2014 American Academy of Neurology Evidencebased Guideline Summary

© 2014 American Academy of Neurology

Evidence-based Guideline Summary: Diagnosis and Treatment of Limb-Girdle and Distal Dystrophies Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine © 2014 American Academy of Neurology

Guideline Endorsement and Funding • This guideline was endorsed by the American Academy of Physical Medicine and Rehabilitation, the Child Neurology Society, the Jain Foundation, and the Muscular Dystrophy Association. • Funding for this publication was made possible (in part) by grant DD 10 -1012 from the Centers for Disease Control and Prevention. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. The remaining funding was provided by the American Academy of Neurology. © 2014 American Academy of Neurology Slide 2

Authors • • • Pushpa Narayanaswami, MBBS, DM, FAAN Michael Weiss, MD, FAAN Duygu Selcen, MD William David, MD, Ph. D Elizabeth Raynor, MD Gregory Carter, MD Matthew Wicklund, MD, FAAN Richard J. Barohn, MD, FAAN Erik Ensrud, MD Robert C. Griggs, MD, FAAN Gary Gronseth, MD, FAAN Anthony A. Amato, MD, FAAN © 2014 American Academy of Neurology Slide 3

Sharing This Information • The American Academy of Neurology (AAN) develops these presentation slides as educational tools for neurologists and other health care practitioners. You may download and retain a single copy for your personal use. Please contact guidelines@aan. com to learn about options for sharing this content beyond your personal use. © 2014 American Academy of Neurology Slide 4

Presentation Objectives • To present the evidence with regard to diagnosis and management of limb-girdle and distal muscular dystrophies. • To present recommendations, based on the evidence and consensus-related factors, regarding the diagnosis and treatment of limb-girdle muscular dystrophies (LGMDs). © 2014 American Academy of Neurology Slide 5

Overview • Background • Gaps in care • AAN guideline process • Analysis of evidence, conclusion, recommendations • Recommendations for future research © 2014 American Academy of Neurology Slide 6

Background • LGMDs are a group of hereditary myopathies characterized by predominantly proximal muscle weakness (pelvic and shoulder girdles). 1 • Initially described as a clinical phenotype, they are now recognized as a heterogeneous group of myopathies that vary in severity and may affect persons at all ages from childhood through adulthood. © 2014 American Academy of Neurology Slide 7

Background • The LGMDs are classified into 2 main groups depending on the inheritance pattern: LGMD 1, autosomal dominant, and LGMD 2, autosomal recessive. Appended to this numeric division is a letter designating the order of discovery for each chromosomal locus. 2, 3 © 2014 American Academy of Neurology Slide 8

Clinical Questions 1. What is the frequency of genetically confirmed limb 2. 3. girdle muscular dystrophy (LGMD) subtypes? How often do patients with muscular dystrophy and its specific subtypes have specific clinical features, including ethnic predilection, diagnostic patterns of weakness, respiratory and cardiac complications, laboratory abnormalities (e. g. , elevated creatine kinase), specific patterns on imaging, and muscle biopsy features? Are there effective therapies for muscular dystrophies? © 2014 American Academy of Neurology Slide 9

AAN Guideline Process • Clinical Question • Evidence • Conclusions • Modified Delphi Consensus • Recommendations © 2014 American Academy of Neurology Slide 10

Methods • Medline, EMBASE, and Cochrane databases searched • Each selected article reviewed for inclusion • Risk of bias determined (AAN classification of evidence schemes for screening and therapeutic articles) • Conflicts of interest disclosed © 2014 American Academy of Neurology Slide 11

Literature Search/Review • Rigorous, Comprehensive, Transparent 3, 246 abstracts Inclusion criteria: • Articles with descriptions of at least 3 patients • Studies of fewer than 3 patients in instances of the initial description of a disorder, rare disorders, or rare manifestations of a disorder • Studies that used genetic testing to confirm all diagnoses (except Becker muscular dystrophy [BMD] or manifest carriers of Duchenne muscular dystrophy) Exclusion criteria: 699 articles © 2014 American Academy of Neurology • Articles reporting group outcomes for more than one disorder and individual disorders that could not be identified within the group Slide 12

AAN Classification of Evidence for Population Screening Studies • Class I: A statistical, population-based sample of patients • studied at a uniform point in time (usually early) during the course of the condition. All patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients’ clinical presentations. Class II: A statistical, non-referral-clinic-based sample of patients studied at a uniform point in time (usually early) during the course of the condition. Most patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients’ clinical presentations. © 2014 American Academy of Neurology Slide 13

AAN Classification of Evidence for Population Screening Studies • Class III: A sample of patients studied during the course of the condition. Some patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation by someone other than the treating physician. • Class IV: Studies not meeting Class I, II, or III criteria, including consensus, expert opinion, or a case report. © 2014 American Academy of Neurology Slide 14

AAN Classification of Evidence for Therapeutic Studies • Class I: Prospective, randomized, controlled clinical trial with masked outcome assessment, in a representative population. The following are required: a. b. c. d. Concealed allocation Primary outcome(s) clearly defined Exclusion/inclusion criteria clearly defined Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias e. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences © 2014 American Academy of Neurology Slide 15

AAN Classification of Evidence for Therapeutic Studies • Class II: Prospective matched group cohort study in a • • representative population with masked outcome assessment that meets criteria a e OR a randomized, controlled trial (RCT) in a representative population that lacks one criterion a d. Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement. Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion. © 2014 American Academy of Neurology Slide 16

Clinical Question 1 • What is the frequency of genetically confirmed LGMD subtypes? © 2014 American Academy of Neurology Slide 17

Q 1. Clinical Context • Overall, LGMDs are uncommon disorders. 6 § The most common adult-onset muscular dystrophies presenting with limb-girdle weakness are BMD (dystrophin), LGMD 2 A (calpain 3), LGMD 2 I (fukutin-related protein), and LGMD 2 L (anoctamin 5), whereas the most common distal myopathy is Miyoshi myopathy (dysferlin and anoctamin 5). § Of those, BMD is the most common, with an estimated prevalence of 2. 38 to 7. 29 per 100, 000. 6 10 § Most LGMDs are rare, with estimated prevalences ranging from 0. 07 (LGMD 2 D and LGMD 2 E) to 0. 43 (LGMD 2 I) per 100, 000. © 2014 American Academy of Neurology Slide 18

Q 1. Clinical Context (cont. ) § The frequency of some muscular dystrophies varies based on the ethnic background of the population (e. g. , LGMD 2 C being more common in Roma and Tunisian populations, with a prevalence of 0. 13 per 100, 000). 6, 11 14 § We found no studies estimating the frequency of disorders due to genetic defects in DNAJB 6, TRIM 32, FHL 1, MYH 7, filamin C, VCP, matrin-3, selenoprotein, cavin, nebulin, nesprin, KLHL 9, and Welander distal myopathies. © 2014 American Academy of Neurology Slide 19

Clinical Question 2 • How often do patients with muscular dystrophy and its specific subtypes have specific clinical features, including ethnic predilection, diagnostic patterns of weakness, respiratory and cardiac complications, laboratory abnormalities (e. g. , elevated creatine kinase), specific patterns on imaging, and muscle biopsy features? © 2014 American Academy of Neurology Slide 20

Q 2. Clinical Context: Clinical Features • Features common to most LGMDs: § Presentation of slowly progressing symmetrical weakness § Age at onset adolescence to early adulthood (can range from early childhood to late adult life) § Most common weakness pattern of limb-girdle weakness affecting proximal muscles of the arms and legs § Other patterns include scapuloperoneal weakness and distal weakness § One genotype can present with different phenotypes; one phenotype can result from more than one genotype © 2014 American Academy of Neurology Slide 21

Q 2. Clinical Context: Distinguishing Features • Distinguishing features of LGMD disorders include: § Early development of foot drop (e. g. , myofibrillar myopathies [MFM]) § Asymmetry in muscle weakness (e. g. , LGMD 1 A, LGMD 2 L, MFM) § Limb contractures (lamin A/C myopathies, Emery Dreifuss muscular dystrophy [EDMD], BAG 3) § Prominent muscle cramps (LGMD 1 C) § Ancestry (e. g. , northern European for LGMD 2 I) © 2014 American Academy of Neurology Slide 22

Q 2. Clinical Context: Distinguishing Features § Family or personal history of frontotemporal dementia, Paget disease of bone, or motor neuron disease (h 1 BMPFD) § Scapular winging (e. g. , sarcoglycanopathies, LGMD 2 A) § Calf hypertrophy (BMD, LGMD 2 I) § Cardiac conduction system abnormalities (e. g. , laminopathy, desminopathy) § Cardiomyopathy (e. g. , LGMD 2 I) § Rippling muscle phenomenon and percussion-induced muscle contractions in LGMD 1 C © 2014 American Academy of Neurology Slide 23

Q 2. Clinical Context: Distinguishing Features § EMG features in MFM (e. g. , myotonic and pseudomyotonic discharges, the latter characterized by runs of decrescendo positive sharp-wave discharges without the typical waxing and waning of amplitudes and frequencies) § Muscle biopsy features that distinguish between muscular dystrophies include: – Rimmed vacuoles – Reducing bodies/cytoplasmic bodies – Derangement of myofibrils consistent with MFM – Nemaline rods in distal myopathies due to nebulin mutations – Reductions of specific proteins on immunohistochemistry suggestive of deficiencies (need to confirm the diagnosis with genetic testing) © 2014 American Academy of Neurology Slide 24

Clinical Question 3 • Are there effective therapies for muscular dystrophies? • The systematic review identified only 12 studies evaluating treatments for patients with LGMD. These studies are summarized in the slides that follow. © 2014 American Academy of Neurology Slide 25

Q 3 a. Gene Therapy • Two randomized double-blind trialse 232, e 233 examined adeno-associated virus (AAV) gene transfer to the extensor digitorum brevis muscle in 6 patients with LGMD 2 D (αsarcoglycanopathy) § The trials demonstrated that AAV gene therapy probably increases the expression of α-sarcoglycan gene § The clinical relevance of this effect is unknown • A case series of patients with LGMD 2 C received escalating doses of AAV-vector expressed human γ-sarcoglycan genes into the extensor digitorum communis § The series found insufficient evidence to determine the clinical effect of AAV-vector expressed γ-sarcoglycan genese 234 © 2014 American Academy of Neurology Slide 26

Q 3 b. Myoblast Transplantation • A case series evaluated myoblast transplantation into the tibialis anterior in 3 males with BMD pretreated with cyclosporine A § The series found insufficient evidence to determine the efficacy of myoblast transfer in BMDe 235 © 2014 American Academy of Neurology Slide 27

Q 3 c. Neutralizing Antibody to Myostatin • A phase 1 randomized controlled study of a neutralizing antibody (MYO-029) to an endogenous inhibitor of muscle growth (myostatin) was performed in 116 subjects with different types of muscular dystrophies § The study found evidence that MYO-029 is probably safe and tolerable in patients with BMD, LGMD 2 A–E, and LGMD 2 I § The study was not designed to assess efficacy or longterm safetye 236 © 2014 American Academy of Neurology Slide 28

Q 3 d. Corticosteroids for BMD • A 12 -month randomized crossover studye 237 examined prednisolone use in 4 boys with BMD § The study showed that prednisolone 0. 35 g/kg/day is probably effective in improving isometric muscle strength in patients with BMD after 3 months of treatment © 2014 American Academy of Neurology Slide 29

Q 3 e. Growth Hormone for BMD • A randomized studye 238 evaluated the effects of subcutaneous growth hormone (s. GH) in 10 patients with BMD § The study found insufficient evidence to support or refute the use of s. GH to improve cardiac and pulmonary function in patients with BMD © 2014 American Academy of Neurology Slide 30

Q 3 f. Hand Training Program in Welander Distal Myopathy • A case series examined a hand training program in 12 patients with Welander distal myopathy § The series found insufficient evidence to support or refute the benefit of the exercise programe 239 © 2014 American Academy of Neurology Slide 31

Q 3 g. Endurance Training • Two case series studied the effect of endurance training in 9 ambulatory patients with LGMD 2 Ie 161 and 11 men with BMDe 136 § The series found insufficient evidence to determine the benefit of endurance training to improve maximal oxygen uptake, maximal workload, and other patient-reported outcomes • Two additional case seriese 240, e 241 evaluated the effects of exercise on h. IBM 3 secondary to a defect in the MYH 2 gene § These series found insufficient evidence to assess the effect of endurance training on maximum workload, muscle strength, or change in the expression of myosin isoforms on muscle biopsy after statistical corrections for multiple outcome measures © 2014 American Academy of Neurology Slide 32

Major Practice Recommendations • The recommendations that follow encompass three major areas: § Diagnosis § Evaluation § Management of muscular dystrophies • The full recommendation set is available online. © 2014 American Academy of Neurology Slide 33

Recommendation: Diagnosis • Clinicians should use a clinical approach to guide genetic diagnosis based on the clinical phenotype, including (Level B): § § The pattern of muscle involvement Inheritance pattern Age at onset Associated manifestations (e. g. , early contractures, cardiac or respiratory involvement) © 2014 American Academy of Neurology Slide 34

Recommendation: Diagnosis • When initial clinically directed genetic testing does not provide a diagnosis, clinicians may: § Obtain genetic consultation or perform parallel sequencing of targeted exomes, whole-exome sequencing, whole-genome screening, or nextgeneration sequencing to identify the genetic abnormality (Level C) © 2014 American Academy of Neurology Slide 35

Recommendations: Evaluation and Management • Cardiac involvement • Dysphagia and nutrition • Pulmonary complications • Spinal deformities • Infection prophylaxis • Osteoporosis © 2014 American Academy of Neurology Slide 36

Recommendation: Cardiac Involvement • In newly diagnosed (1) LGMD 1 A, LGMD 1 B, LGMD 1 D, LGMD 1 E, LGMD 2 C–K, LGMD 2 M–P, BMD, EDMD, and MFM or (2) muscular dystrophy without a specific genetic diagnosis: § Clinicians should refer for cardiology evaluation, including ECG and structural evaluation (echocardiography or cardiac MRI), even if they are asymptomatic from a cardiac standpoint, to guide appropriate management (Level B) © 2014 American Academy of Neurology Slide 37

Recommendations: Cardiac Involvement • If (1) ECG or structural cardiac evaluation (e. g. , echocardiography) is abnormal or (2) episodes of syncope, near-syncope, or palpitations occur: § Clinicians should order rhythm evaluation (e. g. , Holter monitor or event monitor) to guide appropriate management (Level B) • If palpitations, symptomatic or asymptomatic tachycardia or arrhythmias, or signs and symptoms of cardiac failure are present: § Clinicians should refer for cardiology evaluation (Level B) © 2014 American Academy of Neurology Slide 38

Recommendation: Cardiac Involvement • In LGMD 2 A, LGMD 2 B, and LGMD 2 L: § It is not obligatory for clinicians to refer for cardiac evaluation unless overt cardiac signs or symptoms develop (Level B) © 2014 American Academy of Neurology Slide 39

Recommendation: Dysphagia and Nutrition • If dysphagia, frequent aspiration, or weight loss present, clinicians should refer for swallowing evaluation or gastroenterology evaluation, or both (Level B): § To assess and manage swallowing function and aspiration risk § To teach patients techniques for safe and effective swallowing (e. g. , “chin tuck” maneuver, altered food consistencies) § To consider placement of a gastrostomy/jejunostomy tube for nutritional support © 2014 American Academy of Neurology Slide 40

Recommendation: Pulmonary Complications • At diagnosis or if pulmonary symptoms develop late in disease course: § Clinicians should order pulmonary function testing (spirometry and maximal inspiratory/expiratory force in the upright and, if normal, supine positions) or refer for pulmonary evaluation (to identify and treat respiratory insufficiency) (Level B) © 2014 American Academy of Neurology Slide 41

Recommendations: Pulmonary Complications • If high risk of respiratory failure (e. g. , in LGMD 2 I or MFM): § Clinicians should obtain periodic pulmonary function testing (spirometry and maximal inspiratory/expiratory force in the upright position and, if normal, in the supine position) or evaluation by a pulmonologist to identify and treat respiratory insufficiency (Level B) • In LGMD 2 B and LGMD 2 L: § It is not obligatory for clinicians to refer for pulmonary evaluation unless symptoms present (Level C) © 2014 American Academy of Neurology Slide 42

Recommendation: Pulmonary Complications • In instances of excessive daytime somnolence, nonrestorative sleep (e. g. , frequent nocturnal arousals, morning headaches, excessive daytime fatigue), respiratory insufficiency based on pulmonary function tests: • Clinicians should refer for pulmonary or sleep medicine consultation for consideration of noninvasive ventilation to improve quality of life (Level B) © 2014 American Academy of Neurology Slide 43

Recommendations: Spinal Deformities • To prevent resultant complications and preserve function: § Clinicians should monitor for the development of spinal deformities (Level B) • In instances of musculoskeletal spine deformities: § Clinicians should refer to an orthopedic spine surgeon for monitoring and surgical intervention if it is deemed necessary in order to maintain normal posture, assist mobility, maintain cardiopulmonary function, and optimize quality of life (Level B) © 2014 American Academy of Neurology Slide 44

Recommendation: Osteoporosis • In instances of restricted mobility due to muscular dystrophy: § Clinicians may choose to evaluate with bone density studies for osteoporosis in order to institute timely management and minimize fractures (Level C) © 2014 American Academy of Neurology Slide 45

Recommendation: Infection Prophylaxis • To prevent respiratory complications of pneumococcal pneumonia and influenza: § Clinicians should recommend pneumococcal polysaccharide vaccine (as per the Centers for Disease Control and Prevention schedulee 514) and annual influenza vaccine (Level B) © 2014 American Academy of Neurology Slide 46

Recommendations: Rehabilitative Management and Treatment of Muscular Dystrophies • Clinical rehabilitative management • Strength training and aerobic exercise training • Medical treatments © 2014 American Academy of Neurology Slide 47

Recommendation: Clinical Rehabilitative Management • To provide efficient and effective long-term care: § Clinicians should refer to a clinic designed specifically to care for patients with muscular dystrophy and other neuromuscular disorders and with access to multiple specialties (Level B), including: – Physical therapy – – – – Occupational therapy Respiratory therapy Speech and swallowing therapy Cardiology Pulmonology Orthopedics Genetics © 2014 American Academy of Neurology Slide 48

Recommendation: Clinical Rehabilitative Management • For symptomatic and preventive screening: § Clinicians should recommend periodic assessments by a physical and occupational therapist (Level B) © 2014 American Academy of Neurology Slide 49

Recommendations: Clinical Rehabilitative Management • While respecting and protecting patient autonomy: § Clinicians should proactively anticipate and facilitate patient and family decision making as the disease progresses (Level B), including: – Decisions regarding loss of mobility – Need for assistance with activities of daily living – Medical complications – End-of-life care • To preserve mobility and function and prevent contractures: § Clinicians should prescribe physical and occupational therapy, as well as bracing and assistive devices that are adapted specifically to the patient’s deficiencies and contractures (Level B) © 2014 American Academy of Neurology Slide 50

Recommendations: Strength Training and Aerobic Exercise Training • Clinicians may advise that aerobic exercise combined with a supervised submaximal strength training program is probably safe (Level C) • Clinicians may advise that gentle, low-impact aerobic exercise (swimming, stationary bicycling) improves cardiovascular performance, increases muscle efficiency, and lessens fatigue (Level C) © 2014 American Academy of Neurology Slide 51

Training and Aerobic Exercise Training • Clinicians may counsel to hydrate adequately, not to exercise to exhaustion, and to avoid supramaximal, high-intensity exercise (Level C) • In patients participating in an exercise program: § Clinicians should educate about the warning signs of overwork weakness and myoglobinuria (Level B), which include: – – Feeling weaker rather than stronger within 30 minutes after exercise Excessive muscle soreness 24 48 hours following exercise Severe muscle cramping, Heaviness in the extremities, and prolonged shortness of breath © 2014 American Academy of Neurology Slide 52

Recommendation: Medical Treatments • Outside of a research study designed to determine the efficacy and safety of the treatment, clinicians should not currently offer (Level R): § Gene therapy § Myoblast transplantation § Neutralizing antibody to myostatin § Growth hormone © 2014 American Academy of Neurology Slide 53

Recommendations for Future Research • Larger prospective, long-term, population-based studies are • • required to establish the prevalence of these rare disorders, identify the ethnic populations among which they are most prevalent, and evaluate their long-term course, including the incidence of cardiorespiratory complications. Ongoing studies of genotype/phenotype correlation are needed to help establish phenotypic patterns based on genotype and to describe the various phenotypes that are caused by one genotype. The optimal management of cardiorespiratory complications (e. g. , frequency and types of screening, effective treatments) should be evaluated. © 2014 American Academy of Neurology Slide 54

Recommendations for Future Research • Well-designed studies of the effectiveness of exercise programs, physical therapy, and endurance training are needed. • Studies of other treatments should be conducted, including symptomatic treatments such as the effect of orthotics for contractures (nonsurgical/surgical) on mobility and quality of life, as well as specific disease-modifying treatments such as gene therapy and stem cell therapy. • Preliminary data suggest that corticosteroids may be effective in α-dystroglycanopathies. This finding needs to be replicated in larger, controlled studies. © 2014 American Academy of Neurology Slide 55

References • References cited here can be found in the published guideline. • To locate references, please access the guideline summary article and the full-length guideline document (available as a data supplement to the published summary article) at AAN. com/guidelines. © 2014 American Academy of Neurology Slide 56

Access Guideline and Summary Tools • To access the complete guideline and related summary tools, visit AAN. com/guidelines. • Summary guideline article • Complete guideline article (available as a data supplement to the published summary) • Summary for clinicians, summary for patients, clinical case example (available on the AAN guidelines web page) © 2014 American Academy of Neurology Slide 57

Questions? © 2014 American Academy of Neurology