Study sample
The patient registry of Oslo University Hospital, Rikshospitalet, was used to identify ethnic Norwegian patients, aged 19–74 years who were diagnosed with acquired autoimmune MG between 1996 and 2006 (n = 125). Diagnosis was based on conventional diagnostic criteria; all patients had typical exertional muscle weakness, and at least two supportive laboratory results, such as a positive edrophonium test, and/or the presence of AChR antibodies in serum, and/or neurophysiological findings consistent with MG (decrement >10% at 3 Hz repetitive motor nerve stimulation and/or increased jitter on single-fibre electromyogram).
A detailed clinical neurological examination was performed at least twice during the year before participation by two of the authors (AE, EK), including a muscle power test of eye muscles (ptosis test and eye motility), bulbar muscles (swallow and speech), muscle power in extremities, neck and respiratory muscles.
Clinical grading according to the Myasthenia Gravis Foundation of America (MGFA) scale was performed on the basis of the patient’s symptomatology and clinical examination. Only patients with MGFA grade II or better during the year prior to the start of the study, regardless of the severity of their MG in the past, were invited to participate (n = 97). The inclusion criteria for the present study were a definitive MG diagnosis, clinical condition not worse than MGFA grade II during the last year before participation, and age between 19 and 74 years.
The statistical program SPSS 17.0 software (SPSS Inc., Chicago, IL, USA) was used to randomly draw five age- and sex-matched controls per eligible patient from normative data, representative of the Norwegian population (n = 2136, age 19–74) [16]. Information about age, body mass index (BMI), disease duration, comorbidities and use of medication (especially AChEI) was obtained from patient records. A questionnaire was sent to patients and controls regarding sociodemographic status, fatigue and duration of symptoms. MG patients also completed two self-reported questionnaires on severity of MG and symptoms of autonomic disturbance.
All study subjects signed informed consent forms. The study was approved by the appropriate independent hospital ethics committee.
Questionnaires
Study subjects completed the Norwegian version of the FQ (Fatigue Questionnaire) [16, 17], which assessed fatigue symptoms experienced during the past month compared with the last time the subject felt well. Seven items related to physical fatigue and four to mental fatigue. The FQ also included a question about symptom duration. Each of the 11 items had four response alternatives; “less than usual” = 0; “same as usual” = 1; “more than usual” = 2; and “much more than usual” = 3, with a maximum possible score of 33. The sum of responses to all items was designated the “Total fatigue level” with a possible range of scores between 0 and 33. The sum of responses to the seven physical items indicated the level of “physical fatigue” (score range 0–21). The sum of responses to the four mental items indicated the level of “mental fatigue” (score range 0–12).
Responses with alternatives were dichotomised; 0 and 1 = 0, 2 and 3 = 1. Substantial fatigue or “fatigue caseness” was defined as a sum score of dichotomised responses ≥ 4 and chronic fatigue was defined as a sum score of dichotomised responses ≥ 4 and symptom duration of ≥ 6 months [16].
The Myasthenia Gravis Questionnaire (MGQ) is a 25-item, disease-specific, patient-reported questionnaire [18, 19]. The authors used the validated Swedish version [19], translating only a few terms into Norwegian (which is very similar to Swedish). The global MGQ score was the sum of scores for all items and ranged from 0 (maximal impairment) to 50 (absence of any impairment). The score of MGQ was validated as an outcome measure and was found to correlate highly with clinical status and MG severity [18, 19].
The Autonomic Symptom Questionnaire is a validated instrument for assessing symptoms of autonomic dysfunction [20]. The Autonomic Symptom profile (ASP) used in the present study is a translation of an abridged version (22 selected items) of the validated questionnaire, and had been proven feasible in a previous study at our institution [21]. The 22 items assessed orthostatic intolerance, vasomotor function, sudomotor/thermoregulatory function, gastroenterologic function, pupillary function and sleep disturbance. The response alternatives were partly dichotomous (“yes” and “no”), and were partly scored from 1 to 5 on a Likert scale. In this study, the responses to all ASP items were dichotomised and assigned a value of 0 (symptom not/rarely present) or 1 (symptom often/always present). Autonomic symptom scores were the sum across all ASP items and were in the range 0–22. The ASP questionnaire also included three items that addressed social and physical disability on 1–5 Likert scales. The total disability score was the sum of these three items in the range 3–15. There was an Item assessing the symptoms of chronic fatigue syndrome (CFS) [22], an item assessing the level of physical activity during leisure time (total score range from 2–6), and an item to cover comorbidity with possible autonomic consequences either caused by the disease itself, hyper-tension, heart disease, diabetes, thyroid abnormalities, polyneuropathy, rheumatoid arthritis or their treatment. Comorbidity was expressed as none = 0, one disease = 1, and 2 or more = 2.
Statistical analysis
We constructed an analytical model including all plausible factors as outlined in Figure 1. Based on theoretical plausibility we assumed that variables could be grouped into four “explanatory levels” and that each variable on a lower level could be explained by variables on a higher level in the hierarchy (e.g., variables at Level 4 could be explained by all variables at Levels 1–3).
Variables contained within Level 1 were: age, sex, BMI, physical activity during leisure, smoking, comorbidity, disease duration, MGQ score, use of AChEI, and symptoms related to chronic fatigue syndrome. Level 2 contained the score of the ASP items, Level 3 contained the total fatigue score, and Level 4 contained the functional (physical and social) disability.
Data analysis was performed with SPSS 17.0 software (SPSS Inc., Chicago, IL, USA). The Student t-test or the Mann–Whitney U test were used as appropriate to compare the MG and control groups, and to compare fatigue level between patients indicated to be symptomatic or asymptomatic according to autonomic symptoms. Variables that strongly deviated from normality were in-transformed to obtain an approximate normal distribution. The potential relationships between the variables within each explanatory level were first explored using bivariate linear regression analyses, and variables with p < 0.1 were included in the multivariate linear regression analyses. In each multivariate model, the distribution of residuals was assessed for normality. For the multivariate regression analyses, we report unstandardized regression coefficients (Bs) with 95% confidence intervals (CIs). A p-value < 0.05 was considered statistically significant.