Long-term outcomes of plasma exchange versus intravenous immunoglobulin for the treatment of Guillain-Barré Syndrome: A double-blind,randomized clinical trial

2.1 Study design, participants, and ethical approval

This study was a randomized prospective longitudinal parallel design that included 81 patients diagnosed with GBS according to the criteria of the National Institute of Neurological Disorders and Stroke (NINDS) (A. Asbury, 1978; A. K. Asbury & Cornblath, 1990) and the Brighton Collaboration (Fokke et al., 2014; Sejvar et al., 2011). The patients were consecutively recruited from the emergency department of the Neurology, Psychiatry, and Neurosurgery Hospital of Assiut University, Faculty of Medicine, Assiut, Egypt, from September 1st, 2021, to March 3rd, 2023. As the primary tertiary hospital in upper Egypt, Assiut University receives numerous referrals from different cities.

Inclusion criteria: Age ranging from 18 to 70 years within the first two weeks after onset.

Exclusion Criteria patients with metabolic and electrolyte disorders (hypokalaemia or hyperkalaemia), periodic paralysis, hypoglycemia, or malignancy, or other causes of peripheral neuropathy, other causes of acute paralysis of limbs such as ascending myelitis, myositis, inflammatory myopathies, hypothyroidism, porphyria, vitamins B1, B12 deficiency, and critical illness polyneuropathy.

This study was approved by the Institutional Review Board (IRB) of the Faculty of Medicine, Assiut University, as part of a research project with Approval Number: 17300680 and was registered on clinicaltrial.gov with ID: NCT05104762. The research complied with the 1964 Declaration of Helsinki of the World Medical Association and its subsequent revisions or a comparable ethical standard. All participants signed an informed written consent form to participate in the study.

2.2 Randomization

Patients with GBS receive PE or IVIG after being randomly classified into two groups using a closed envelope with a ratio of 2 : 1, respectively, as the IVIG is expensive and not available all the time in the hospital (see the flow chart in Fig. 1). The study was double-blind (participant and the outcomes assessor): the patients were not informed of the potential alternative therapies used in the trial. The outcome assessor did not know the type of treatment the patients received.

2.3 Baseline clinical data collection

All patients gave a complete medical history, and symptoms were quantified using the GBS Disability Scale (GDS), the Medical Research Council sum score (MRC sum score), and the Functional Assessment of Acute Inflammatory Neuropathy (FAAIN). Also, the neurophysiological assessment included nerve conduction studies, including the F wave and H reflex. Because the FAAIN was published in February 2022, we retrospectively assessed the scale at onset, ten days, one, and three months in approximately half of the patients recruited during the first six months of the trial with follow-up at one year while the remaining patients were assessed prospectively from the time of admission until the end of the year. In the current study, we retrospectively applied this scale based on the original study that validated the FAAIN in 2022. Their authors detected that the scale was reliable and valid in the functional assessment of GBS in the first validation step, which was based on a retrospective study (Lestayo O’Farrill, González-Quevedo, Gutierrez-Gil, Hernández-Cáceres, & Sistach-Vega, 2022).

Two groups were included in this study: The PE group (54 patients) underwent PE (COM.TEC- 9008021- Fresenius Kabi AG, Homburg, Germany), with 200–250 mL of plasma/ kg in five sessions (40–50 mL/kg per session) were exchanged every other day within 7–14 days with replacement by fresh frozen plasma. The IVIG group (27 patients) received IVIG (Immunoglobulin-G, Sk Plasma Co., Ltd., Seongnam, South Korea) in a dose of 0.4 g/Kg/day for five consecutive days.

2.4 Follow up

Clinical follow-up of each patient was performed using the GDS, MRC sum score, and FAAIN at ten days of treatment, then at one month, three months, and one year after treatment (Fig. 1). The neurophysiological assessment was performed at baseline and after the end of 3rd month of treatment.

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Fig. 1

Flow chart.

2.6 Statistical analysis

Statistical analysis was conducted using Statistical Package for the Social Sciences (IBM SPSS Statistics for Windows, Version 26; Armonk, NY: IBM Corp.). Graph Pad Software Inc. prism version 8 was used for graphs. A frequency and proportion analysis was performed for qualitative variables, while quantitative variables were presented as Mean±SD. The Chi-square test was used to compare differences in frequency between the two groups, and an independent t-test was used to compare differences in means between them. A paired t-test was used to compare differences in means in the same group. One-way repeated measure ANOVA was used to assess the effect of time in each group separately. Two-way repeated measure ANOVA was used to assess group X time interactions. Non-sphericity was compensated using the Greenhouse-Geisser correction.

4.1 Clinical outcome

There was no significant difference in the number of patients in each group who needed ICU admission, MV, the number of days on MV and the length of hospital stay. This agrees with the recent findings published in a systematic review in 2023, which reported that there were no significant differences between PE and IVIG regarding the length of hospitalization and duration of MV (Zaki et al., 2023). However, this contrasts with the findings reported in other studies on adults. Van der Meché and Schmitz, 1992 and Kleyweg et al. 1994 reported that IVIG treatment required less artificial ventilation and for a shorter duration (R. P. Kleyweg, van der Meché, & Schmitz, 1994; van der Meché & Schmitz, 1992). Also, El-Ghanem et al. 2016 reported that patients who received IVIG were less likely to need endotracheal intubation and spent less time on MV, with decreased mortality and a shorter length of hospital stay (El-Ghanem et al., 2016). Moreover, Charra et al. 2014 found easier withdrawal of MV and shorter hospital stays in the IVIG group when comparing the efficacy of IVIG versus PE in the treatment of MV adults with GBS (Charra et al., 2014).

The current findings contrast with some previous results in children. Elahi et al. 2019, found that patients treated with PE had considerably longer mean ICU and ventilator stays than the IVIG group in children (Elahi et al., 2019). Also, Saad et al. 2016 reported that children were less likely to need MV and reduced the length of hospital stay after PE (Saad et al., 2016), and El-Bayoumi et al. 2011, found that children who did require MV received it for less time after PE, with a tendency for a shorter Paediatric Intensive Care Unit (PICU) stay (El-Bayoumi et al., 2011).

4.2 Effect of therapy on the primary and secondary outcomes of GBS

The current study did not find statistically significant differences between groups at baseline clinical data and at ten days after treatment; however, a significant interaction between groups along the course of follow-up (time X groups) with more improvement in the IVIG group for MRC sum score and for FAAIN at 1 and 3 months, while at one year, outcomes were equivalent. However measuring the effect sizes at one year suggested that there were measurable differences between the PE and IVIG groups across the different measures (MRC, GDS and FAAIN). Larger effect sizes generally indicate more substantial differences between the groups. There was also more improvement in a small number of electrophysiology outcomes at three months in the IVIG group.

This agrees partially with previous studies, which assessed the disability outcome of both therapies using the HDS. Van der Meché and Schmitz 1992 and Kleyweg et al. 1994, reported that the superiority of IVIG over PE was due to greater improvement in disability grade, quicker time to improve one functional grade, and a shorter time to achieve independent mobility (R. P. Kleyweg et al., 1994; van der Meché & Schmitz, 1992).

Kuwabara et al. compared the efficacy of PE and IVIG in 24 patients with IgG anti-GM1 positivity in 2001 (10 were treated with IVIg and 14 with plasmapheresis). The IVIg group had significantly lower HDS 1, 3, and 6 months after commencement and a greater chance of resuming independent locomotion at six months. IVIg therapy resulted in faster recovery and fewer residual problems than PE therapy (Kuwabara et al., 2001). In addition, Kishore et al. 2014, observed that both PE and IVIg therapies were beneficial in reducing the disability grade at all time points, i.e., at presentation, immediately after therapy, and four weeks later, with a marginal advantage of PE over IVIg (Kishore et al., 2014). Meregildo-Rodriguez and Bardales-Zuta 2021, in their retrospective investigation, found that functional outcome as measured by the modified Rankin scale (MRS) was statistically comparable among patients treated with IVIG or PE. (Meregildo-Rodriguez & Bardales-Zuta, 2021). Jacobs et al. 1996, reported that among their 31 anti-GM1–positive GBS patients, IVIG therapy was more effective than PE, with 21 patients treated with IVIg recovering faster than 10 patients treated with PE, although detailed data of prognostic factors such as distal CMAP amplitudes were not provided (Jacobs et al., 1996). Bril et al. 1996, determined that IVIG’s efficacy in treating GBS was comparable to that of PE (Bril et al., 1996).

Regarding therapeutic complications, there was no significant difference between therapies in the present study. The complications related to PE were hypersensitivity reaction (allergic reaction) in three patients (with discontinuation of PE in two patients and shifted to receive IVIG). DVT complicated by pulmonary embolism was recorded in one patient. Complications related to IVIG included DVT in two patients with no allergic reactions reported. This agrees with the findings reported in a recent systematic review in 2023, which demonstrated that the risk of patients experiencing complications after treatment with PE and IVIG was statistically insignificant (Zaki et al., 2023). However, Bril et al. 1996 found that IVIG may be administered safely without an excessive relapse risk despite a greater complication rate in patients treated with PE (Bril et al., 1996).

For PE, additional complications were catheter placement procedures, hypotension, hypocalcaemia, and allergic reactions (Ara et al., 2017; Kaya et al., 2013). For IVIG, they were a higher risk of thromboembolic complications in patients treated with a second immunoglobulin dose (Kapoor et al., 2020; Y. A. Rajabally, 2022; Y. A. Rajabally & Kearney, 2011)

Regarding mortality, in this study, there were no differences between therapies. However, Meregildo-Rodriguez and Bardales-Zuta 2021 found a tendency toward decreased mortality among PE patients (Meregildo-Rodriguez & Bardales-Zuta, 2021). On the other hand, El-Ghanem et al. 2016 reported that patients who received IVIG had decreased mortality (El-Ghanem et al., 2016). A recent systematic analysis from 2023 found that it was impossible to delineate the effect of treatment regimens on the mortality rate of GBS patients because most studies did not analyse mortality rates. (Zaki et al., 2023).

4.3 Electrophysiological findings as a secondary outcome in GBS

In the current trial, there was no significant difference in the electrophysiological findings between the two groups at baseline; nevertheless, there was a substantial improvement in the electrophysiological data three months following therapy for both groups, with significant improvement in amplitude of distal CMAP of both ulnar and posterior tibial nerve among IVIG group compared with PE. This partially agrees with the previous results reported by Kuwabara et al. 2001, who demonstrated that the CMAP sum score at six months tended to be greater for the IVIg group (Kuwabara et al., 2001).

We also observed recovery of electrophysiological responses in patients with no electrical response at baseline, although there was no significant difference between the two treatments.

From an economic point of view, PE had lower drug costs than IVIG, and since there were no significant differences between groups in terms of needing MV, number of days on MV, length of hospital stay, or complications, PE was cheaper than IVIG. This differs from the report of Tsai et al. 2007 who found that even though IVIG therapy has high drug costs, it was associated with statistically significant cost savings due to a shorter hospital stay, lower costs for procedures and hospitalisation, fewer complications, and fewer patients who need assisted MV compared to a PE group (Tsai, Wang, Liu, Sheng, & Lee, 2007).

Strengths of the study: In the present study, we used the newly proposed clinical rating scale (FAAIN-GBS) for the functional assessment of GBS, which underwent the first validation step based on a retrospective study (Lestayo O’Farrill et al., 2022). To our knowledge, the current clinical trial is the first prospective study to use it in assessing GBS. The second point of strength was the inclusion of different clinical scales (motor and functional scales) as well as electrophysiological assessment.

Limitations of the study: the first limitation is the relatively small sample size. Second, the lack of long-term electrophysiological assessment at a one-year follow-up. Third, the lack of comprehensive assessment of treatment-related complications. Finally, we were unable to assess the IgG anti-GM1 positive subgroup of GBS in the current study, as these tests are unavailable in our city.