Management of Guillain–Barré syndrome with plasmapheresis or immunoglobulin: our experience from a tertiary care institute in South India

Abstract

Guillain–Barré syndrome (GBS), an acute inflammatory demyelinating polyneuropathy is the most common generalized paralytic disorder. The objective was to study the outcome of disability grade in two groups of GBS treated with plasmapheresis alone and treated with IVIg alone. A retrospective analysis of all consecutive patients with GBS, admitted in our intensive care unit during the period of 3 years, 2009–2012 were included in the study. All patients of GBS who were to be treated with plasmapheresis or IVIg, the modality of management were always decided at their preference and consent after explaining the modalities to patient/family. The plasma exchange done was ∼200–250 mL of plasma per kilogram weight in five sessions (40–50 mL/kg per session) within 7–14 days. The replacement fluid contained 100 mL of 20% albumin diluted in 1000 mL of normal saline and 1000 mL of fresh frozen plasma. IVIg was administered as 0.4 g/kg body weight daily for 5 days. Our observations brought out the following, both the plasmapheresis and IVIg treatments were effective in reducing the disability grade amongst all time points, i.e., at presentation, immediate post-therapy and after 4 weeks. There was a marginal superiority in plasmapheresis over IVIg effect. However, whether the delay in presentation as noted in our study probably would have contributed to this effect was conjectural.

• Developing country
• disability
• Guillain–Barre syndrome
• immunoglobulin
• plasmapheresis

Introduction

Guillain–Barré syndrome (GBS), an acute inflammatory demyelinating polyneuropathy is the most common generalized paralytic disorder with an approximate incidence of two cases per 100,000 population. The disorder usually presents with acute motor deficits and sensory symptoms involving peripheral nerves. GBS is believed to be an autoimmune process due to the finding of complement binding IgM antibodies directed against peripheral nerve myelin.1,2 Although many patients with GBS recover spontaneously, 10–23% require mechanical ventilation, 7–22% are left with some disability, 3–10% relapse and 2–5% die. The likelihood of permanent disability increases with severity and duration of disease and patients may require prolonged stays in the hospital.3,4 Therefore, keeping the disability and prognosis in view, the disease needs specific treatment. Oral and intravenous steroids were proved to be ineffective.5,6 The rationale for plasmapheresis is the existence of a circulating factor that reproduces in vitro, the electrophysiological and histological patterns of demyelination.7 Subsequently, several large randomized trials were taken up to study the effect of plasmapheresis in the treatment of GBS. The North American GBS study group,3 the French study group,8,9 the English study group,10 and the Swedish study group,11 have all shown comparable benefit with plasmapheresis. They found plasmapheresis was beneficial when applied within first 4 weeks of onset, but largest effect was seen when started early (with in first 2 weeks). A review of literature revealed that the intravenous immunoglobulin (IVIg) had comparable efficacy with the plasmapheresis in the management of GBS. The objective was to study the outcome of disability grade in two groups of GBS treated with plasmapheresis alone and treated with IVIg alone.

Materials and methods

Study design and patients

A retrospective analysis of all consecutive patients with GBS, admitted in our intensive care unit during the period of 3 years, 2009–2012 were included in the study. The data were recorded on a ProForma.

Definitions

1. Diagnosis of GBS: The diagnosis of GBS was done based on National Institute of Neurological and Communicable Disorders and Stroke (NINCDS) 1990 criteria.12

2. Disability grade: The degree of motor function was expressed on a seven-point functional scale used in previous trials, on which 0 denotes healthy; 1, having minor symptoms and signs but fully capable of manual work; 2, able to walk ≥10 m without assistance; 3, able to walk ≥10 m with a walker or support; 4, bedridden or chair bound (unable to walk 10 m with a walker or support); 5, requiring assisted ventilation for at least part of the day; and 6, dead.3,10,13

Treatment modalities

All patients of GBS who were to be treated with plasmapheresis or IVIg, the modality of management were always decided at their preference and consent after explaining the modalities to patient/family. The neurologist played an active role in these discussions.

Patients with vital capacity <15 mL/kg, partial pressure of oxygen of <70 mmHg or a partial pressure of carbon-dioxide of >45 mmHg were placed on mechanical ventilator.

The plasma exchange (membrane based apheresis) done was ∼200–250 mL of plasma per kilogram weight in five sessions (40–50 mL/kg per session) within 7–14 days. The replacement fluid contained 100 mL of 20% albumin diluted in 1000 mL of normal saline and 1000 mL of fresh frozen plasma. IVIg was administered as 0.4 g/kg body weight daily for 5 days. Patients received other supportive medication like prophylactic doses of heparin, antibiotics and proton pump inhibitors. Neurorehabilitative care was also given. The disability grade was studied measured at three different periods, i.e., at presentation, immediately post-therapy and after 4 weeks.

Statistics

The statistical software used was PASW SPSS 18.0 version. For categorical data, chi-squared test has been used. Mann–Whitney U test was applied to compare the plasmapheresis and IVIg groups. Friedman test was used to compare the disability grading at different time points, i.e., at presentation, immediate post-therapy and after 4 weeks. p-Value < 0.05 was taken as significant.

Results

The study included data from GBS patients treated in our institute during 2009 and 2012. During the study period 90 patients of GBS were treated. Of them 29 patients were treated with IVIg and 61 patients were treated with plasmapheresis. The mean ages were 30.862 and 35.737 years, respectively. The male to female ratio was 63.33%/36.67% and there was uniform distribution in both the groups (IVIg: 62.06%/37.93%; plasmapheresis: 63.93%/36.06%). There were no statistically significant clinical differences between the groups in age and duration before the treatment was initiated after the diagnosis of GBS (Table 1).

Table 1. Comparison of characteristics of patients in IVIg group and plasmapheresis.

	All patients					Respiratory (mechanical ventilation) patients
	IVIg		Plasmapheresis			IVIg		Plasmapheresis
	Mean	Std. Error Mean	Mean	Std. Error Mean	t Value (p value)	Mean	Std. Error Mean	Mean	Std. Error Mean	t Value (p value)
Age (years)	30.8621	3.775	35.737	1.874	1.297 (0.198^NS)	28.571	7.341	34.667	6.242	0.636 (0.535^NS)
Duration (days)	8.4483	1.085	6.442	0.358	2.207 (0.030*)	6.571	1.020	6.667	1.000	0.066 (0.949^NS)
Distal motor amplitude  (mV)	1.272	0.2156	1.807	0.1353	2.171 (0.033*)	0.643	0.3939	1.089	0.3454	0.852 (0.409^NS)
Sex (M/F)	18/11		39/22			5/2		6/3
History of preceding  infection (present/no)	13/16		29/32			3/4		6/3

Notes: “*” represents significance and “NS” represents not significant. For sex and history of preceding infection, p values were not computed as they are categorical variables.

We observed on comparison using Friedman test, both modalities of treatments were found to be significant in improving the patient disability grade (Table 2).

Table 2. Comparison of the effect of treatments on the disability grade at different time points.

	All patients		Respiratory (mechanical ventilation)
	I.V.Ig	Plasmapheresis	I.V.Ig	Plasmapheresis
Duration	Mean ± SE	Mean ± SE	Mean ± SE	Mean ± SE
Disability grade at presentation	4.00 ± 0.131	4.02 ± 0.068	5.00 ± 0.000	5.00 ± 0.000
Disability grade at immediate post-therapy	3.31 ± 0.150	3.00 ± 0.096	3.86 ± 0.261	3.67 ± 0.167
Disability grade at after 4 weeks	2.28 ± 0.267	1.33 ± 0.161	3.14 ± 0.634	2.33 ± 0.441

Table 2 shows that there was a statistically significant improvement in the disability grade in both the modalities of the treatments not only when studied as an overall effect but also in the respiratory patients who were on ventilator support.

However, plasmapheresis was found to be associated with more improvement in comparison to IVIg with the application of Mann–Whitney U test in both the groups (Table 3).

Table 3. Superiority of plasmapheresis over IVIg in reducing the disability grade.

Treatments	N	Mean ± Std. Error Mean
Plasmapheresis	61	1.65 ± 0.147
IVIg	29	1.07 ± 0.230
The Z value is 2.329 (p = 0.000*)

*Significance at 0.05 level.

On graphical representation of the same it was further evident that the average reduction in disability grade was superior in plasmapheresis group over IVIg group (Figure 1).

Figure 1. Reduction in disability grade between immediate post-therapy and after 4 weeks in both the groups.

We further studied the association between the prognostic variables: age, sex, history of preceding infection, duration of illness till the start of the treatment and distal motor amplitude values and the differenced value of disability grade obtained from immediate post-therapy and after 4 weeks of therapy. We found a significant association between the distal motor amplitude and differenced disability grade with both the treatments using chi-squared test (p value < 0.01) and there was no association between the remaining factors and differenced disability grade (p value > 0.05). However, we observed that the duration of illness at presentation was found to be more in IVIg group (8.4483 days) in comparison to plasmapheresis group (6.442 days) amounting to late presentation in IVIg group (2.001 days).

Discussion

The present study is a retrospective study done with an objective to find the outcome in disability grade in GBS with plasmapheresis or with IVIg. The number of patients in plasmapheresis and IVIg groups was different. But there were no statistically significant clinical differences between the groups in age and duration of before the treatment was initiated after the diagnosis of GBS. The results suggested that the plasmapheresis was marginally, superior to the IVIg (the Z value is 2.329, p value = 0.000*) in improving the disability grading in the entire group and also in respiratory (mechanical ventilation) patients.

In a recent systemic review the immunotherapy of GBS has been discussed.14 There were six publications comparing plasma exchange and IVIg with adults constituting as predominant population. In addition, there was one similar study in pediatric patients of GBS.13,15--20

The previous studies are reviewed in the Table 4. A review of these studies revealed that the IVIg had comparable efficacy in five of the studies and PE was found to be superior only in one study. This last study was in pediatric population. In this study, it is possible that the children might have had an intense autoantibody production with a high percentage of these antibodies already bound to nerves on development of respiratory failure. Hence, the removal of already bound antibodies with PE, in comparison to blocking antibody production, IVIg is helpful.

Table 4. Intravenous immunoglobulin versus plasma exchange in Guillain–Barré syndrome.

Reference	Type of study	Age and treatment regimes	Results	Conclusion
13	Randomized	Adults IVIg: 0.4 g/kg daily for 5 days; n = 74 PE: 200–250 mL of plasma/kg in five sessions in 7–14 days; for days; n = 73	53% of IVIg group improved >1 disability grade versus 34% in the PE group, difference 19% (95% CI 3–24%; p = 0.024)	IVIg is at least as effective as plasma exchange and may be superior
16	Randomized	Adults IVIg: 0.5 g/kg daily for 4 days versus PE 40–50 mL/kg daily for 5 days Total n: 50	61% PE treated group and 69% of the IVIg-treated group improved by one disability grade at 1 month	The efficacy of IVIg is comparable with that of PE
17	Randomized	IVIg 0.4 g/kg daily for 5 days; n = 130 versus PE 250 mL/kg over 8–13 days; n = 121	Mean change in disability grade after 4 weeks −0.9 (SD 1.3) in PE group and −0.8 (SD 1.3) in IVIg group, difference 0.10 (95% CI 0.22–0.42)	During first 2 weeks after onset, plasma exchange and IVIg had equivalent efficacy
18	Randomized	IVIg n = 20 PE n = 21	At least a one grade improvement in the functional score by day 28: achieved by 16/20 patients after IVIg and 15/21 patients with plasma exchange (difference not significant)	Study was stopped due to poor recruitment in IVIg group
19	Randomized	Adults IVIg group n = 23 PE group n = 24 The immunoadsorption technique was used mainly in the PE group	There was no significant difference between the two groups (p = 0.853)	IVIg therapy was considered to be as useful as PE therapy for early treatment of GBS
20	Retrospective	IVIg n = 31, LVP n = 45, SVP n = 30	Mean duration of MV (p = 0.61), total hospital stay (p = 0.44) and Hughes scale at discharge (p = 0.31) did not differ among the three groups	The outcome of patients treated with these three immunomodulatory treatment modalities did not vary
15	Randomized	Pediatric population; IVIg: 0.4 g/kg/day for 5 days; n = 20 PE: one volume PE daily for 5 days; n = 21	PE group: shorter period of MV (median 11 days, IQR 11.0–13.0) compared to IVIG group (median 13 days, IQR 11.3–14.5) with p = 0.037. PE group: a tendency for a shorter PICU stay (p = 0.094). 20/21 (95.2%) and 18/20 (90%) children in the PE and IVIg groups, respectively. could walk unaided within 4 weeks (p = 0.606)	PE is superior to IVIg regarding the duration of MV but not PICU stay or the short-term neurological outcome

Notes: IVIg, intravenous immunoglobulin; PE, plasma exchange; LVP, large volume plasmapheresis; SVP, small volume plasmapheresis; MV, mechanical ventilation; PICU, pediatric intensive care unit.

Guillain–Barré syndrome is appeared to be mediated by a monophasic IgM, anti-peripheral nerve myelin antibody and by high titers of IgG antiganglioside antibodies. The IgM antibody can be removed by plasma exchange. The plasma exchange reduces the antibody to <20% by 2–3 weeks, whereas without plasma exchanges the antibody levels decrease to 20% by 3–9 weeks.21 The advantage of the removal of autoantibodies, by plasma exchange is that it creates a concentration gradient between the lowered blood level and the extravascular space forcing antibody movement from the extra to the intra vascular space to be removed during the subsequent session.22 Plasma exchange is most beneficial when started within 7 days of disease onset, but is also efficacious when started after 30 days.23 In the present study, the plasma exchange was started within 7 days, but there was approximately a median difference of 2 days between the initiation of plasma exchange and IVIg. This difference was, however not significant as the disability grade was similar both groups at the initiation of treatment. In the Plasma Exchange/Sandoglobulin Guillain–Barré Syndrome Trial Group study,17 the patients randomized later had a significantly more improvement. The explanation for this finding was that those randomized later were closer to spontaneous recovery. With the same analogy the IVIg group, in our study should have done better.

We also present the strengths and the deficiencies in our study. The literature is sparse on the role plasmapheresis from developing countries. Management with plasmapheresis is comparatively cheaper than IVIg. Plasmapheresis costs ∼$1300 while the IVIg is ∼$2400. Ours is a retrospective study. A prospective study would definitely answer whether the patients from developing nations would respond in the similar way as was seen from the developed world.

Our observations brought out the following, both the plasmapheresis and IVIg treatments were effective in reducing the disability grade amongst all time points, i.e., at presentation, immediate post-therapy and after 4 weeks. There was a marginal superiority in plasmapheresis over IVIg effect. However, whether the delay in presentation as noted in our study probably would have contributed to this effect was conjectural.