1. Myasthenia Gravis: from Functioning and Disability evaluation towards new healthcare approaches Alberto Raggi Raggi A, Leonardi M, Antozzi C, Confalonieri P, Maggi L, Cornelio F, Mantegazza R. Neurological Institute C. Besta IRCCS Foundation

2. Disability in MG Disability evaluation in MG patients, has been performed focussing on neuromuscular symptoms’ severity (with no or poor consideration of impairments not directly linked to MG), and on limitations in executing a limited set of ADL, directly linked to MG symptoms (e.g. MG-ADL. Wolfe, 1999). These approaches fail in establishing a connection between MG symptoms, patients difficulties in executing tasks or activities and the environmental factors that contribute to reducing difficulties and improving patients’ ability in performing daily activities and participating to social situations (leisure activities as well as work activities).

3. Disability in MG: a biopsychosocial approach The biopsychosocial approach endorsed by WHO’s ICF Classification (International Classification of Functioning, Disability and Health, 2001) is a useful approach to evaluate patients’ disability status in connection to the context they live in. Myasthenia Symptoms (weakness, mood disturbances…) Limitations and restrictions in performing activities and in participating to social situations Adequate environment (good treatments, positive context…): improvement Unfavourable environment (hindering context…): worsening

4. Quality of Life in MG Since 2000, when MGFA recommended to evaluate HRQoL in MG patients to evaluate intermediate levels of clinical improvement, there has been a strong interest towards its evaluation. Research that employed the SF-36 demonstrated HRQoL to be compromised in MG patients both in its physical and mental components (Paul, 2001; Rostedt, 2006). In 2008, two MG-specific HRQoL instruments have been developed to capture aspects of quality of life specific to MG patients (Burns, 2008; Mullins, 2008).

5. Disability and HRQoL in MG: Besta Institute experience We administered the ICF Checklist (a selection of 128 ICF codes), the SF-36 and the WHO-DAS II (WHO Disability Assessment Schedule, 2 nd version) to 102 MG patients. –ICF codes describe the presence of a problem (from no problem to mild- complete) in body functions/structures and activities. They also describe the presence of barriers/facilitators within the environment. –SF-36: evaluates HRQoL – two main indexes: PCS and MCS –WHO-DAS II: evaluates disability – 6 areas and a global score MG patients were classified with the MG Score System, that describes MG muscle involvement in four areas – ocular, generalized, bulbar and respiratory – and with MGFA classification.

6. Sample characteristics 102 MG patients (68,8% females), aged 18-78 (mean 47.2) 24.5% symptom-free 28.4% with ocular symptoms 25.4% with generalized symptoms 21.7% with bulbar symptoms Following MGFA’s classification 24.5% in Pharmacological Remission 28.4% in Class 1 12.7% in Class II 10.8% in Class III 23.6% in Class IV 52% of patients was not employed (or student) at the timepoint of evaluation, although only 32.4% was retired.

7. Relationship between Disability, HRQoL and MG severity WHO-DAS II total score and SF-36 composite scores have been used to define groups of patients with similar features through a k-means cluster analysis. Three groups have been identified –Cluster A: 51 cases, with low levels of disability and low QoL decrement; –Cluster B: 28 cases, with intermediate levels of disability and intermediate QoL decrement; –Cluster C: 23 cases with high levels of disability and high QoL decrement. ClusterF ABC Dtot8.916.642.6115.6 PCS48.048.632.729.6 MCS51.436.829.373.3

8. Relationship between Disability, HRQoL and MG severity There is a strong relationship between these clusters and MG severity: Cramer’s V=0.456 (P<0.001); Contingency Coefficient=0.542 (P<0.001). Clusters A and C are well defined. In cluster B there is an intermediate area with patients whose disability and HRQoL levels – and therefore whose problems – are not described by traditional severity measurements. MGFAClusterTotal ABC PR196025 class 11512229 class 265213 class 362311 class 4531624 Total512823102

9. Relationship between Disability, HRQoL and MG severity The correlation between disability and HRQoL life tools is strongly significant (*P<.01), but generally moderate. WHO-DAS IISF-36 PFRPBPGHVTSFREMHPCSMCS Understandin & communicating -0,37*-0,30*-0,2-0,23-0,51*-0,31*-0,44*-0,37*-0,28*-0,43* Getting around -0,67*-0,58*-0,46*-0,31*-0,54*-0,32* --0,70*- Self care -0,53*-0,57*-0,28*-0,36*-0,63*-0,43*-0,41*-0,42*-0,49*-0,41* Interactions -0,21-0,33*--0,27*-0,39*-0,34*-0,27*-0,29*-0,25-0,31* Household act. -0,59*-0,61*-0,42*-0,37*-0,55*-0,44*-0,38*-0,31*-0,64*-0,29* Work act. --0,36--0,31-0,53*-0,44*-0,45*-0,42*--0,48* Participation -0,39*-0,53*-0,38*-0,39*-0,56*-0,55*-0,45*-0,48*-0,45*-0,50* Total score -0,62*-0,65*-0,43*-0,44*-0,68*-0,54*-0,50*-0,43*-0,64*-0,46* PF physical functioning, RP role physical, BP bodily pain, GH general health, VT vitality, SF social functioning, RE role emotional, MH mental health, PCS physical composite score, MCS mental composite score

10. Relationship between Disability, HRQoL and MG features Mann-Whitney U test reports significant differences, consistent with MG features, in WHO-DAS II and in PCS scale. No inter-group difference is observed in MCS scale. P<0.01 P<0.05

11. The description of Disability in MG Through a direct application of the ICF checklist to MG patients, we identified 54 relevant categories (i.e. those reported as a problem by more than 30% of patients): –14 Body Functions –2 Body Structures –22 Activities and Participation –16 Environmental Factors

12. ICF relevant categories from Body Functions and Structures domain Most of impaired functions are mental (emotional, energy and drive, sleep..). MG-specific functions (seeing functions, muscle endurance, voice, ingestion…) are all reported as a problem. Around 60% of our sample reports pain as a problem. ICF category description% b435 Immunological system functions100.0 b210 Seeing functions83.3 b740 Muscle endurance functions77.5 b152 Emotional functions72.6 s220 Structure of eyeball67.6 s420 Structure of immune system63.7 b130 Energy and drive functions62.7 b510 Ingestion functions61.8 b280 Sensation of pain60.8 b134 Sleep functions58.8 b730 Muscle power functions54.9 b440 Respiration functions48.0 b144 Memory functions41.2 b310 Voice functions41.2 b235 Vestibular functions37.3 b140 Attention functions33.1

13. ICF relevant categories from Activities and Participation domain Most of problematic activities refer to mobility (carrying objects, driving, walking….), to self care and to activities requiring a physical effort (doing housework, acquisition of goods and services…). Approximately one-third of the identified areas deal with relational abilities and skills (conversation, formal relationships, remunerative employment…). ICF category description% d430 Lifting ad carrying objects87.3 d110 Watching86.3 d475 Driving79.5 d640 Doing housework81.3 d450 Walking78.5 d220 Undertaking a multiple task78.4 d350 Conversation77.5 d620 Acquisition of goods and services77.4 d330 Speaking74.5 d560 Drinking74.5 d550 Eating73.5 d630 Preparing meals72.5 d510 Washing oneself71.5 d440 Fine hand use57.9 d520 Caring for body parts47.1 d540 Dressing48.0 d730 Relating with strangers46.0 d470 Using transportation44.1 d920 Recreation and leisure41.2 d740 Formal relationships39.2 d750 Informal social relationships31.4 d850 Remunerative employment30.4

14. ICF relevant categories from Environmental factors domain The majority of EF are herein reported as facilitators: health SSP, drugs, support from family members and doctors. Several areas, generally not covered by established assessment tools are evidenced. Among them, attitudes and support from friends and colleagues, as well as transportation SSP. ICF category description% (% barriers) e580 Health services systems and policies100 (11.8) e110 Products or substances for personal consumption 99.0 (0) e310 Immediate family99.0 (3.0) e355 Health professionals98.0 (1.0) e450 Individual attitudes of health professionals98.0 (6.9) e320 Friends92.2 (6.9) e410 Individual attitudes o immediate family members 93.1 (10.8) e540 Transportation services systems and policies81.4 (16.7) e125 Products and technology for communication77.5 (1.0) e420 Individual attitudes of friends75.7 (8.8) e325 Acquaintances, peers, colleagues and community members 71.6 (11.9) e570 General social support services systems and policies 65.7 (10.8) e330 People in position of authority41.2 (10.8) e120 Products and technology for personal indoor and outdoor mobility and transportation 36.4 (2.0) e225 Climate37.2 (25.5) e590 Labour and employment services systems and policies 30.4 (7.8)

15. The effect of Environmental Factors on disability in MG Through an ICF-based approach to the evaluation of functioning and disability of MG patient, we recognized the positive effect of Environmental Factors (EF) in determining MG patients disability staus. Impairments have play a primary role in the definition of disability of MG patients: but their functional status is also improved by the effect of some relevant EF. Therefore, future studies on MG patients’ health status should endorse this new perspective.

16. HRQoL and Disability in MG We stressed that physical aspects of HRQoL are more closely related to disability profiles than mental health ones. Clinical status is also a relevant issue: the impact of MG on disability and HRQoL increases consistently with the disease’s severity. If worsening of HRQoL’s physical aspects is predictable by the disease, less evidence supports hypotheses on the decrement of mental aspects. This decline might be a consequence of the disease itself: however, the role of the context in which daily activities are carried out should be considered too.

17. Why functioning and disability data in MG? Clinical evaluation answers to the need of highlighting disease features and providing medical treatment, through the description of muscle strength and resistance. On the contrary, functioning and disability data, as well as HRQoL ones, report information on the lived experience of disability of patients, and on their needs to overcome some of their difficulties: for this reason, such kind of measures should be employed in MG research.

18. Future directions The results of this research could be used to develop MG-specific assessment measures, able to distinguish MG features from activity limitations and participation restrictions that patients experience. At the same time, such assessment tools should be able to provide a measure of the facilitating/hindering role of the environment. Once such measures are developed, they could be employed to evaluate treatment effectiveness, as well as other health and social interventions, not only on MG clinical status, but also on patients’ everyday lives.