IVIG Treatment and Prognosis in Guillain–Barré Syndrome

There is convincing evidence that GBS at least in some patients is caused by an infection-induced aberrant immune response that damages the peripheral nerves. Four key factors were identified that control this process [1, 2, 5].

In up to 50% of patients, serum antibodies to various gangliosides present in human peripheral nerves, including GM1, GD1a, GalNAc-GD1a, and GQ1b, can be demonstrated. Other antibodies may bind to mixtures or complexes of different gangliosides instead of individual ones. Interestingly, most of these antibodies are related to defined clinical subgroups of GBS.

C. jejuni isolates from GBS patients express lipooligosaccharides (LOS) that mimic the carbohydrates of gangliosides. The type of ganglioside mimic in C. jejuni seems to determine the specificity of the anti-ganglioside antibodies and the associated variant of GBS. Antibodies in these patients usually are cross-reactive; they recognize LOS as well as gangliosides or ganglioside complexes.

GBS after Campylobacter infection in anti-GM1/GD1a/GQ1b antibody-related cases is considered to be true example of molecular mimicry-related disease.

Postmortem studies demonstrated that local complement activation occurs at the side of nerve damage. A mice model for GBS showed that some anti-ganglioside antibodies are toxic for peripheral nerves and can cause blockade of nerve transmission and paralysis of the nerve-muscle preparation. Additionally, there is destruction of the nerve terminal and perisynaptic Schwann cells [6]. Antibodies to GM1 affect the sodium channels at the nodes of Ranvier of rabbit peripheral nerves [7]. All of these effects appear to be dependent on complement activation and formation of the membrane attack complex. The neurotoxic effects of these antibodies can be inhibited by IVIG and the complement inhibitor eculizumab [8].

Less than 1:1,000 patients with a C. jejuni infection will develop GBS. Host factors may influence this susceptibility to develop GBS or the extent of nerve damage and outcome. Single nucleotide polymorphisms (SNPs) showed no consistent association with the susceptibility to develop GBS. Evidence indicates, however, that these SNPs may be important as disease-modifying factors. An association has been demonstrated between disease severity or outcome and SNPs in genes encoding for mannose-binding lectin, FcγRIII, MMP9, and TNF-α [2]. However, confirmation in more extensive studies is required.

Randomized controlled trials (RCTs) have shown that PE and IVIG are effective in patients with GBS [9, 10]. Most RCTs have used the GBS disability scale to determine the effect of therapy. The GBS disability scale is a 7-point scale, ranging from no symptoms (F = 0), the ability to walk 10 m without assistance (F = 2), bedbound (F = 4), to death (F = 6). The first RCT on the use of IVIG in GBS was published in 1992 and demonstrated that IVIG is as effective as PE [11]. IVIG is applied in a regimen of 2 g/kg bodyweight, usually as 0.4 g/kg bodyweight per day for five consecutive days. IVIG has replaced PE as the preferred treatment in many centers, mainly because of its greater convenience and availability [9]. The combination of PE followed by IVIG was not significantly better than PE or IVIG alone [12]. It appeared that oral steroids and, surprisingly, intravenous methylprednisolone 500 mg/day for five consecutive days alone is not beneficial in GBS [13]. The combination of IVIG and intravenous methylprednisolone was not significantly more effective than IVIG alone. Although when a correction was made for known prognostic factors, the combined treatment shows some short-term effect [14]. These trials show that there is an effect of immunotherapy on the course of GBS, but new studies with different regimens or another therapy that is directed toward improving the prognosis and outcome of GBS are needed.

The clinical course of GBS in individual patients is highly variable and difficult to predict. Advanced age is generally reported to be a negative prognostic factor. Previous studies indicate that the difference in severity of GBS can be determined in an early phase of the disease [15]. Peroneal nerve conduction block and age above 40 years turned out to be independent predictors of disability at 6 months [16]. We have developed a simple clinical prognostic scoring system that accurately predicts the chance of independent walking after 6 months. The Erasmus GBS Outcome Scale (EGOS) can be easily calculated after the first 2 weeks from disease onset using age, presence of preceding diarrhea, and GBS disability score [17]. Based on the EGOS, the predicted chance to recover to independent walking after 6 months ranges from 1% to 83%. The accuracy of the scale was confirmed in an independent cohort of GBS patients. The EGOS can be used to inform individual patients about their prognosis, additionally it can be used in new treatment trials that more specifically target GBS patients with poor prognosis. A slightly modified EGOS that can calculate the prognosis only 1 week after hospital admission is currently being constructed.

In a recent study by Kuitwaard et al., serum IgG levels from 174 GBS patients were determined in samples obtained pretreatment, and at 2 weeks, 4 weeks, 3 months, and 6 months after treatment [19]. The variation in serum IgG levels was most pronounced in the samples at 2 weeks and to a lesser extent at 4 weeks after IVIG treatment. The IgG level at 2 weeks showed a weak correlation with baseline IgG level. To investigate the pharmacokinetics of IVIG, the change in IgG was calculated by subtracting the baseline level from the level at 2 weeks (ΔIgG). There was a large variability in ΔIgG 2 weeks after IVIG treatment. It turned out that patients with a low ΔIgG (lower quartiles) had a significantly prolonged time to reach GBS disability score ≤2 (able to walk independently; log-rank P < 0.001). Using multivariate logistic regression, it was shown that baseline IgG levels or IgG levels at 2 weeks were not significantly associated with outcome. However, the increase in IgG level 2 weeks after standard IVIG (ΔIgG) was associated with outcome (P = 0.027). It appeared that patients with a ΔIgG <3.99 g/L were four times less likely (OR 0.25) and patients with a ΔIgG of 3.99 to 7.30 g/L were three times less likely (OR 0.26, 9) to walk unaided after 6 months than patients with a ΔIgG >10.92 g/L. This is the first study to show that a high increase in IgG levels after IVIG treatment for GBS is associated with a better prognosis.