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Leventhal’s Self-regulatory Model and Patient Behaviour

Traditionally, medical thought on how illness affects an individual has been governed by the bio-medical model; this posits that pathological biological processes, attenuated by the ability of pharmacological or surgical intervention to stop or manage these processes, explain disease outcomes. A full, if early, critique of the biomedical model is given by Engel (1977). Here Engel labels this approach ‘reductionist’; not taking into account how patient behaviour, emotional response to illness, and beliefs about illness may also contribute to disease outcomes. Engel instead argues for a bio-psychosocial model of disease, which, as well as including underlying biological pathology, implicates patient behaviour, illness perceptions and emotions, within the wider societal and social context of disease, as having a bearing on disease progression and outcome.

As medicine has progressed, the bio-psychosocial model has become more widely embraced by clinicians (though not uniformly embraced, see Adler, 2009); exemplified, in the last chapter, by the acceptance amongst many in the medical community of the need to measure QoL when considering the impact of disease and the effectiveness of treatments (Burns et al., 2012; Cella & Tulsky, 1990). Indeed, even a physician most sceptical of the impact of patient behaviour or cognition on disease outcome would be unlikely to deny the role of adherence to medication in determining the success of a pharmacological intervention.

Social Cognition models

The bio-psychosocial model has limited practical application. This is because it is vast; incorporating all potential disease, environmental, societal, psychological and behavioural factors impinging on a patient; meaning that it cannot propose a clear relationship between included variables. For these reasons it has been criticised for not being a model but rather a theory; vague, and lacking in predictive value (McLaren, 1998).


Social cognition models as applied to health are born out of the tradition of the bio-psychosocial model, but are more focal in what they aim to explain; how patient health cognitions combine to drive health behaviours. The central tenent underlying social cognition is the idea that a given person’s behaviour is best explained by their own interpretation of reality, rather than by the objective properties of reality.

Social cognition models are considered a part of self-regulation research (Connor, 2010). Self-regulation can be defined as “ mental and behavioural processes by which people enact their self-conceptions, revise their behaviour, or alter the environment so as to bring about outcomes in line with their self- perceptions and personal goals” (Fiske & Taylor, 1991, p.181). Self-regulation therefore involves associations, or feedback, between cognitive factors such as beliefs or motivation, goal setting and the evaluation of goal-directed behaviour.

Self-regulation can be considered to consist of two phases; a motivational phase and a subsequent volitional phase. The motivational phase involves selection of a desired outcome via the goals and implied actions necessary to meet the outcome, whilst the volitional phase involves planning and action towards a set goal (Connor & Norman, 1996).

Leventhal’s SRM is a social cognition model, but there are a range of other social cognition models, with the two most prominent being the Health Belief Model (Rosenstock, 1974) and the Theory of Planned Behaviour (Azjen, 1988). The Health Belief Model posits that the likelihood of a person performing a given health behaviour can be predicted by beliefs about the level of threat, based on perceived susceptibility and perceived severity, alongside the perceived costs or benefits of undertaking the health behaviour (Connor, 2010). Specific cues, such as a media campaign or a salient symptom, and the person’s degree of health motivation may also increase the likelihood of a particular health behaviour being carried out. The Theory of Planned Behaviour, places more emphasis on a person’s intentions to perform certain behaviour, with intentions determined by the attitude towards a particular behaviour, subjective norm and perceived behavioural control.


However, the Health Belief Model and the Theory of Planned Behaviour, may provide an inadequate explanation of QoL in muscle disease. As outlined in Chapter 2, muscle diseases are generally chronic and progressive, requiring the constant management of symptoms through the application of functional aides, hospital trips, monitoring of symptoms etc. The Health Belief Model and Theory of planned behaviour are designed to account for the volition of specific health behaviours, rather than the self-management of a chronic disease where goals are multiple, over-lapping or concurrent, and coping procedures are required to manage both the physical aspects of treatment of disease (application of functional aides and home adaption), as well as the emotional and social consequences. Leventhal’s SRM allows for dynamic ongoing cognitive and behavioural processing and incorporates the multiple, overlapping goals required for the self-management a chronic disease, such as muscle disease. For these reasons, Leventhal’s SRM is the explanatory framework applied to QoL and mood muscle disease in the present course of research.

Description of Leventhal’s self-regulatory model

Leventhal’s SRM specifies how illness representations guide coping responses to illness-related experiences and health threats. Here individuals are conceived as protagonists, whose goal is to maintain the ‘status quo’ of their own health, avoid pain and suffering or improve their health (Petrie, Broadbent & Meechen, 2003; Cameron & Moss-Morris, 2010) using continuously updating cognitive representations of their illness to guide their choice of actions. This is achieved through the process of self-regulation as an individual must select and monitor their behaviour over time in order to make progress toward their goals.

Illness representations may be informed by a range of sources (stored memories, interactions with health professionals, personal experience, social or cultural influences). The perception of a health threat activates pre-existing illness representations stored in memory and, through integration with current contextual information, individuals are guided in their selection of behaviours used to cope with, manage, or remove a threat. This is a dynamic system where the outcomes of these coping procedures are monitored and appraised;


feedback loops ensure that illness representations and coping behaviours undergo a process of change and refinement.

Figure 3.1 shows that, in addition to processes for regulating the cognitive and behavioural response to a health threat, there is a second motivational process regulating the emotional response. The processes in this emotional arm of Leventhal’s SRM occur in parallel to the cognitive arm. This involves the elicitation of anxiety and fear, which motivate behaviours to control distress. As in the cognitive arm, coping strategies are monitored and appraised for success, with emotional representation updated by feedback loops between these factors (Cameron & Jago, 2008). It should be noted from Figure 3.1 that the cognitive and emotional arms are not exclusive processes, but rather, are inter-related. For example, an anxious emotional representation of an illness is likely to be related to perceived high consequences (Moss-Morris et al., 2002).

Therefore, Leventhal’s SRM can be said to comprise three distinct stages which occur in parallel for the cognitive and emotional arms: (1) A perceptual stage, in which a discrepancy between a perceived input and a reference value is detected (representation of a potential health threat); (2) A response stage in which an action is sought and performed to remove the discrepancy (removal of the threat); (3) an appraisal stage, in which the results of the action used to remove the threat are evaluated (Leventhal et al., 2010).


Illness representations/Illness perceptions

Illness representations are frameworks or working models that patients construct to make sense of their symptoms and medical conditions. A patient’s cognitive representation of his or her illness then guides behaviour directed at managing the condition (Leventhal, Nerenz, & Steele, 1984). An illness representation comprises a number of interrelated beliefs about an illness and what it means for the patient’s life (Petrie & Weinman., 2012).There are a number of roughly synonymous terms for illness representations which are used interchangeably across the literature, often depending on how the illness representations are measured or conceptualised in a particular course of research, including: illness perceptions; illness cognition, and; illness schemata.

Leventhal’s SRM identifies five key components of illness representations, in the present course of research these components as conceptualised individually will be called illness perceptions, they are: (1) Identity: this includes the label given to the health threat and the symptoms attributed to it. This involves noticing or monitoring functional or experiential changes in oneself; (2) Timeline: the perceived temporal trajectory of the health threat, with symptoms increasing, decreasing or coming and going in a cyclical fashion; can be


assessed objectively with clocks and calendars; (3) Consequences: the perceived impact on one’s life in terms of the physical, psychological, social, economic impact; (4) Causes: the causal factors, these may be physical, as well as behavioural or psychological – for example, a pathogen, stress, getting wet in the rain, medication, diet, stress etc., and; (5) Controllability: relates to whether this threat is perceived to be controllable by either patients’ own behaviour or by medication, it is distinct from the efficacy of the response to control it – this occurs in the response stage (Leventhal et al., 2010).

An Illness representation may comprise abstract information (labels given to a potential health threat, or linguistic phrases or ideas held in memory ‘I get these 24 hour vomiting bugs every year’), concrete images (vivid images of being sick), (Cameron & Moss-Morris, 2010) and somatic feelings (nausea, sweating etc.). Once a scan of the body sensation identifies discrepancy from normal somatic sensation, an individual may then test prototypes for various previous or possible health threats. Each potentially applicable prototype will include information relating to the five components of the illness representation. So for example, a 24 hour vomiting bug may be perceived to be caused by a virus caught at work (as someone else has it). The consequences are major in the short term (major impairment in activities of daily living and unpleasant symptoms for 24 hours), temporally it is acute not chronic (‘this is unpleasant but it will pass soon’); it can only be controlled minimally with medication or with personal behaviour (‘there is little that I, or my doctor, can do to treat this – it just has to be endured). Current contextual factors, and symptom changes are then integrated into, or tested against existing prototypes; these representations then guide coping responses (e.g. as neither I, nor my doctor or medication can help me with this vomiting bug – I will fast, drink water and wait for this bug to go away). Appraisals of the coping procedure will update the illness representation (‘I have had this 24 hour bug now for 3 days; perhaps this is something more serious’) which in turn may update the coping procedure (‘now need to see my general practitioner’).

As hinted above, Illness representations are informed by inter-personal communication. A process of social comparison can emerge from the “How are you?” conversation. In the presence of a health threat a dyadic interaction may


proceed to “What is bothering you?”. Then through to questions about which symptoms are involved; where, when, and what has been tried to get rid of the health threat etc. This interaction not only reinforces the individual checking process, but also opens the checking process up to include social comparison; where prototypes are compared against the other individual’s apparent objective health status or past experiences of illness; Leventhal et al. (2010) state:

“We assign meaning to symptoms and functional changes by checking for common exposure (e.g. exposure to someone with SARs), familial linkage (Family member had cancer), similarities in physiognomy, temperament, and response to aging (e.g. parental dementia a sign of risk to self)”

Leventhal et al., (2010) p4

Relating Illness representations to action plans

The illness representation guides the selection of behaviours used to manage the health threat (prevent, detect, cure or control); in this way illness representations can be said to instigate plans of action. The specific coping procedure can be selected from a number of sources – from herbal remedies, to getting more exercise, to preparing one’s self to endure discomfort, or visiting the accident and emergency department. Procedures are highly valued if they are believed to attack the disease at its source, or mode of action, and to do so quickly or affect a perceptible target (removal of a rash, headache, nausea) (Leventhal et al., 2010).

Leventhal et al., (2010) go on to state that the course of action taken to control a health threat is determined by the match between the procedural representation and the illness representation: if cancer is a growth or lump then surgical removal makes good “common sense”, whilst radiation makes less sense because it still leaves something in the body. Similarly, in asthma, if patients perceive that they have asthma only when they experience symptoms, then they are unlikely to use prescribed inhalers when asymptomatic (Halm et al., 2006; Horne & Weinman, 2002). The decision as to whether to discontinue a procedure may also rely on temporal feedback. For example, in diabetes,


attempts to control blood glucose levels by using diet and exercise, as opposed to using medication, may provide delayed feedback which does not fit as comfortably as medication with the idea of a disease.

Empirical evidence for the self-regulatory model

Questionnaires have been developed to capture the components of illness representations. The first of these was the Illness Perception Questionnaire (IPQ) (Weinman, Petrie, Moss-Morris, & Horne, 1996), which included domains measuring representations on the ‘cognitive arm’ of the SRM (identity, causes, timeline, consequences, cure/control). This was later expanded in the Illness Perception Questionnaire Revised (IPQ-R) (Moss-Morris et al., 2002) to include emotional representations (from the ‘emotional arm’ of Leventhal’s SRM) and to divide control perceptions into personal control and treatment control domains. A further domain, illness coherence, was also introduced in the IPQ-R to capture the extent to which an individual feels that they understand their illness. The IPQ-R is designed to be adapted to capture illness perceptions in a range of health conditions, but there is also a version for healthy people (IPQ-RH) (Figueras & Alves, 2007). There also exists a shortened version of the IPQ, the Brief IPQ. The Brief IPQ was developed (Broadbent, Petrie, Main & Weinman, 2006) to reduce participant burden and subsequently consists of nine single- item scales (as opposed to the 71 items in the IPQ-R).

The arrival of the illness perceptions questionnaires has afforded the opportunity to quantitatively test the predictive power of Leventhal’s SRM. Thus, over the past 15 years a large number of studies have emerged showing associations between illness perceptions and a range of health behaviours or outcomes.

Associations between Illness perceptions and patient outcomes

In terms of outcome variables, research which has sought to investigate the explanatory role of illness perceptions can be separated in four broad categories: QoL; emotional distress; survival; and treatment related behaviour such as adherence (adapted from Petrie & Weinman, 2012). Given the size of the literature investigating a link between illness perceptions and health


outcomes, a comprehensive review is beyond the scope of this chapter. Therefore in this section some seminal and interesting findings across a range of disease groups in each of the four areas identified by Petrie & Weinman (2012) will be described. Then, in the following section, a review (with systematic search strategy) of studies investigating illness perceptions in neurological populations will be undertaken.

An early meta-analytic review by Hagger & Orbell (2003) synthesised data from studies which used Leventhal’s SRM to explain QoL in various disease groups. Here 45 studies were assessed, and many of these reported associations between illness perceptions and QoL. Averaged across included studies, they reported moderate to strong associations (r = -.28 – -.67) between Identity and all QoL domains, and consequences and all QoL domains (r = -.18 – -.50). Cure/control (r = -.03 – -24) and timeline (r = -.03 – -20) were shown to have weaker correlations with all QoL domains.

Studies which have used regression analyses to allow for the explanatory role of other variables have observed illness representations to explain large amounts of unique variance in QoL even after disease severity has been accounted for; in a range of disease groups (e.g. multiple sclerosis, renal disease, heart disease) (see: Aalto et al., 2006; Jopson & Moss-Morris, 2003; Rose et al., 2012; Spain et al., 2007; Timmers et al., 2008). To illustrate, Aalto et al. (2006) assessed the explanatory value of illness perceptions for QoL in a sample of over 3000 people with coronary heart disease. Here demographics explained between 2-3% of the variance in QoL, with disease severity variables (including physiological markers: nitrates, revascularisation) explaining an additional 8-13% of the variance, and illness perceptions adding an additional 16-18% to the proportion of explained variance. Similar results were returned by Arat et al., (2011) who observed illness perceptions to add an additional 12 – 30% to the proportion of explained variance in QoL score for 217 people with systemic sclerosis; this after demographics, disease severity and coping variables had been considered.

Significant associations have been observed between illness perceptions and emotional outcomes in several disease groups (Chilcot, Wellsted, Davenport &


Farrington, 2011; Dickens et al., 2008; Husain, Dearman, Chaudhry, Rizvi & Waheed, 2008; Murphy, Dickens, Creed & Bernstein, 1999; Philip, Lindner & Lederman, 2009). For example, Chilcot et al., (2011) using logistic regression analysis, observed 24.3% of the variance in depression in renal patients to be explained by illness perceptions, after clinical variables and demographic factors had been accounted for. Here, consequences, illness coherence and personal control were independent predictors of depression. In a longitudinal regression analysis, Dickens et al., (2008), recorded illness perceptions in the days following myocardial infarction in 269 participants; those who became depressed within the next 12 months had stronger baseline perceptions of a chronic timeline and lower treatment control.

In a recent study Vollman, Kalkouskaya, Langguth & Scharloo (2012), showed that Illness perceptions explained 58% of the variance in symptomatic complaints in people with tinnitus. A very poignant example of the ability of illness perceptions to predict outcome was demonstrated by Chilcot, Wellsted & Farrington (2011). Here illness perceptions were found to predict mortality in patients with renal failure; even after controlling for both clinical factors and depression, the perception of treatment control was predictive of all cause mortality.

Research has shown that a range of behavioural outcomes such as adherence to medication, screening uptake and return to work following myocardial infarction are associated with illness representations. Petrie & Weinman (2012) posit that non-adherence is due to a poor fit between a patient’s model of the illness and the course of treatment, meaning that the treatment doesn’t make sense to the patient. To illustrate this, Halm, Mora & Leventhal (2006) reported that patients who believe that their asthma is only present when they are symptomatic are less likely to adhere to inhaler medication. Also, 11% of the variance in uptake of mammography screening was explained by illness representation in a logistic regression analysis; this after demographic and risk variables had been taken into account (Anagnostopoulos et al., 2012).


Associations between Leventhal’s SRM and coping

As links between illness representations and coping are made explicit in Leventhal’s SRM this has led many researchers to assess associations between the illness perception questionnaires and measures of coping (Hagger & Orbell, 2003). In most coping measures coping is operationalized as a set of emotional/behavioural traits, or tendencies which are used to deal with adverse situations. So, for example, in one of the most widely used measures, the Brief COPE (Carver, 1997), there are domains measuring the propensity to use support seeking, denial, planning, behavioural disengagement. Paraphrasing findings by Hagger & Orbell (2003), low-to-moderate correlations between illness perceptions and coping behaviours were found across the reviewed studies. The most convincing associations were positive correlations between; consequences and avoidant coping (r =.23) and expressing emotions (r =.21); cure/control and cognitive reappraisal and generic problem focused coping; identity and avoidant coping and expressing emotions.

These weak correlations seem to contradict the SRM as the model makes associations between illness perceptions to coping method explicit. However, as the correlations above are all based on illness perceptions held in the ‘cognitive arm’ of the SRM (Hagger & Orbell, [2003] only reviewed studies which used the IPQ which does not record emotional representation), one would expect specific behavioural strategies to be used (taking medication, controlling diet, visiting GP, doing exercise) to cope with a health threat, as opposed to generalised emotional/ behavioural traits. The coping methods used in the ‘emotional arm’ of Leventhal’s SRM (i.e. the coping methods used to cope with the emotional response to a health threat) are more likely to occur in a way analogous to that which is operationalized in measures of coping (e.g. Brief COPE); since coping response to ‘feelings’ may require less concrete action and more emotional regulation or social coping methods.

Hagger & Orbell (2003) also found too few studies to test the assumption that coping mediates the effect of illness perceptions on outcomes. However, the very idea that coping should mediate a health outcome may be inconsistent with Leventhal’s SRM. One must not forget that in Leventhal’s SRM coping refers to


any action taken to control the health threat (taking medication, doing exercise, resting) so in Leventhal’s SRM the coping method may be considered the outcome – a coping method would be used to reduce the impact of the health threat.

Literature review of Leventhal’s self-regulatory model as applied to neurological populations

To get a more cohesive view of how the SRM might help explain patient behaviour, it may be helpful to focus in on what the SRM has taught us about a particular disease, or group of diseases. Given the present course of research, it would, of course, be optimal to examine the SRM as applied to muscle disease. However, as there has been just one study investigating illness perceptions (as conceptualized by Leventhal) in muscle disease (Rose et al., 2010), it is necessary to broaden the focus to include other illness groups. Though some inflammatory myopathies may also be cared for my rheumatologists, muscle diseases generally come under the care of neurologists. Therefore, we have undertaken a review of studies which have applied Leventhal’s SRM to neurological populations.

A systematic search strategy was used to find peer-reviewed publications investigating the role of illness perceptions in neurological populations. The following databases were searched: Ovid, PubMed, PsychINFO and EMBASE. The key search terms were: ‘illness perceptions’, ‘illness representations’, ‘illness cognitions’, combined with ‘neurology’, ‘neurological’, ‘neuromuscular’, ‘epilepsy’, ‘head injury’, ‘dementia’, ‘multiple sclerosis’. This search strategy returned 173 articles, from which 14 were relevant. Following this the references sections of all included papers were examined, and any studies which were missed by the initial search strategy (an additional 3) were then included.


Muscle Disease: an overview

Muscle diseases are a diverse group of inherited and acquired neuromuscular conditions which cause wasting of muscle tissue, and, in turn, an insidious decline in mobility. Their age of onset is wide, and they are predominantly chronic in timeline. Alongside muscle symptoms, muscle diseases may bring cardiorespiratory complications, fatigue, pain and a range of other symptoms depending on the diagnosis.

Unfortunately, at present, there are no cures for muscle disease and treatment options are limited for muscle symptoms in the majority of muscle diseases. Therefore, medical management usually involves the monitoring of symptoms and treatment of non-muscle symptoms, such as cardiorespiratory problems, alongside physiotherapy and occupational therapy input to maximise remaining muscle function.

The diversity of muscle disease diagnoses means that there can be profound differences in pathophysiology, age of onset, the pattern of muscles affected, levels of functional impairment, and treatment possibilities between two typical presentations of different muscle diseases; such that someone with the genetic condition Myotonic Dystrophy I may experience progressive myotonia, muscle weakness and fatigue alongside cataracts, hair-loss, arrhythmia, cognitive impairment and glucose intolerance, with all these symptoms starting at an early age and leading to high levels of functional impairment for which there are few effective treatments. Whilst someone presenting with an inflammatory myopathy may only acquire this disease in later age and experience selective muscle wasting, for which immunosuppressive treatment and corticosteroids provide good control over symptoms. Indeed, great differences between clinical presentations may occur even within the same muscle disease diagnoses groups in terms of age of onset, symptoms, and levels of functional impairment.


Included and excluded of muscle diseases

Whilst muscle diseases may also bring with them a range of other symptoms, in the present thesis only diseases which primarily affect muscle tissue, as opposed to affecting nerve tissue and/or the neuromuscular junction, were included. This meant that diseases which involve the neuromuscular junction (e.g. Myasthenia Gravis) or anterior horn diseases, such as motor neurone disease, spinal muscular atrophy, Charcot-Marie-Tooth disease, poliomyelitis and progressive muscular atrophy were not under study.

The present course of research aimed to explain and change adverse illness perceptions in adults with muscle disease. Therefore the most prevalent of the muscle diseases, Duchene muscular dystrophy, was excluded from the diseases under study as Duchene is associated with early mortality – limiting progression into adulthood.

Prevalence of muscle disease

It is estimated that between 50,000 (Merrison & Hanna, 2009) and 73,060 people (Muscular Dystrophy Campaign, 2010) within the UK currently have a muscle disease. Whilst most individual diagnoses are quite rare (see prevalence figures for individual muscle diseases in Table 1.1), Norwood et al., (2009) in a detailed population study of patients with muscle disease in the northern region of England, observed the muscle diseases to have a combined prevalence of 37/100 000. This figure compared to the estimated prevalence of 180/100 000 for multiple sclerosis (Forbes & Swingler, 1999), and 7/100 000 for motor neurone disease (Traynor et al., 1996) in proximal geographical and demographical regions, suggests that, if taken together, muscle disease represents a significant sized patient-group. However, the figure given by Norwood et al., (2009) included those with Duchene muscular dystrophy and spinal muscular atrophy, which were excluded from the sample under study in the present course of research.

On the other hand, the figure given by Norwood et al., (2009), did not include patients with inflammatory myopathies (IM) which are included in the present course of research. The inflammatory myopathies category includes


polymyositis, dermatomyositis and inclusion body myositis. Studies investigating the prevalence of polymyositis and dermatomyositis in a Canadian sample (21.5/100 000) (Bernatsky et al., 2009) and inclusion body myositis in an Australian sample (0.93/100 000) (Phillips, Zilko & Mastaglia., 2000), suggest that together the inflammatory myopathies also represent a significantly sized group of patients.

As many individual muscle diseases are hereditary, the prevalence of these diagnoses can vary greatly depending on the geographical area studied. So for example, the prevalence of oculopharyngeal muscular dystrophy (OPMD) is relatively high in French Canada, having been traced back to immigrants from France in 1634, and Fukuyama congenital muscular dystrophy is prevalent in Japan (second only to Duchene muscular dystrophy in prevalence) but extremely rare elsewhere (Emery, 2002).

The general pathophysiology of muscle disease

The muscle diseases included in the present course of research may be genetic or acquired.

Genetic muscle disease pathophysiology

The phenotype of a genetic muscle disease arises from a range of genetic pathways. Genes associated with muscular dystrophies encode proteins of the plasma membrane, extracellular matrix, the sarcomere, Z band and nuclear membrane components. Muscle has distinctive structural and regenerative properties, meaning that, many of the genes implicated in muscle disease target pathways unique to muscle, or highly expressed in muscle (McNally & Pytel, 2007). The expression of affected genes may also occur in other organ systems, and it is this which gives rise to cardiac, cognitive and other clinical presentations.

Figure 1.1 shows the proteins involved in many genetic muscle diseases. Particular detail is given to the sarcloemma, where the dystrophin associated protein complex (DAPC) is located; an area which contains many of the proteins affected by genetic muscle diseases. The sarcolemma is a thin membrane


covering striated muscle; it is made up of the true cell membrane, called the plasma membrane, and an outer coat made of a thin layer of polysaccharide material with numerous thin collagen fibrils. It receives and conducts stimuli, and, at the end of the muscle fibre the outer layer of the sarcolemma fuses with tendon fibres, which in turn collect into bundles to form muscle tendons. So for example, abnormal expression of the gene coding for the sarcoglycans causes muscle dystrophy in some limb-girdle muscular dystrophies (LGMD 2D,2E, 2C, 2F), whereas abnormal expression of genes coding for dysferlin (LGMD 2B) or calpain (LGMD 2A) can cause muscular dystrophy in other limb-girdle muscular dystrophies.

Outside of the DAPC, abnormal expression of genes coding for lamin in the muscle nuclei may cause another variant of limb-girdle muscular dystrophy (LGMD 1B); whereas myotonic dystrophy may be caused by an abnormal phenotype of enzyme dystrophia myotonica protein kinase. Other main genetic muscle diseases include facioscapulohumeral muscular dystrophy (FSHD), myotonic dystrophy (MyoDys) and oculopharyngeal muscular dystrophy (OPMD).


Acquired muscle disease pathophysiology

The inflammatory myopathies (IM) (polymyositis/dermatomyositis) and inclusion body myositis (IBM) are diseases in which the skeletal muscle is damaged by the immune system. The autoimmune response in dermatomyositis is mediated by a humoral immune response i.e. secreted antibodies produced in the cells of B lymphocytes, rather than cell-mediated immune responses. This immune response leads to destruction of capillaries in muscle and other tissues (including the skin). In the muscle tissue, the resulting microangiopathy leads to the characteristic pathological features of infarction and perifascicular atrophy; it has been proposed that the muscle pathology is caused by resulting ischemia. However, alternative accounts for muscle pathology have also been suggested (see Greenberg, 2007 for a review).


Polymyositis is believed to occur via a cell-mediated auto-immune response in which myofibers are invaded by antigen-specific cytotoxic T cells (Hilton-Jones, 2003). Inclusion body myositis is also believed to occur via a cell mediated auto-immune response. However, in inclusion body myositis, compared with polymyositis, there is less frequent myofibre necrosis and more frequent invasion of non-necrotic myofibres by mononuclear cells (Greenberg, 2007). In addition, a degenerative process of uncertain origin may occur in muscle fibres in inclusion body myositis; this has been likened to the process of neural degeneration which occurs in Alzheimer’s disease (Hilton-Jones, 2003).

The diagnosis of muscle disease

Depending on the type of muscle disease suspected, diagnosis generally involves examination of presenting features: patterns or weakness, contractures, myotonia, cramps, cataracts, skin involvement etc. Guided by these features investigations may then progress directly to blood tests, muscle biopsy and neurophysiology to discern muscle pathology, and in many cases, genetic analysis. Frequently, getting a diagnosis of a specific muscle disease can prove elusive; even with genetic testing the results may not point to one diagnosis in particular, and new types of muscle disease do continue to emerge. This means that a significant proportion of people who have muscle disease do not have a specific diagnosis; leaving many newly diagnosed people in the unenviable position of knowing that they have a serious, likely progressive and incurable chronic disease, but without a clear idea of the symptoms which may emerge in the future, or heritability for any children etc.

Clinical features of the major included muscle disease groups

Here the main included muscle diseases will be discussed individually in terms of: patterns of muscle involvement; associated symptoms and characterising features; functional impairment, and; treatment and management options.

Facioscapulohumeral muscular dystrophy (FSHD)

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic autosomal dominant disorder, though the exact genes involved remain unconfirmed. It has a variable age of onset, but is, in most cases, detected by late adolescence (Lovering, Porter & Bloch., 2005). Figure 1.2, shows the pattern of muscle weakness evident in FSHD. FSHD is characterised by sequential weakness of the muscles in the face followed by the proximal upper extremity, including the muscles which stabilize the scapula, progressing to weakness in the distal muscles. FSHD may also have cardiac, cognitive, visual, auditory, and in rare cases, respiratory, involvement. There is a wide range of clinical severity, from asymptomatic individuals to those who are wheelchair-dependent, and speed of progression also differs greatly across cases. Given the distinctive pattern of muscle involvement in conjunction with an autosomal dominant family, a clinical diagnosis of FSHD can be made with relative certainty without the need for muscle biopsy. However, FSHD may also be confirmed with molecular diagnosis (Tawil, 2008).

Given that the pathophysiology of FSHD is currently unknown, it is unsurprising that treatment options, particularly pharmacological interventions, remain limited. However, interventions designed to manage symptoms and maximise function exist. Firstly a surgical procedure called scapular fixation may enhance arm mobility (Rhee & Ha, 2006). Other surgical options may also help maximise function: gold weights have been implanted into upper eyelids to correct lagophtalmos (Sansone, Boynton & Palenskil, 1997), and tendon transfer may fix a foot drop (Tawil, 2008). Management of symptoms may also include: tailored orthoses to maximise function of muscles and reduce discomfort;

antidepressants to reduce pain; biPAP for respiration problems when sleeping. Moderate exercise is sometimes recommended but does not appear to improve strength significantly (Voet et al., 2010).

Figure 1.2. Typical patterns of muscle involvement for several included muscle diseases (adapted from Emery et al., 2002; reproduced with permission).

Myotonic Dystrophy (MyoDys)

There are two main types of MyoDys (myotonic dystrophy type 1 [MyoDys 1], and; myotonic dystrophy type 2 [MyoDys 2]) but even within MyoDys1 there are four further sub-groups (mid/late onset; classic; childhood onset and congenital).

DM1 is caused by an expansion of an unstable CTG trinucleotide repeat in a region of the gene which codes for myosin protein kinase. Generally speaking,


longer CTG repeat expansions correlate with an earlier onset, and more severe presentation of MyoDys. Usually people without MyoDys have between 5 and 37 CTG repeats. CTG repeat lengths exceeding 37 are considered abnormal; patients with up to 49 repeats may be asymptomatic, but due to anticipation (repeat lengths increasing generationally), they are more likely to have children with pathologically expanded repeats. Symptomatic repeat sizes can range from 50 CTG repeats up to 4000+ CTG repeats (Turner & Hilton-Jones, 2010).

In this section we will focus on classic MyoDys1. The main symptoms of classic MyoDys1 are distal muscle weakness and myotonia, leading to a difficulty performing tasks which require fine dexterity of the hands (doorknobs, knives and forks etc.) and foot drop. Myotonia may also affect speech production. Facial wasting and weakness alongside neck weakness and ptosis cause what is refered to as a ‘hatchet’ appearance. Muscle weakness in MyoDys tends to be slowly progressive.

MyoDys has multi-system involvement (central nervous system, gastrointestinal tract, endocrinopathy and respiratory). This leads to: cardiac symptoms (tachyarrhythmias and bradyarrhythmias) which are significant contributors to mortality and morbidity of the disease; cognitive impairment and sleep disturbance; gallstones; disturbance of thyroid, pancreas, hypothalamus and gonads, alongside; cataracts and frontal balding.

In terms of treatment, there are no cures for MyoDys1 and, as with FSHD, medical intervention usually involves managing expected complications associated with the disease. There is little evidence supporting any treatment of muscle weakness or myotonia, and exercise does not appear to improve muscle strength (though it does not appear to be harmful: Voet et al., [2010]). The management of other symptoms requires multi-disciplinary specialist input. For example: insertion of pacemakers may reduce the risk of sudden cardiac deaths; modafinil may aid excessive fatigue or sleepiness; cataracts may benefit from surgery, and; occupational therapy and physiotherapy input in the form of home adaption and orthoses may help maximise function.

MyoDys2 involves the same systems as MyoDys1, though to a less severe extent. Pain and hyperhidrosis are more prominent in MyoDys2 than in


MyoDys1. Treatment options are the same for both myotonic dystrophy sub- types.

Limb-girdle muscular dystrophy (LGMD)

The limb-girdle muscular dystrophies involve abnormal gene expression which may affect proteins in the DAPC or elsewhere (see Table 1.1 for a selection of LGMDs and involved proteins). Currently, over 15 different types of LGMD have been discovered (Guglieri, Straub, Bushby & Lochmuller, 2008), with inheritance patterns either autsomal recessive or dominant; autosomal dominant forms are very rare and tend to be less severe than recessive types (Emery, 2002).

LGMD has a wide range of clinical heterogeneity, though it generally manifests with progressive weakness of pelvic and shoulder girdle muscles. The disease tends to start in late childhood but may also happen up until middle age (Tsao & Mendell, 1999). Scapular winging may also occur due to gradual weakness of the shoulder girdle. Several limb-girdle muscular dystrophies involve significant cardiac and respiratory involvement, contractures and scoliosis.

Treatment options for LGMD are limited, and, as in FSHD and MyoDys, the medical management of LGMD usually requires a multi-disciplinary team to monitor the progression of weakness, monitor cardio-respiratory functioning, and help retain muscle function. Behaviourally exercise may not be harmful and may help retain joint flexibility (Santra, 2008).

Inflammatory myopathy (IM)

In the present course of research, the inflammatory myopathies will be used to describe polymyositis and dermatomyositis. As discussed earlier, the inflammatory myopathies are acquired autoimmune disorders.

The characteristic feature of, polymyositis and dermatomyositis is generalised proximal muscle wasting and weakness, with the pelvic girdle musculature more severely affected than the shoulder girdle muscles. Functionally, this results in difficulty climbing stairs and rising from a low chair, and difficulty with tasks at


and above shoulder height such as grooming and lifting objects onto shelves. Distal weakness may be a late feature but is never as severe as proximal weakness (Hilton-Jones, 2003).

As suggested in the name, dermatomyositis usually also presents with skin involvement; in many cases causing rash, photosensitivity, dry cracked skin and fingernails. With severe dermatomyositis respiration failure may occur and dysphagia may cause risk of aspiration. There may also be cardiac involvement. Polymyositis presents with similar features to dermatomyositis (muscle pathology, cardiac and lung involvement), but without skin involvement, and progresses at a slower rate than dermatomyositis (Hilton-Jones, 2003). Diagnosis consists of blood tests assessing levels of serum creatine kinase and electromyography of muscles, but the gold standard is a muscle biopsy: this involves making a puncture wound (usually into the thigh muscle) and collecting a sample of muscle tissue. This muscle tissue is then examined for pathological features.

What is notable about the inflammatory myopathies, in comparison to the other muscle diseases under study, is that they respond well to pharmacological intervention; and symptoms can, in many cases, be well managed with a combination of corticosteroid and immunosuppressant treatment. Exercise may also help reduce the risk of contractures and enhance recover from immunosuppressant treatment (Hilton-Jones, 2003).

Inclusion Body Myositis (IBM)

As described earlier, IBM is sometimes considered to be a type of IM. It has a distinct pattern of muscle involvement (see Figure 1.2) involving the quadriceps and long finger flexors. IBM usually has a later age of onset (over the age of 50 years). Muscle symptoms are progressive and generally cause mobility problems and falls.

In this thesis we consider IBM to be distinct from polymyositis and dermatomyositis. This is because IBM: a) involves unique muscle pathology – a degenerative process; b) shows remarkably selective muscle involvement compared to polymyositis and dermatomyositis – where muscle involvement is


more diffuse; c) presents with selective involvement of muscle tissue such that even within a muscle there may be atrophy and hypertrophy, and importantly; d) does not response as well to steroid or immunosuppressant treatment (Hilton- Jones, 2003; Engel & Askanas, 2006).

Other miscellaneous MDs

As mentioned earlier, muscle diseases are legion. With this in mind, this section will briefly introduce some muscle disease diagnosis groups with smaller sized populations. First, Oculopharyngeal muscular dystrophy (OPMD) is a genetic disease which has a distinctive pattern of muscle involvement (see figure 1.2) involving the muscles around the eyes (oculobulbar), then progressing onto dysphagia, tongue weakness and proximal muscle weakness. Other smaller muscle disease diagnoses groups include myofibrillar myopathy (a genetic adult-onset muscle disease with generally starts in the distal muscles, but can also affect the proximal muscles), and Bethlem myopathy (a childhood onset, slowly progressive genetic muscle disease). Small populations of patients are also diagnosed with distal myopathy (a genetic progressive muscle disease which affects the distal muscles primarily) and mitochondrial myopathy (a genetic condition involving mitochondrial pathology). Again, as with all other genetic muscular dystrophies, there are no effective pharmacological treatments or cures for these muscle diseases, and medical intervention consists of symptom monitoring and management.

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