Chapter 1 is the general introduction of this thesis, in which di.erent aspects of the Guillain-Barré syndrome (GBS) are described. GBS is an acute post-infectious polyneuropathy, in which the immune system plays an important role. Insight in pathogenesis, clinical and electrophysiological features, functional outcome, and residual complaints is increasing. To date, fatigue is considered one of the most disabling residual symptoms, seriously a.ecting quality of life. The considerable percentages of (long-lasting) morbidity and mortality, as well as the residual complaints of severe fatigue, were the most important reasons to initiate this study, entitled; ‘treatment of GBS and causes and treatment of residual fatigue’. Items discussed in the introduction range from diagnosis to pathogenesis and treatment of GBS. Attention is partially focused towards prognosis and outcome, in particular towards residual fatigue. Chapter 2.1 is a review about the peripheral neuropathies GBS, chronic in.ammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN), all potentially treatable immune-mediated disorders. It was postulated that the use of appropriate assessment scales to evaluate the e.ects of treatment is essential. Recent clinical trials and Cochrane reviews on the e.ect of various treatments in patients with GBS, CIDP and MMN are discussed. It is concluded that intravenous immunoglobulin (IVIg) remains the cornerstone of treatment for GBS, but that combinations of treatment may be even more e.ective. Also studies on prognostic factors related to improvement are discussed. Whether patients with Miller Fisher syndrome or those with mild GBS should also be treated remains a matter of debate. IVIg is the best studied therapy for CIDP patients. IVIg is e.ective and is one of the most important treatments in these patients. Whether steroids are able to eradicate the disease besides suppressing disease activity in CIDP remains to be established. Some GBS patients have secondary deterioration or .nally turn out to have CIDP; additional information in this group of patients may lead to more appropriate disease management. Most patients with CIDP and those with MMN need long-term treatment. New treatment strategies should also focus on the e.ect and the costs of treatment during long-term follow up. In chapter 2.2 a multi-center open label study on the additional e.ect of Mycophenolate Mofetil (MM) when added to the combination of IVIg and intravenous methylprednisolone (MP) is described. An important reason for this study was that, despite di.erent treatments, GBS remains associated with considerable co-morbidity, mortality, and long-lasting residual de. cits. The aims of this pilot study were to investigate the safety of this treatment combination and to study the potential additional e.ect of MM on the outcome in patients with GBS. Patients were treated for 6 consecutive weeks with MM in a dosage of 2g daily, and for 5 days with 0.4 g/kg of body weight IVIg and 500 mg MP daily. Because the IVIg-MP treatment group of the Dutch IVIg-MP trial was used as control group, identical outcome measures were used. The primary endpoint was the percentage of patients showing improvement with at least one grade on the GBS-disability scale, 4 weeks after inclusion. Twenty-six patients were included in analysis. Sixty- 189 two percent reached the primary endpoint in the group of patients treated with IVIg-MP-MM, as compared with 68% in the group treated with IVIg-MP (OR 1.3, 95% CI 0.6-3.2, p=0.54). None of the secondary endpoints showed any signi.cant di.erences either. Complications and adverse events were comparable in both groups. It was concluded that although side e.ects were generally mild, there appears to be no signi.cant improved outcome in the group of patients additionally treated with MM. It was concluded that new treatment studies are warranted. In chapter 3.1 a double-blind, placebo controlled, cross-over study is described, aiming to reduce fatigue with amantadine treatment, in 80 severely fatigued GBS patients. Fatigue was assessed using the Fatigue Severity Scale (FSS) and Fatigue Impact Scale (FIS). Patients could participate when they were severely fatigued (de.ned as FSS = 5.0), and other possible confounding factors causing fatigue were excluded. Amantadine was not superior to placebo. However, some reduction of fatigue was observed both during the pre-treatment period and during the consecutive visits, both in the placebo and amantadine treated group, suggesting that increased attention for fatigue provided by this study already had an ameliorating in.uence on fatigue. Also secondary outcome measures including impact of fatigue, anxiety and depression, handicap, and quality of life did not reveal any signi.cant di.erence. Fatigue scores obtained from the FSS (fatigue severity) as well as from the FIS (impact of fatigue on cognitive, physical, and social functioning) showed the same trends and changes during the consecutive follow-up visits. In chapter 3.2 the favourable results are discussed of a 12-week during bicycle exercise training in 20 severely fatigued patients. Sixteen patients were relatively good recovered from GBS and 4 had stable chronic in.ammatory demyelinating polyneuropathy (CIDP). Selfreported fatigue scores as measured with the FSS, as well as aerobic capacity and isokinetic muscle strength improved signi.cantly compared to baseline measurements. Daily physical activity, as measured with the Rotterdam activity monitor (RAM) showed that endurance related physical activities (e.g., duration of standing, walking, cycling and transitions from positions), did not show any signi.cant improvement. It was suggested that changing the level of daily physical activity is not an important adaptation strategy in these fatigued patients. Maybe the maintenance of normal activity patterns contributes to fatigue. Both GBS and CIDP patients showed comparable signi.cant improvements on the FSS and FIS. Patients reported that increased physical activity in the past often resulted in increased neurological complaints, resembling the initial phase of GBS or CIDP, and resulting in threatening and anxious feelings of getting a relapse. This medical supervised training showed the opposite, patients became con.dent, and a negative circle seemed to be broken. It was suggested that the motivational aspect of increased social contacts with fellow-patients, besides promoting exercise adherence, has also lead to better psychological performances. Quality of life improved, mainly on the physically focused domains of the SF-36, suggesting being a result of improved physical .tness and muscle strength. Most patients (80%) were motivated to continue with regular training activities. Marcel BW.indd 189 02-11-2005 16:23:25 In chapter 3.3 the long-term follow-up of fatigue, quality of life, physical .tness and muscle strength in GBS and CIDP patients is described, evaluated 2 years after training intervention. Mean reduction of self-reported fatigue compared to pre-training values was not di.erent from the fatigue reduction observed directly after the training intervention. Also maximal ‘power output’and muscle strength (except elbow .exion), remained signi.cantly improved compared to pre-training values. It seemed that lower fatigue scores and improved functional scores were not a result of natural reduction of fatigue after GBS nor could be explained by ongoing reconditioning activities. Patients became more convinced of their physical capabilities, and were less afraid and more capable to perform rather high level (short-lasting) maximal physical e.ort, as measured by the increased maximal power output and muscle strength measurements. Presumably, training has taught the patients that increased physical activity can be performed without getting new neurological complaints or ‘relapse’feelings, and thus helped them to take the barrier. Although some methodological remarks had to be made, these results favoured a long-term e.ect of a physical training intervention. The results of a cross-sectional study within a prospective nationwide study in the Netherlands, in which the presence of fatigue after GBS was investigated, is described in chapter 4.1. The occurrence of severe fatigue, and its relation with disease course, clinical characteristics, and antecedent infections was studied in 100 GBS patients. Severe fatigue, again expressed as a mean FSS-score of at least 5.0, was present in 60% of all patients; it was more frequently present in females and in patients over 50 years (p<0.01). It was noticed that complaints of fatigue are already present rather early after the initial phase of disease. There was no signi.cant relationship between fatigue severity and the level of functional disability at nadir (impaired muscle strength, GBS-disability score, and sensory de.cits), antecedent events or infections in the initial phase of GBS, and time to follow-up after GBS. The percentage of severe fatigue was lower than reported before (60 vs 80%), which might be due to di.erences in methodology and in study population; the lower mean age of patients in this study, and the shorter duration of symptoms after GBS. It was suggested that patients who are still in the recovery phase of GBS might not be fully aware of other residual complaints like fatigue, mainly because they are not able to perform the same physical activities like neurologically ‘recovered’ patients may do. In chapter 4.2 we describe standardized motor and sensory nerve conduction (NC) studies in 13 well-recovered but fatigued GBS patients and 3 stable CIDP patients, mean 6.5 years after diagnosis. The aim was to determine whether residual subclinical peripheral nerve dysfunction is a possible underlying mechanism of fatigue. Motor NC measurements were performed in the peroneal, median, and ulnar nerve, and sensory NC measurements in the sural, median, and ulnar nerve. In contrast to CIDP, most NC values in GBS patients were remarkably within normal ranges. No correlations were found between the electrophysiological .ndings and the fatigue scores, muscle strength, functional scores, and quality of life. The single GBS patient with the lowest fatigue scores had the most NC abnormalities, which further illustrated the lack of a 191 relation between NC abnormalities and fatigue. This study demonstrated that severe fatigue in GBS is not explained by residual nerve dysfunction, using conventional NC measurements. In chapter 4.3 a study concerning conduction velocity distribution (CVD) in the median nerve in 13 fatigued but neurologically well-recovered GBS patients, 2 fatigued and stable CIDP patients, and 19 healthy controls is described. Although conventional NC studies showed no gross abnormalities in motor NC, it was shown that both GBS and CIDP patients had signi.cant narrowing of the conduction velocity distribution, with loss of the fastest and slowest conducting .bers. These changes were most pronounced in the subgroup of patients with the lowest fatigue scores. We concluded that it was unlikely that the CVD changes contribute to persisting complaints of severe fatigue after GBS. However, CVD values of the (non)-severely fatigued GBS patients were only compared with healthy individuals, and not with non-fatigued GBS patients. In chapter 4.4 the relative contribution of peripheral and central factors during a fatiguing sustained maximal voluntary contraction (MVC), in ten (self-reported) fatigued but neurologically relatively ‘well-recovered’ GBS patients, and 12 age and sex matched healthy controls is described. Self-reported fatigue was evaluated using the FSS and Abbreviated Fatigue Questionnaire (AFQ). Physiological fatigue was de.ned as the decline of voluntary force during a 2-minute sustained MVC of the biceps brachii. The relative amounts of peripheral fatigue and central activation failure (CAF) were determined combining voluntary force and force responses to electrical stimulation. Additionally, surface EMG was used to determine muscle .ber conduction velocity (MFCV) during the contraction. During the .rst minute of sustained MVC, peripheral fatigue developed slower in patients, and central fatigue occurred in patients but not in controls. The MFCV was higher in patients. Because the initial MVC, the decrease of MVC, initial force response and the initial CAF did not signi.cantly di.er between both groups, it was suggested that mainly peripheral changes seem to be involved in the pathogenesis of fatigue after GBS. However, also central mechanisms cannot be ruled out. In chapter 4.5 a study is described aiming to obtain more insight into the mechanisms behind the favourable e.ects of physical exercise in a group of fatigued GBS and CIDP patients, and aiming to clarify the mutual relationships between the domains fatigue, physical .tness, objectively measured actual mobility, and perceived physical and mental functioning. Generally, no or only few relationships were found between physical .tness and the other four domains, which strongly suggested that physical .tness is not the main contributor to functional improvement during the treatment of these patients. More signi.cant relationships were found between fatigue and perceived physical functioning, between perceived physical and mental functioning, and between perceived mental functioning and actual mobility. It was postulated that training results in improved .tness, which has to be attributed to the training program, but changes in perceived fatigue and functioning do not seem to be signi.cantly in.uenced by improved .tness. This study stressed the presence and importance of additional e.ects of a physical training program, not directly related to its focus of increasing .tness. A possible explanation could be that additional or secondary e.ects of the training program like -attention provided to the patients and the social aspect of training with fellow-patients and increased self-con.dence - mainly caused these e.ects. The methodology and validity of data analysis in this non-controlled study was discussed, however, additional data exploration using other data analysis strategies showed that the main conclusions did not change when using other methods. Chapter 5 is the general discussion describing the most important .ndings of the studies in this thesis related to what is known from literature. It starts with the discussion about several aspects of fatigue assessment. An arbitrarily dissection in central and peripheral fatigue is made. The relations between the occurrence, treatment and possible pathophysiological mechanisms of residual fatigue are discussed. Finally, the treatment options during the acute phase of GBS and future perspectives about GBS treatment are discussed. 193

P.A. van Doorn (Pieter)
Erasmus Medisch Centrum, Rotterdam, NWO
hdl.handle.net/1765/7159
Erasmus MC: University Medical Center Rotterdam

Garssen, M.P.J. (2005, December 14). Treatment of Guillain-Barré syndrome and causes and treatment of residual fatigue. Retrieved from http://hdl.handle.net/1765/7159