Guillain-Barre syndrome (GBS) is an acute post-infectious immune-mediated peripheral neuropathy with a variable clinical course and outcome. Identifying patients with poor outcome in the early stage might provide an opportunity for more effective and aggressive treatment and better prognosis. We aimed to determine early clinical factors associated with poor functional outcome in GBS.
Forty-seven patients with GBS were enrolled and followed up at Dongguk University Ilsan Hospital during May 2005– June 2015. Data collected retrospectively were used to identify risk factors of being unable to walk at 6 months. Potential predictors of poor outcome at 6 months were analyzed.
Older age (≥55 years, P=0.002), low Medical Research Council (MRC) scale sum score (P=0.001), high GBS disability score (P=0.042), respiratory failure (P=0.042), severe weakness unable to walk (P=0.005), or voiding difficulty (P=0.001) at hospital admission were associated with being unable to walk at 6 months. Preceding infections, subtype of acute motor axonal neuropathy (AMAN), and existence of GM1 antibody were not associated with poor prognosis in our study.
Our study confirmed that the poor outcome is associated with older age, severity indicated by GBS disability score or MRC sum score, and ventilator support or walking disability at admission, but was not consistent with the previous literatures reporting preceding infection, AMAN subtype, and GM1 antibody as poor prognostic factors. Our study identified initial voiding difficulty as a novel poor prognostic factor, which implicates severe involvement of sacral roots.
Guillain-Barre syndrome (GBS) is an acute post-infectious immune-mediated peripheral neuropathy with a variable clinical course and outcome. Although the etiology of GBS is not totally understood, infection-induced aberrant immune response including molecular mimicry and formation of cross reacting antibodies has been implicated in the immunopathogenesis of GBS [1,2]. Approximately 70% of cases of GBS occur 1–3 weeks after an acute infectious process commonly due to Campylobacter jejuni (diarrhea), Mycoplasma pneumonia, Haemophilus influenzae, cyto-megalovirus, Epstein-Barr virus and, influenza [1,2]. Global annual incidence is reported to be 0.81–1.89 cases per 100,000 per year [1,3]. Men are commonly affected by approximately 1.5 times than women [1,2].
In general, the diagnosis is based on clinical manifestations as acute onset areflexic quadriparesis with or without bulbar palsy and sometimes leading to weakness of respiratory muscles thus requiring mechanical ventilator support. Clinical features reach a maximum severity within 2–4 weeks . The diagnosis of GBS is clinical but may be supported by electrophysiological findings of polyneuropathy or elevated protein with normal cellularity in the cerebrospinal fluid (CSF) .
Although intravenous immunoglobulin or plasma exchange is beneficial in patients who are severely affected [1,4], one-third recover incompletely . GBS frequently remains a severe disease, as 25% of patients require artificial ventilation during a period of days to months, 20% of patients are still unable to walk after 6 months, and 3%–10% of patients die [1,3,6]. Identifying early patients with poor outcome might provide an opportunity for effective or additional treatment in early stage when nerve dysfunction is potentially reversible. To identify patients with potential poor outcome, who are eligible for aggressive additional treatment, we investigated early clinical factors associated with prognosis in GBS.
MATERIALS AND METHODS
This study included forty-seven patients with a confirmed clinical and laboratory diagnosis of GBS who were recruited over a period of May 2005–June 2015. The diagnosis of GBS was made based on the criteria suggested by Asbury and Cornblath . All the included patients had no history of disease in the corticospinal or urogenital tract which may cause limb weakness or urinary difficulty. However, 2 patients with diabetes mellitus who had no previous sensory symptoms suggesting polyneuropathy were included.
The clinical characteristics included age, gender, antecedent infections, days from onset, cranial nerve involvement, sensory deficit, weakness, voiding difficulty, and clinical severity with GBS disability scale and Medical Research Council (MRC) scale sum score. The MRC sum score is defined as the sum of MRC scores of 6 different muscles measured bilaterally, which results in a sum score ranging from (tetraplegic) to 60 (normal) . The GBS disability score is a widely accepted scale for assessing the functional status of patients with GBS, ranging from 0 (normal) to 6 (death) . Patients were classified according to electrophysiological findings as acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor sensory axonal neuropathy, or Miller Fisher syndrome [10–12].
Poor outcome was defined as the inability to walk unaided 10 meters across an open space (GBS disability score of 3 or higher). Data collected retrospectively were used to identify potential predictors of poor outcome at 6 months or 1 year by chart review and outpatient survey.
Statistical analysis was done using IBM SPSS ver. 20.0. (IBM Co., Armonk, NY, USA). Comparisons were performed using the Student t-test or Mann-Whitney test for continuous variables and Fisher’s exact test or chi-square test for nominal-level variables. Multiple logistic regression analysis was used to assess early predictors of poor outcome. Odds ratios were used to express the strength of prognostic effects. P<0.05 was considered as significant.
This study included forty-seven GBS patients. Mean age was 47 years and median days from onset to admission were 5 days (Table 1). In this cohort, the primary endpoint was determined as walking ability at 6 months since the outcome profiles were not significantly different between 6 months and 1 year. Twenty-five Patients (53%) were unable to walk at admission, while 11 patients (23.4%) and 9 patients (19.1%) were unable to walk at 6 months and 1 year, respectively.
Based on electrodiagnostic criteria in about 2 weeks from onset, patients were classified into each subtypes and AIDP was the commonest subtype of GBS (Table 1).
Gender, cranial nerve deficit (bulbar and facial weakness), sensory deficit, time to nadir, treatment type (intravenous immunoglobulin or plasma exchange), GBS subtype, autoantibody, previous infection such as diarrhea or upper respiratory infection, abnormal CSF protein, and abnormal creatine kinase were not significantly related with poor prognosis in our study. In univariate analysis, several early predictors of poor outcome were identified: old age (≥55 years), initial low MRC sum score, initial waking difficulty, initial respiratory failure, and initial voiding difficulty (Table 2). After adjusting for age, these findings for predictors of poor outcome did not change.
The variation in clinical severity and outcome in patients with GBS obstructs the decision of optimal treatment and would reduce the statistical power of treatment trials. Our study revealed a prognostic model which could identify patients with potential poor outcome and might be used for the optimizing treatments. The main predictors of being unable to walk independently at 6 months or 1 year were old age, low MRC sum score, walking difficulty, respiratory difficulty, and voiding difficulty at the initial presentation.
Our study confirms that the poor outcome is associated with older age [2,3] and initial severity (weakness in limbs or respiration) [2,3,13], but is not consistent with the previous studies suggesting preceding infection [2,3], AMAN subtype , and GM1 antibody  as poor prognostic factors.
Initial voiding difficulty was proved as a novel poor prognostic factor in our study, implicating severe involvement of sacral roots which is associated with difficulty in urination and walking. Patients with initial voiding difficulty presented significantly severe weakness in the initial MRC sum score (32.4 versus 48.9 in groups with normal voiding, P<0.001) or initial GBS disability scale (4.1 versus 1.8 in groups with normal voiding, P<0.001). This also supports a shared mechanism of urination and walking. The nerve roots from L4-S4 join in the sacral plexus which coalesce into the sciatic nerve (L4 to S3), which travels caudally. Voiding dysfunction is associated with S2-S4 nerve roots which provide the primary autonomic and somatic innervation to the bladder, urethra, and pelvic floor. The GBS attacks of nerve roots related with the sciatic nerve could cause both voiding difficulty (S2-S3) and gait disturbance (L4-S1) simultaneously. In this reason, initial voiding difficulty implicates severe damage in nerve roots related with sciatic nerve.
Our study had several limitations. First, this prognostic model only predicts the ability to walk independently, and not the full ordinal GBS disability scores, though this walking ability measure is usually chosen by most therapeutic trials in GBS. Second, some cautions are needed in the clinical application of poor predictors because these factors were derived from relatively small number of patients, while these prognostic factors were consistent with the previous literatures studying larger populations.
This study suggests that initial voiding difficulty could be added to the poor prognostic factors and guide to decide more aggressive treatments. There are many studies establishing GBS scoring scales such as mEGOS (modified Erasmus GBS Outcome Score) or EGRIS (Erasmus GBS respiratory Insufficiency Score), and collaborative efforts by IGOS (International GBS Outcome Study). We wish that modified GBS scoring systems would include voiding difficulty. Evaluating whether or not a patient with GBS has poor outcome in early stage may improve long-term prognosis by more aggressive and active therapeutic interventions.