Transcript Slide 1

©2014 American Academy of Neurology
Evidence-based Guideline Summary:
Diagnosis and Treatment of LimbGirdle 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 DD10-1012 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
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Pushpa Narayanaswami, MBBS, DM, FAAN
Michael Weiss, MD, FAAN
Duygu Selcen, MD
William David, MD, PhD
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
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©2014 American Academy of Neurology
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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
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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: LGMD1,
autosomal dominant, and LGMD2, 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
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Clinical Questions
1. What is the frequency of genetically confirmed limbgirdle muscular dystrophy (LGMD) subtypes?
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?
3. 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
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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
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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
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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.
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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
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AAN Classification of Evidence
for Therapeutic Studies
• Class II: Prospective matched group cohort study in a
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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
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Clinical Question 1
• What is the frequency of genetically confirmed
LGMD subtypes?
©2014 American Academy of Neurology
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Q1. Clinical Context
• Overall, LGMDs are uncommon disorders.6
 The most common adult-onset muscular dystrophies
presenting with limb-girdle weakness are BMD
(dystrophin), LGMD2A (calpain 3), LGMD2I (fukutin-related
protein), and LGMD2L (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 (LGMD2D and LGMD2E) to 0.43 (LGMD2I) per
100,000.
©2014 American Academy of Neurology
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Q1. Clinical Context (cont.)
 The frequency of some muscular dystrophies varies based on the
ethnic background of the population (e.g., LGMD2C 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 DNAJB6, TRIM32, FHL1, MYH7, filamin C, VCP,
matrin-3, selenoprotein, cavin, nebulin, nesprin, KLHL9, 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
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Q2. 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
Q2. 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., LGMD1A,
LGMD2L, MFM)
 Limb contractures (lamin A/C myopathies,
EmeryDreifuss muscular dystrophy [EDMD], BAG3)
 Prominent muscle cramps (LGMD1C)
 Ancestry (e.g., northern European for LGMD2I)
©2014 American Academy of Neurology
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Q2. Clinical Context: Distinguishing
Features
 Family or personal history of frontotemporal dementia,
Paget disease of bone, or motor neuron disease
(h1BMPFD)
 Scapular winging (e.g., sarcoglycanopathies, LGMD2A)
 Calf hypertrophy (BMD, LGMD2I)
 Cardiac conduction system abnormalities (e.g.,
laminopathy, desminopathy)
 Cardiomyopathy (e.g., LGMD2I)
 Rippling muscle phenomenon and percussion-induced
muscle contractions in LGMD1C
©2014 American Academy of Neurology
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Q2. 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:
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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
Q3a. Gene Therapy
• Two randomized double-blind trialse232,e233 examined
adeno-associated virus (AAV) gene transfer to the extensor
digitorum brevis muscle in 6 patients with LGMD2D (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 LGMD2C 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 genese234
©2014 American Academy of Neurology
Slide 26
Q3b. 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 BMDe235
©2014 American Academy of Neurology
Slide 27
Q3c. 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, LGMD2A–E, and
LGMD2I
 The study was not designed to assess efficacy or longterm safetye236
©2014 American Academy of Neurology
Slide 28
Q3d. Corticosteroids for BMD
• A 12-month randomized crossover studye237
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
Q3e. Growth Hormone for BMD
• A randomized studye238 evaluated the effects of
subcutaneous growth hormone (sGH) in 10 patients
with BMD
 The study found insufficient evidence to support or
refute the use of sGH to improve cardiac and pulmonary
function in patients with BMD
©2014 American Academy of Neurology
Slide 30
Q3f. 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 programe239
©2014 American Academy of Neurology
Slide 31
Q3g. Endurance Training
• Two case series studied the effect of endurance training in
9 ambulatory patients with LGMD2Ie161 and 11 men with
BMDe136
 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 seriese240,e241 evaluated the effects of
exercise on hIBM3 secondary to a defect in the MYH2 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
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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):
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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) LGMD1A, LGMD1B, LGMD1D,
LGMD1E, LGMD2C–K, LGMD2M–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 LGMD2A, LGMD2B, and LGMD2L:
 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 LGMD2I 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 LGMD2B and LGMD2L:
 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 schedulee514) 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
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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
Recommendations: Strength 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:
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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
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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