Guillain-Barré syndrome - albumin - neutrophil-lymphocyte ratio - platelet-lymphocute
ratio
síndrome de Guillain-Barré - albumina - relação neutrófilo/linfócito - relação linfócito-plaquetas
Guillain-Barré syndrome (GBS) is an acute immune-mediated inflammatory disease of
the peripheral nervous system. It is characterized by acute onset and rapid progressive
symmetric weakness and areflexia[1]. Human and animal studies have provided convincing evidence that GBS, at least in
some cases, is caused by an infection-induced aberrant immune response that damages
peripheral nerves[1],[2]. Molecular mimicry of pathogen-borne antigens, leading to the generation of cross-reactive
antibodies that also target gangliosides, is part of the pathogenesis of GBS, and
the nature of the antecedent infection and specificity of such antibodies partly determine
the subtype and severity of the syndrome[3]. The most common type of GBS is acute inflammatory demyelinating polyradiculoneuropathy
(AIDP). In AIDP, the immune response damages myelin, which is the covering that protects
axons and promotes the efficient transmission of nerve impulses. In acute motor axonal
neuropathy (AMAN), only the axons of motor neurons are damaged, whereas the axons
of sensory neurons are also damaged in acute motor sensory axonal neuropathy (AMSAN).
Neurological disorders can stimulate the production of a high level of inflammation,
resulting in an increase or decrease in acute phase reactans[4]. Some acute phase proteins, such as albumin, decrease during inflammation, and albumin
levels may be related to the course and outcome in GBS[4]. The neutrophil-to-lymphocyte ratio (NLR) is calculated from the white blood cell
count and is a novel prognostic and inflammatory marker in patients with neurological
diseases[5],[6]. The platelet-to-lymphocyte ratio (PLR) is a new biomarker of inflammation[7]. The PLR is thought to be a sensitive marker and to be a prognostic factor in many
malignancies[8]. Changes in the levels of acute phase reactants, such as albumin, the NLR, and the
PLR have not been well studied in patients with GBS. In this study, we aimed to evaluate
the albumin level, NLR, and PLR in patients with GBS. We also evaluated the association
between disease prognosis and the albumin level, NLR, and PLR.
METHODS
This study was conducted retrospectively in the Neurology Department of Dicle University,
Diyarbakir, Turkey. The data for the study were extracted from the medical records
of patients who attended the hospital between January 2011 and January 2016. The study
included 62 patients with GBS. Demographics, age, sex, clinical features, electrophysiology,
subtype, and treatment-related outcomes were assessed. A diagnosis of GBS was based
on the criteria of the Brighton Collaboration GBS Working Group[9]. The strength of the proximal and distal muscles of the upper and lower limbs was
classified as 0–5, according to the criteria of the Medical Research Council. Each
patient was evaluated according to Hughes et al.’s disability score at the time of
hospital admission and discharge[10].
All the patients underwent physical and neurological examinations, liver and kidney
function tests, and lipid profiling. In all cases, a complete blood count was also
obtained, and electrolyte levels were tested. Electromyography (Nihon-Kohden) was
performed in each patient. The classification of the patients as having an axonal
or demyelinating subtype was based on the electrodiagnostic criteria of Hadden et
al.[11], and an AMSAN diagnosis was based on the criteria of Rees et al.[12].
Exclusion criteria included severe heart failure, autoimmune disease, diabetes mellitus,
malignant hypertension, Cushing’s syndrome, central nervous system vasculitis, congenital
vascular disease, trauma, dissection, thyroid and kidney dysfunction, liver failure,
and local and systemic infection.
Venous blood samples were collected when the patient initially presented to the emergency
department or intensive neurology care unit (pretreatment-1) and 96–120 h after the
first observation (post-treatment-2). The serum albumin levels were measured using
a Beckman Coulter CX9 (Beckman Coulter, Inc., Brea, CA) chemistry analyzer. At our
hospital, a serum albumin range of 3.5–5.5 gr/dL is considered normal. Hematologic
indices were measured using an automated hematology analyzer system (Abbott Cell-Dyn
3700; Abbott Laboratory, Abbott Park, ILs). All subsequent analyses were based on
absolute cell counts. The baseline NLR was measured by dividing the neutrophil count
by the lymphocyte count, and the PLR was measured by dividing the platelet count by
the lymphocyte count.
Statistical analysis
The statistical analyses were performed using SPSS software, version 20.0 (SPSS Inc.,
Chicago, IL). Continuous data are presented as mean ± standard deviation (SD). Between-group
differences in continuous variables were determined by a Student’s t test or the Mann–Whitney U test for variables, with or without a normal distribution, respectively. To test
whether the data showed a normal distribution, the Kolmogorov–Smirnov test was used.
Categorical variables were summarized as percentages and compared with a one-way ANOVA
test. Relationships between the variables were examined by calculating Pearson’s and
Spearman’s correlation coefficients. To find independent associates of the Hughes’
score, variables with a p value of ≤ 0.05 in a bivariate correlation analysis and
univariate analysis were selected for multiple linear regression analyses. The cut-off
values and corresponding sensitivity and specificity values for the prediction of
the AIDP based on the serum albumin level, NLR, and PLR were estimated by receiving
operator characteristic (ROC) curve analysis. A p value of < 0.05 was accepted as
the threshold for determining statistical significance.
RESULTS
Sixty-two patients were enrolled in this study. Of the patients with GBS, 36 were
men (58.1%), and 26 were women (41.9%). The mean age of the patient group was 48.0
± 19.84 (17–89). Four of the patients died. Intravenous immunoglobulin was administered
to all the patients.
The mean serum albumin levels were 3.58 ± 0.55 (2–4.6) at the first observation (albumin-1),
and 30.6% of the patients (n = 19) had hypoalbuminemia. The mean serum albumin levels
after 96–120 h (albumin-2) were 3.32 ± 0.59 (1.5–4.5), and 54.8% of the patients (n
= 34) had hypoalbuminemia. Three patients were treated with 100 ml of 25% albumin
via intravenous infusion. The albumin-1 (baseline/pretreatment) levels were significantly
lower than the albumin-2 (post-treatment) levels (p < 0.05). The albumin-1 and -2
levels were negatively correlated with the Hughes’ scores (admission/discharge). Thirty-five
of the patients had AIDP, 12 had AMAN, and 15 had AMSAN. The [Table] shows the comparisons of the demographic features and laboratory findings among
the subgroups. In the patients with AIDP, the neutrophil-1 and -2 levels (pre- and
post-treatment levels, respectively) and NLR-1 (pretreatment) were significantly higher
than those of the patients with AMAN and AMSAN. (p < 0.05). The pretreatment PLR (PLR-1)
was significantly higher in the patients with AIDP when compared with those with AMAN
(p < 0.05) The neutrophil-1 and -2 and lymphocyte-1 (pretreatment) and -2 (post-treatment)
levels were significantly higher in the patients with AIDP, as compared to those of
the patients with AMSAN (p < 0.05). When the results of the pre- and post-treatment
measurements were compared, there were no correlations between the Hughes’ scores
(admission/discharge) and neutrophil-1 and -2, lymphocyte-1 and -2, platelet-1 and
-2, NLR-1- and 2, and PLR-1 (p > 0.05).
Table
The demographic and laboratory characteristics of the patients with Guillain-Barré
syndrome (GBS).
|
Variables
|
AIDP (n = 35)
|
AMAN (n = 12)
|
AMSAM (n = 15)
|
p
|
p1
|
p2
|
p3
|
|
Age
|
50.23 ± 20.63
|
41.08 ± 18.24
|
48.33 ± 19.17
|
0.393
|
0.360
|
0.949
|
0.616
|
|
Hughes’ score
|
3.29 ± 0.96
|
3.25 ± 0.75
|
3.47 ± 1.06
|
0.792
|
0.993
|
0.811
|
0.826
|
|
Albumin-1 (gr/dl)
|
3.52 ± 0.61
|
3.70 ± 0.48
|
3.63 ± 0.50
|
0.597
|
0.613
|
0.806
|
.946
|
|
Neutrophil-1 (103/mL)
|
9.07 ± 4.53
|
5.36 ± 2.23
|
5.30 ± 2.00
|
0.001
|
0.011
|
0.005
|
0.999
|
|
Lymphocyte-1 (103/mL)
|
1.910 ± 0.740
|
2.361 ± 0.498
|
2.570 ± 1.160
|
0.028
|
0.239
|
0.032
|
0.792
|
|
Platelet-1 (103/mL)
|
289.57 ± 82.52
|
233.00 ± 84.28
|
288.40 ± 87.67
|
0.124
|
0.119
|
0.999
|
0.213
|
|
NLR-1
|
5.78 ± 5.23
|
2.36 ± 1.20
|
2.15 ± 0.54
|
0.004
|
0.035
|
0.013
|
0.990
|
|
PLR-1
|
177.48 ± 104.97
|
98.58 ± 32.22
|
124.91 ± 46.70
|
0.012
|
0.018
|
0.115
|
0.699
|
|
Hughes’score*
|
3.37 ± 1.33
|
2.92 ± 0.67
|
2.87 ± 1.36
|
0.321
|
0.521
|
0.391
|
0.994
|
|
Albumin-2 (gr/dl)
|
3.18 ± 0.64
|
3.471 ± 0.526
|
3.52 ± 0.47
|
0.105
|
0.302
|
0.142
|
0.969
|
|
Neutrophil-2 (103/mL)
|
7.60 ± 5.10
|
4.31 ± 1.30
|
4.45 ± 1.93
|
0.011
|
0.046
|
0.037
|
0.996
|
|
Lymphocyte-2 (103/mL)
|
1.81 ± 0.81
|
2.14 ± 0.74
|
2.44 ± 0.87
|
0.046
|
0.460
|
0.041
|
0.611
|
|
Platelet-2 (103/mL)
|
252.88 ± 94.50
|
232.50 ± 73.34
|
262.53 ± 55.50
|
0.638
|
0.744
|
0.925
|
0.621
|
|
NLR-2
|
6.66 ± 9.93
|
2.34 ± 1.31
|
1.90 ± 0.73
|
0.070
|
0.210
|
0.112
|
0.988
|
|
PLR-2
|
173.09 ± 109.83
|
120.65 ± 64.22
|
117.20 ± 40.13
|
0.070
|
0.199
|
0.118
|
0.995
|
Data are presented as mean standard deviation. NLR: neutrophil/lymphocyte ratio; PLR:
platelet/lymphocyte ratio; AIDP: acute inflammatory demyelinating polyradiculoneuropathy;
AMAN: acute motor axonal neuropathy; AMSAN: acute motor sensory axonal neuropathy;*after
discharge; p: ANOVA test significance value. p1: significance between AIDP and AMAN.
p2: significance between AIDP and AMSAN. p3: significance between AMAN and AMSAN.
A cut-off NLR-1 of 3.275 predicted AIDP, with 83% sensitivity and 93% specificity
(ROC area under the curve [AUC] of 0.928, 95% CI, 0.860–0.995, p < 0.001). A cut-off
PLR-1 of 121.8 predicted AIDP, with 74% sensitivity and 70% specificity (ROC AUC of
0.761, 95% conficende interval [CI] 0.638–0.883, p < 0.001; [Figure])
Figure The Receiving Operator Characteristic (ROC) curve analysis of NLR and PLR for prediction
Guillain-Barre syndrome (GBS).NLR: neutrophil/lymphocyte ratio; PLR: platelet/lymphocyte
ratio.
DISCUSSION
This study demonstrated that serum albumin levels decreased in GBS patients in the
subacute period and that there was a negative correlation between albumin levels and
Hughes’ scores (admission/discharge). The NLR and PLR increased in AIDP during the
acute period. To the best of our knowledge, this is the first clinical study to evaluate
the association of GBS subtypes with serum albumin levels and the NLR and PLR.
The serum albumin concentration depends on various factors, such as the synthesis,
rate of degradation, distribution, and exogenous loss of albumin, as well as nutritional
intake and colloid oncotic pressure changes. The presence of systemic inflammation
affects the synthesis of albumin[13],[14],[15],[16]. Albumin is a late-reacting negative acute-phase protein[17].
The present study demonstrated the following: hypoalbuminemia is common in patients
with GBS, it decreases after the subacute period, and there is a negative correlation
between albumin levels and GBS disability. The mean pre- and post-treatment serum
albumin levels of the AIDP group were lower than those of the other groups. Such decreases
in mean albumin levels in AIDP are thought to be mainly due to inflammation, hemodilution,
or an acute phase response.
Pathophysiological changes in GBS depend upon the subtype. Immune reactions directed
against epitopes in Schwann cell surface membrane or myelin can cause AIDP[18]. Cellular and humoral immune responses participate in these pathophysiological processes,
with infiltration of epineural and endoneural small vessels by lymphocytes and monocytes
causing segmental myelin degeneration throughout the nerve[19]. In demyelination forms of GBS, Berciano et al. showed that spinal root sections
had extensive and almost pure macrophage-associated demyelination, with the occasional
presence of T lymphocytes and neutrophil leukocytes[20]. On the other hand, immune reactions against epitopes in the axonal membrane cause
AMAN and AMSAN[21]. In these variants of GBS, the axon is affected, without an inflammatory response[21]. The primary immune process is directed at the nodes of Ranvier, leading to functional
axonal involvement with conduction block caused by paranodal myelin detachment, node
lengthening, sodium channel dysfunction, and altered ion and water homeostasis[22]. These pathophysiological processes may be rapidly reversed in some patients or
it may progress to axonal degeneration. Acute motor axonal neuropathy involves the
motor nerves of the ventral roots, peripheral nerves, and preterminal intramuscular
motor twigs[23]. In AMSAN, sensory nerves are also affected. These pathophysiological processes
may increase the importance of lymphocytes and neutrophils as diagnostic features
of GBS subtypes. In this study, neutrophilia was detected in AIDP.
According to some studies, the NLR and PLR are new biomarkers of the presence of inflammation[24],[25]. Alan et al.[24] showed that the NLR and PLR might be associated with the presence and severity of
Behçet’s syndrome. Kokcu et al.[26] reported that the NLR, platelet count, and PLR were elevated in late stages of ovarian
cancer. They also claimed that the PLR was an independent prognostic factor of the
stage of epithelial ovarian cancer. In the present study, NLR-1 was a statistically
significant biomarker in AIDP, and PLR-1 was a statistically significant biomarker
in AIDP but not AMAN. When the results of the pretreatment and post-treatment measurements
were compared, there were no correlations between the Hughes’ scores (admission/discharge)
and neutrophil-1 and -2, lymphocyte-1 and -2, platelet-1 and -2, NLR-1 and -2, and
PLR-1. The data demonstrated that a pretreatment NLR value of 3.275 predicted the
presence of the acute period of AIDP with 83% sensitivity and 93% specificity. A pretreatment
PLR of 121.8 predicted the presence of the acute period of AIDP, with 74% sensitivity
and 70% specificity.
In conclusion, decreased albumin levels may exacerbate GBS-related disability. Decreased
NLRs and PLRs may indicate the presence of AIDP, but they are not associated with
the severity of the disease. The NLR may be a useful diagnostic marker of AIDP. Larger
prospective studies are needed to support the findings of the present study.
