Functional outcomes following inpatient rehabilitation of Guillain-Barré syndrome patients: Intravenous immunoglobulins versus plasma exchange

1 Introduction

Guillain-Barré Syndrome (GBS) is an acute inflammatory neuropathy which leads to a rapid development of impairments including motor and sensory deficits, autonomic dysfunction and respiratory failure (Pithadia & Kakadia, 2010; Ropper, 1992). The disease has several variants: acute inflammatory demyelinating polyradiculoneuropathy (AIDP), the most common variant in North America and Europe (Hughes & Cornblath, 2005; Pithadia & Kakadia, 2010), acute motor axonal neuropathy (AMAN), more prevalent in Asia and South America (Hadden et al., 1998; Hughes & Cornblath, 2005), acute motor sensory axonal neuropathy (AMSAN) and the less common atypical Miller Fisher syndrome.

Intravenous immunoglobulin (IVIg) and plasma exchange (PE) are the common effective medical treatments in hastening recovery (Hughes et al., 2003; Pithadia & Kakadia, 2010).

PE is thought to remove substances such as pathologic antibodies, immune complexes and cytokines from the blood. Additional evidence suggests that it may have an immunomodulatory effect beyond the removal of antibodies (Reeves & Winters, 2014). Although the precise mechanism of action of IVIg is not fully understood, it is known for providing anti-idiotypic antibodies, modulating expression and function of Fc receptors, interfering with activation of complement and production of cytokines, and interfering with activation and effector functions of T and B cells (Buchwald et al., 2002; Dalakas, 2004).

Several studies compared the effect of IVIg and PE on functional outcomes in GBS. Effectiveness was primarily measured by the degree of improvement on a seven-point functional disability scale, originally proposed by Hughes and today referred to as the GBS disability scale (GDS) (Hughes et al., 1978). The time to improvement by one disability grade and the time to recovery of independent ambulation were commonly used as secondary outcomes (Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome (PSGBS) Trial Group, 1997; van der Meché & Schmitz, 1992). The general consensus in literature is that the efficacy of both treatments is similar (Bril et al., 1996; Diener et al., 2001; Hughes et al., 2014; Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome (PSGBS) Trial Group, 1997), although a few sporadic papers have shown conflicting results (Kuwabara et al., 2001; Saad et al., 2016; van der Meché & Schmitz, 1992). Recently, a large retrospective cohort study demonstrated that patients who underwent PE experienced both prolonged hospitalization, by approximately 7.5 days, and increased in-hospital death rates when compared to treatment by IVIg (Beydoun et al., 2020).

The choice of treatment generally depends on local availability and on patient-related risk factors, contra-indications and preferences. IVIg has a practical advantage as it is easier to implement and available at most hospitals (Hughes et al., 2014; van der Meché & Schmitz, 1992).

The GDS solely focuses on ambulation and respiratory function and does not assess other aspects of disability, such as upper limb function and the ability to perform the basic activities of daily living (BADL). The sensitivity of this scale in determining the levels of activity and participation is, thus, limited, and therefore, a wide array of functional outcome scales have been suggested for assessment following GBS. These scales cover all three domains of the International Classification of Functioning, Disability and Health (ICF) (International Classification of Functioning, Disability and Health. World Health Organization: Geneva 2001., n.d.). For example, in earlier GBS studies, the Medical Research Council (MRC) sum-score scale evaluated impairments in muscle strength (Kleyweg et al., 1991), the Functional Independence Measure (FIM) (Linacre et al., 1994) scale was used to assess limitations in activity, and World Health Organization Quality of Life questionnaires were utilized to measure participation (Khan et al., 2011).

As previous studies focused on GDS as the primary outcome, this study set out to explore additional functional outcomes and compare the effect of each treatment on these outcomes.

2 Materials and methods

The study group consisted of all consecutive patients diagnosed with GBS and admitted to the Department of Neurological Rehabilitation at a tertiary hospital between January 2007 and October 2013. In this retrospective study, the patients were divided into two groups based on the treatment they received in the acute phase of the illness, i.e., IVIg or PE. Both groups received a similar rehabilitation program based on their functional impairments and activity limitations. Data collection and analysis were conducted following the Research Ethics Board approval.

Inclusion criteria consisted of a confirmed diagnosis of GBS, treatment with IVIg or PE, and available neurological and functional assessments upon admission and discharge from rehabilitation. Exclusion criteria consisted of AIDP which had evolved into chronic inflammatory demyelinating polyneuropathy (CIDP), treatment with both PE and IVIg, and/or concurrent neurological conditions such as multiple sclerosis. Individuals with other significant medical conditions influencing the patient’s functional state, e.g., cardiac or respiratory diseases, were also excluded.

Each patient underwent an initial assessment within the first week following admission to rehabilitation and a final assessment within the week prior to discharge. Data consisting of demographics, neurological and functional variables were gathered and compared between the two treatment groups. Length of stay (LOS) in the rehabilitation department was also used in the comparison.

FIM was documented on admission and discharge. This scale assesses the BADL and consists of two subscales, motor and cognitive. The motor subscale includes 13 items grouped in different categories: self-care (6) - eating, grooming, bathing, dressing upper extremity, dressing lower extremity and toileting; sphincter control (2) - bowel and bladder management; and mobility (5) - transfers (to bed/chair/wheelchair, to tub/shower, to toilet) and locomotion (walking/wheelchair, stair climbing). The cognitive subscale includes 5 items: comprehension, expression, social interaction, problem solving and memory (Linacre et al., 1994). A minimum score of 1 indicates total dependence and a maximum score of 7 total independence. The FIM instrument has been validated and shown to be reliable in multiple inpatient rehabilitation facility populations with neurological disorders (Hobart et al., 2001; Stineman et al., 1996).

Several additional scores were calculated using the FIM scores: the absolute functional gain (AFG) score - the difference in total FIM score between admission and discharge; the FIM Efficiency score, also known as rehabilitation efficiency (REy) - the average increase in FIM score per day (Shah et al., 1990); The rehabilitation effectiveness (REs), assessed through FIM using the Montebello Rehabilitation Factor Score (MRFS) efficacy score (Drubach et al., 1994; Koh et al., 2013). This score is obtained by the actual improvement divided by potential improvement, reflecting the proportion of potential improvement achieved during rehabilitation; MRFS efficiency was defined as MRFS efficacy divided by LOS (Heruti et al., 1999; Zwecker et al., 2002).

All formulas are shown in Table 1.

The GDS was also recorded on admission and discharge: 0 - healthy, 1 - minor symptoms and capable of running, 2 - able to walk 10 m without assistance but unable to run, 3 - able to walk 10 m across an open space with help, 4 - bedridden or wheelchair-bound, 5 - requiring assisted ventilation for at least part of the day, and 6 – dead (Hughes et al., 1978).

3 Results

Of the 102 individuals admitted to the department, 32 were excluded: 11 were diagnosed with a condition other than GBS, e.g., CIDP; 10 had missing data in their medical record; four had another comorbidity such as a prior stroke or multiple sclerosis; three were transferred to another medical facility and did not complete their inpatient rehabilitation program; three individuals received both IVIg and PE treatments, and one died on the day of admission.

70 individuals with GBS were included in this study. Of these individuals, 31 received IVIg and the remaining 39 underwent PE. Their demographic and clinical characteristics were remarkably similar, as seen in Table 2.

In the general cohort, we observed a statistically significant improvement in functioning when comparing between admission and discharge, demonstrated by an increase of 30 points in the average FIM score (p < 0.0001). We also noted a significant improvement in all the FIM motor subgroups. We did not observe a statistically significant change in the cognitive element of the FIM between admission and discharge, but there was a trend towards significance. See Table 3 for further details.

Similarly, we observed an improvement in the GDS in the general cohort, with an average grade improvement of 1.23 (SD 0.92) between admission and discharge.

There were no significant differences in rehabilitation outcomes measurements between the two treatment groups, as shown in Table 4. Specifically, we did not observe any statistically significant difference between the two treatment groups, both in the total FIM scores and the FIM subgroups (self-care, sphincter control, mobility and cognitive).

The known effective treatments for GBS, i.e., IVIg and PE, reduce disability and shorten recovery time (Hughes et al., 2003; Pithadia & Kakadia, 2010). Nevertheless, the course of rehabilitation of patients is difficult to predict and varies widely, regardless of treatment. Outcomes are still unfavorable with 3–7% dying within one year (Dhar et al., 2008; Rajabally & Uncini, 2012; Van Den Berg et al., 2013), 20% unable to walk after six months (Rajabally & Uncini, 2012), and many patients suffering from residual symptoms, including pain and severe fatigue (Hughes & Cornblath, 2005; Rajabally & Uncini, 2012).

Whereas most studies have demonstrated that both treatments have a similar effect on mobility and respiratory function, as measured by the widespread GDS, this study set out to explore additional functional assessment tools. In this paper, we analyzed several functional scales, some of which were not previously used in the evaluation of disability of individuals with GBS. Moreover, this is the first paper to use these scales to compare the effect of IVIg and PE treatments on GBS outcomes. Our findings are consistent with previous results, showing no difference in outcomes between these treatments.

The FIM assessment tool (Linacre et al., 1994), one of the most widely used disability assessment instruments in rehabilitation medicine, has had a limited use in GBS till now. A few studies described a significant increase in the total FIM score (Khan, Stevermuer, et al., 2010) and its motor subscores (Alexandrescu et al., 2014; Meythaler et al., 1997; Prasad et al., 2001) following the rehabilitation of individuals with GBS. Two of these studies also noted a significant improvement in the cognitive subscores (Alexandrescu et al., 2014; Prasad et al., 2001).

In our study, we also observed an increase in the motor elements of the FIM scale. Mobility, self-care and sphincter control all significantly improved after rehabilitation. With regards to the cognitive subscale, we observed a trend towards significance. In a prior study, Prasad et al. (Prasad et al., 2001), showed that the increase was significant in three out of five FIM’s cognitive elements (social interaction, problem solving, and memory). Since we referred to the combination of all five elements, this may account for the difference between the results. Our comparison did not yield any difference between IVIg and PE in the total and subtotal FIM scores.

In the next stage, we explored additional FIM-based formulas. Commonly used as a marker for cost-efficiency (Khan, Stevermuer, et al., 2010), the FIM efficiency (REy) measures the rate of change qualified by the increase in FIM per day. We showed that FIM efficiency was slightly better in the IVIg group with a value of 0.68 (SD 0.5) compared to 0.57 (SD 0.4) in the PE group, but this was not statistically significant. Mostly used for stroke assessment, the few GBS studies that incorporated the FIM efficiency have shown a great variability in score (from 0.39 to 1.0) (Alexandrescu et al., 2014; Khan, Stevermuer, et al., 2010). A possible explanation for this variance is that FIM efficiency is highest for the moderate GBS and lower for milder and more severe GBS, probably reflecting the ceiling and floor effects of the FIM scale, respectively (Alexandrescu et al., 2014; Khan, Stevermuer, et al., 2010).

The MRFS efficacy (REs) and efficiency (see Table 1 for formulas) are measured relative to the patient’s specific potential for improvement. They are often used to overcome the ceiling effect of the FIM scale (Shah et al., 1990). Though not previously used in the study of GBS, in our research we did not observe a difference in the MRFS measures between the treatments.

In this paper, we also validated results of earlier studies that used the GDS to measure functional outcome. The GDS, specifically designed to measure disability in GBS, is frequently used in GBS studies (Hughes & Cornblath, 2005). Within the subgroup of studies that compared IVIg and PE treatments, to the best of our knowledge, it is the only disability scale that has been used so far (Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome (PSGBS) Trial Group, 1997; van der Meché & Schmitz, 1992).

In our study, regardless of treatment regimen, the GDS on admission was 3.57 (SD 0.9) and average grade improvement during inpatient rehabilitation was 1.23 (SD 0.9). A large randomized controlled trial (RCT) by the PSGBS study group demonstrated in the PE group: an initial GDS score of 3.9 (SD 0.5) and an average improvement of 0.9 (SD 1.3), and in the IVIg group: an initial 4.0 (SD 0.5) and an average improvement of 0.8 (SD 1.3) (Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome (PSGBS) Trial Group, 1997). In the PSGBS trial, as well as in another randomized trial (van der Meché & Schmitz, 1992), the initial GDS assessment was performed prior to randomization and treatment, while in our study this assessment was performed upon admission to inpatient rehabilitation, following at least one round of IVIg or PE treatments. This probably explains the lower initial GDS score (i.e., better functioning) in our study. Another interesting point is the higher average improvement in our study as compared to the PSGSB study. This may be explained by PSGBS study assessing the GDS grade four weeks after treatment, while our study assessed the GDS prior to discharge. This allowed for more time for improvement as an average length of stay in rehabilitation was 61 days.

We did not observe any significant difference in the GDS between the two treatments. This is in line with findings from previous studies. Specifically, a Cochrane review from 2013 including 536 participants showed that although IVIg hastens recovery as much as PE and adverse events were not significantly more frequent with either treatment, IVIg was significantly more likely to be completed than PE (Hughes et al., 2014). The PSGBS study group had 383 participants and had also shown that both treatments had equivalent efficacy (Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome (PSGBS) Trial Group, 1997), and similar results were obtained by Bril et al. (1996) and Diener et al. (2001).

The secondary outcomes of these studies, time to improvement by one GDS grade (Bril et al., 1996; Diener et al., 2001) and time to recovery of independent ambulation (Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome (PSGBS) Trial Group, 1997), were similar for IVIg and PE treatments. Accordingly, our findings demonstrate that the average length of stay in rehabilitation was similar for both treatments.

Nevertheless, some conflicting results also appear in literature: van der Meché & Schmitz (1992) showed that four weeks following the treatment, 53% of those who received IVIg improved by one or more GDS grades, compared with only 34% of the individuals that had received PE. Kuwabara et al. (2001) showed that IVIg was superior to PE, with a better functional recovery after four weeks, as well as six months later. In both studies, median time to improvement by one or two GDS grades was shorter for the IVIg group. Despite these results, Saad et al. (2016) reported the opposite outcomes in children, for whom PE hastened recovery better than IVIg. Of note, Kuwabara et al. and Saad et al. had a fairly small sample size in their studies (Kuwabara et al., 2001; Saad et al., 2016).

In the past, it was suggested that GDS may not be sensitive enough to detect subtle changes in function with various treatment options (Meythaler, 1997), highlighting the need to examine additional functional scales.

In summary, the additional outcomes that were measured in our paper failed to show a difference between IVIg and PE. It is known that both treatments have an immunomodulatory effect, but their therapeutic efficacy in GBS in not completely understood (Buchwald et al., 2002; Reeves & Winters, 2014). As there is a different pathogenesis for the various subtypes, e.g., AIDP and AMAN, it is possible that an individual with AMAN should receive a different treatment from one with AIDP (Hughes & Cornblath, 2005; Van Den Berg et al., 2014). Further larger studies are required to explore the effect of the different treatments on the different subtypes of GBS.

The ICF provides a framework for describing the impact of disease at the level of impairment, limitation in activity and participation (International Classification of Functioning, Disability and Health. World Health Organization: Geneva 2001., n.d.). Most scales used in GBS are biased towards activity, including the GDS and FIM assessment tools. The Modified Barthel Index (Shah et al., 1989) is another activity biased tool, also used in the evaluation of BADL and mobility in GBS (Gupta et al., 2010; Nicholas et al., 2000).

The Overall Disability Sum Score (ODSS) highlights problems not only with walking but also with daily arm activities, and shows good reliability and validity in GBS studies (Merkies et al., 2002). The clinical applicability of the ODSS was shown in a trial evaluating the efficacy of IVIg against oral prednisolone in patients with CIDP (Hughes et al., 2001). So far, it has not been used in comparison of outcomes following IVIg or PE.

Of note, the PSGBS study group also described a disability arm grade to measure disability, however it was not used in the comparison itself (Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome (PSGBS) Trial Group, 1997).

Participation is often discussed in studies of the long-term sequela of GBS, and various outcome measures are used to evaluate it. The Modified Rankin Scale (van Swieten et al., 1988) which is occasionally used in GBS studies (Gupta et al., 2010) measures both activity and participation, yet it is biased towards limitation of activity. Additional scales for participation that have been used in GBS studies include the World Health Organization Quality of Life (WHOQOL-BREF) (Harper et al., 1998; Khan et al., 2011), the Perceived Impact of Problem Profile (PIPP) (Khan et al., 2011; Pallant et al., 2006), and scales that were discussed in a Cochrane review on the multidisciplinary care for GBS (Khan, Ng, et al., 2010), including the Environmental Status Scale (ESS) (Kurtzke, 1984; Nicholas et al., 2000) and the Handicap Assessment Scale (HAS) (Nicholas et al., 2000).

In a 2013 European Neuromuscular Centre meeting (Vanhoutte et al., 2013), the Peripheral Neuropathy Measures Outcome Study (PERINOMS) group recommended the use of a recently developed scale, the Rasch-built Overall Disability Scale (R-ODS) (Van Nes et al., 2011), to measure activity and participation following GBS, in addition to the commonly used GDS (maintained mostly for historical reasons) (Vanhoutte et al., 2013). This promotes further IVIg and PE comparison studies, with a focus on scales that amalgamate both activity and participation measures.

Our study had several limitations. Because of a limited sample size we could not compare the effects of IVIg and PE on different subgroups (for instance, by gender or type of GBS). Nevertheless, our sample size is comparable to several other comparison studies mentioned in our paper (Bril et al., 1996; Diener et al., 2001; Kuwabara et al., 2001; Saad et al., 2016).

Moreover, as mentioned earlier in the discussion, our paper differs from major studies in the timing of the functional assessment (Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome (PSGBS) Trial Group, 1997; van der Meché & Schmitz, 1992). Since this was a retrospective and not a randomized control trial, the initial assessment took place on admission to rehabilitation and not prior to treatment, and the final assessment occurred prior to discharge and not four weeks following the treatment.

5 Conclusions

FIM and subsequent FIM-based measures that assess the rate and potential for improvement, may be used to evaluate limitations of activity following GBS. Similarly to previous studies that used the conventional disability grade assessment tool, we did not observe a difference in outcomes between IVIg and PE treatments using the new measures. Additional studies are needed to assess the effect of these treatments on different subtypes of GBS, and to evaluate their effect on additional outcomes for activity and participation.

Conflict of interest

Nothing to declare.