship between the number of GBS cases and the interval between vaccination and the onset of symptoms. Majority (97.9%) of cases developed symptoms within 3 weeks after vaccination. Particularly, more than half of cases (54.2%) occurred were within 2 days after vaccination.
GBS = Guillain-Barré syndrome.
The time from onset of symptoms to nadir was 3 days (IQR, 2–7 days), from nadir to start of recovery was 2 days (IQR, 1–5 days), and the total duration of admission was 14 days (IQR, 6–33 days). Comparing clinical progression between the 0–19 years old group (n = 32) and the ≥ 20 years old group (n = 16), there was a significant difference between the groups for time from vaccination to onset of symptoms (0–19 years: 1 day, IQR, 1–3 days; ≥ 20 years: 10 days, IQR, 3–15 days;
GBS progression according to age groups. Young age group (0–19) showed more rapid recovery than adult age group (≥ 20).
GBS = Guillain-Barré syndrome.
The neurological symptom patterns were analyzed at both the entry and nadir time points (
Neurologic symptoms | At entry | At nadir | |
---|---|---|---|
GDS | |||
0: a healthy state | 0 (0) | 0 (0) | |
1: minor symptoms and capable of running | 11 (22.9) | 6 (12.5) | |
2: able to walk 10 m without assist, unable to run | 16 (33.3) | 6 (12.5) | |
3: able to walk 10 m with help | 19 (39.6) | 11 (22.9) | |
4: bedridden or chair bound | 2 (4.2) | 19 (39.6) | |
5: requiring assisted ventilation | 0 (0) | 6 (12.5) | |
6: dead | 0 (0) | 0 (0) | |
Motor | |||
Normal strength | 8 (16.7) | 3 (6.3) | |
Unilateral limb weakness | 7 (14.6) | 2 (4.2) | |
Asymmetrical limb weakness | 4 (8.3) | 2 (4.2) | |
Weakness in bilateral lower limbs | 17 (35.4) | 16 (33.3) | |
Weakness in bilateral upper limbs | 2 (4.2) | 1 (2.1) | |
Weakness in bilateral upper and lower limbs | 10 (20.8) | 24 (49.9) | |
Sensory | |||
Normal | 18 (37.5) | 14 (29.2) | |
Sensory deficit | 7 (14.6) | 5 (10.4) | |
Pain | 23 (47.9) | 26 (54.2) | |
Both sensory deficit and pain | 0 (0) | 3 (6.2) | |
Cranial nerve involvement | |||
Facial muscle weakness | 6 (12.5) | 9 (18.7) | |
Oropharyngeal weakness | 7 (14.6) | 9 (18.7) | |
Extraocular muscle weakness | 3 (6.2) | 3 (6.2) | |
Respiratory disturbance | 1 (2.1) | 13 (27.0) | |
Ventilator support | 0 (0) | 7 (14.6) | |
Ataxia | |||
Absent | 46 (95.8) | 46 (95.8) | |
Present | 2 (4.2) | 2 (4.2) | |
DTR | |||
Normal | 18 (37.5) | 16 (33.3) | |
Decreased | 27 (56.2) | 23 (47.9) | |
Absent | 3 (6.3) | 9 (18.8) | |
Autonomic dysfunction | |||
BP, HR fluctuation | 0 (0) | 4 (8.3) | |
Urogenital dysfunction | 1 (2.1) | 5 (10.4) | |
GI dysfunction | 2 (4.2) | 3 (6.2) | |
Pupillary abnormality | 0 (0) | 1 (2.1) |
Values are presented as number (%).
GDS = Guillain-Barré syndrome disability score, DTR = deep tendon reflex, BP = blood pressure, HR = heart rate, GI = gastrointestinal.
Missing values were excluded from the analysis of the CSF and NCS (
Diagnostic study (No. of cases) | No. of patients (%) |
---|---|
CSF examination | |
WBC count (n = 36), cells/µL | |
< 5 | 33 (91.6) |
5–50 | 4 (5.6) |
> 50 | 2 (2.8) |
Protein concentration (n = 40) | |
Median (IQR) | 33 (22–60) |
Abnormal value | 12 (30.0) |
Normal value | 28 (70.0) |
NCS | |
NCS subtype (n = 42) | |
Normal | 16 (38.1) |
Abnormal | 26 (61.9) |
Abnormal NCS parameters (n = 32) | |
Abnormal F-wave response | 12 (37.5) |
Abnormal H-reflex response | 12 (37.5) |
Prolonged terminal latency | 12 (37.5) |
Conduction block | 7 (21.9) |
Abnormal MNCV | 13 (40.6) |
Abnormal CMAP | 14 (43.8) |
Abnormal SNCV | 10 (31.3) |
Abnormal SNAP | 12 (37.5) |
Sural sparing pattern | 12 (37.5) |
Abnormal blink reflex (n = 4) | 3 (75.0) |
Abnormal brain and/or spine MRI (n = 48) | 0 (0) |
GBS = Guillain-Barré syndrome, CSF = cerebrospinal fluid, WBC = white blood cell, IQR = interquartile range, NCS = nerve conduction study, MNCV = motor nerve conduction velocity, CMAP = compound muscle action potential, SNCV = sensory nerve conduction velocity, SNAP = sensory nerve action potential, MRI = magnetic resonance imaging.
The number of cases and percentages with elevated protein concentration in CSF analysis and the timing of lumbar puncture after symptom onset. During the first week, most of CSF examinations were performed (86.8%) but albuminocytologic dissociation was found in less than 20%. In the second week, positive rate of albuminocytologic dissociation increased up to 75%.
CSF = cerebrospinal fluid.
The present study analyzed the clinical and laboratory characteristics of 48 cases of GBS that occurred after immunization between 2002 and 2014. Each case was selected based on the data of experts meeting for compensation of vaccination, ACVIC in Korea. Although some cases did not fulfill the Brighton criteria level 1–3, we regarded these cases as possible GBS because they were also reviewed thoroughly and concluded having GBS by experts meeting.
In this study, majority of the patients (66.7%) were under 20 years old, and this is believed to be the direct result of the mass immunization in schools in response to the influenza virus (H1N1v) epidemic in 2009. In almost all cases, GBS developed within 3 weeks of immunization and it is consistent with previous reports (
In addition to influenza vaccines, cases of GBS have been reported after immunization with various vaccines, including measles, mumps, and rubella (MMR), hepatitis B, diphtheria, tetanus, and pertussis (DTP) and polio (
The most important study in the diagnosis of GBS is NCS. It often shows no or only subtle abnormality in the very early stage of GBS (
Most previous study with post-vaccination GBS focused on the incidence and prevalence. However, subtypes of GBS after immunization are not well characterized. Subtypes in this study included axonal type as well as demyelinating type and this finding suggests heterogeneous pathogenesis although after exposure to the same causative triggering factor.
The main reasons for the level 4 in Brighton criteria were test results (i.e., CSF testing, NCS, and DTR) that were not compatible with diagnosis of GBS, or insufficient testing data. Comparing Brighton criteria level 1–3 groups and level 4 group, we did not find significant differences in the entire clinical course, including the time from immunization to symptoms, symptoms to the nadir, as well as the time from the nadir to the start of recovery, and total length of stay (
The Brighton criteria are used worldwide for the evaluation of GBS following immunization. In order to increase diagnostic accuracy when symptoms develop within 6 weeks of immunization and in the absence of alternative diagnoses to explain the symptoms and clear causative factors such as previous infection, vaccine-related GBS should be suspected. Detailed tests should be subsequently performed to aid early diagnosis. Due to the nature of NCS and CSF tests, follow-up testing need to be performed 1–2 weeks after the presentation of symptoms.
The authors have no potential conflicts of interest to disclose.