Definitions of the levels of the recommendations (A, B, C, U) and classification of the evidence (Class I-IV) are provided at the end of the "Major Recommendations" field.
The recommendations below encompass 4 major areas: diagnosis, predictors of severity, surveillance for complications, and treatment.
Diagnosis of Facioscapulohumeral Muscular Dystrophy (FSHD)
When clinical presentation of FSHD is typical and the inheritance pattern is consistent with autosomal dominant inheritance, clinical diagnosis is usually straightforward. If, in such circumstances, the diagnosis is genetically confirmed in a first-degree relative, genetic testing is not necessary for each affected individual. However, atypical presentations are not uncommon. In the setting of atypical or sporadic cases, genetic confirmation is important for genetic counseling, especially with the recent discovery of 2 genetically distinct forms of FSHD.
In the most common FSHD type, FSHD1, disease results from contraction of a DNA repeat sequence, termed D4Z4 repeat, on 1 copy of 4q35 from >10 repeats to 1–10 repeats. In addition, the contraction must occur in the presence of 1 particular (A variant) of 2 (A/B) sequence variants distal to the repeats. Available molecular testing for FSHD1, which measures only the presence of a repeat contraction on initial testing, is highly sensitive and specific. In studies that utilized strict diagnostic criteria for FSHD, determining whether a contraction occurs on an A variant genetic background does not appear to improve diagnostic specificity. However, in clinical practice, strict clinical diagnostic criteria might not be adhered to, increasing the chances of a false-positive result. In consequence, determining that a D4Z4 contraction is occurring on an A variant is warranted when the clinical presentation is atypical for FSHD. At present, commercial genetic testing in FSHD is limited to FSHD1 testing.
Clinicians should obtain genetic confirmation of FSHD1 in patients with atypical presentations and no first-degree relatives with genetic confirmation of the disease (Level B). The figure in the original guideline document shows the recommended FSHD molecular diagnosis decision tree.
Predictors of Severity in FSHD
Factors that predict disease severity in FSHD are important for counseling patients and for screening for and managing potential complications. The D4Z4 deletion size appears to be somewhat predictive of the overall rate of disease progression. D4Z4 deletion size should be used cautiously for predicting disease progression rate in any particular individual due to other sources of variation affecting disease severity, including intrafamilial factors. Clinical experience suggests that patients with severe childhood-onset disease almost invariably have very large deletions (i.e., contracted D4Z4 allele of 10–20 kb or 1–4 repeats), suggesting a much more robust correlation between disease severity and large deletions.
Large D4Z4 deletion sizes (contracted D4Z4 allele of 10–20 kb) should alert the clinician that the patient is more likely to develop more significant disability and at an earlier age. Patients with large deletions are also more likely to develop symptomatic extra muscular manifestations (Level B) (see the next section, "Monitoring for Complications of FSHD").
Monitoring for Complications of FSHD
The guideline panel's systematic review revealed that some patients with FSHD develop respiratory muscle weakness that can result in respiratory failure and need for mechanical ventilator assistance (e.g., nocturnal bilevel positive airway pressure), although this complication is uncommon. Patients with chronic respiratory failure from neuromuscular-related weakness often do not have classic symptoms of ventilatory failure (i.e., overt dyspnea). Impending respiratory failure, therefore, may begin with respiratory insufficiency mainly during sleep, resulting in excessive daytime somnolence or nonrestorative sleep. Respiratory insufficiency in patients with FSHD, therefore, may be evident only through pulmonary function testing. Respiratory failure constitutes a major source of morbidity in patients with most MD types and can severely disrupt sleeping, daily activities, and quality of life (QOL). Early intervention with noninvasive mechanical ventilation leads to improved survival and QOL.
Clinicians should obtain baseline pulmonary function tests on all patients with FSHD. Patients should be monitored regularly if they have abnormal baseline pulmonary function test results or any combination of severe proximal weakness, kyphoscoliosis, wheelchair dependence, or comorbid conditions that may affect ventilation (e.g., chronic obstructive pulmonary disease, cardiac disease) (Level B).
In patients who have FSHD and either (1) compromised pulmonary function studies (e.g., forced vital capacity <60%) or (2) symptoms of excessive daytime somnolence or nonrestorative sleep (e.g., frequent nocturnal arousals, morning headaches), clinicians should refer patients for pulmonary or sleep medicine consultation for consideration of nocturnal sleep monitoring or nocturnal noninvasive ventilation in order to improve QOL (Level B).
Patients with FSHD who do not get regular pulmonary function testing should be tested prior to surgical procedures requiring general anesthesia, as such testing may uncover asymptomatic respiratory compromise (Level B).
The guideline panel's systematic review revealed very little evidence for structural cardiac abnormalities in FSHD. Also, data are insufficient to suggest that patients with FSHD are susceptible to cardiac arrhythmias. Routine electrocardiographic/echocardiographic testing is therefore unnecessary in patients with FSHD who are asymptomatic.
Patients with FSHD should be referred for cardiac evaluation if they develop overt signs or symptoms of cardiac disease (e.g., shortness of breath, chest pain, palpitations). However, routine cardiac screening is not essential in the absence of cardiac signs or symptoms (Level C).
Retinal Vascular Disease
The guideline panel's systematic review suggests that symptomatic retinal vascular disease in the form of an exudative retinopathy (Coats disease) is very rare in FSHD but tends to affect patients with large deletions almost exclusively. Untreated exudative retinopathy can lead to significant visual loss, which may be prevented by early intervention.
Clinicians should refer patients with FSHD and large deletions (contracted D4Z4 allele of 10–20 kb) to an experienced ophthalmologist (e.g., retina specialist) for dilated indirect ophthalmoscopy (Level B). The presence and severity of retinal vascular disease at initial screening should be used to determine the frequency of subsequent monitoring (Level B).
The guideline panel's systematic review shows that the available studies fail to capture the prevalence and clinical relevance of hearing loss in FSHD. In clinical practice, most patients with FSHD and hearing loss requiring the use of a hearing aid have childhood-onset FSHD with large D4Z4 deletions. Two recent studies support this clinical impression. Moreover, one of the studies suggests that hearing loss is progressive in some patients. Adults and older children are cognizant of the hearing loss onset, and therefore intervention can occur early when required. However, failure to detect hearing loss in infants and younger children may significantly delay or impair language development.
Clinicians should screen all young children with FSHD at diagnosis and yearly thereafter until these children start school, as hearing loss may not be present at diagnosis and can be progressive (Level B).
Pain is a common complaint in FSHD and appears to be mostly musculoskeletal in origin. Pain compounding muscle weakness can have a significant impact on QOL. Physical therapists often can provide insight into the mechanism of pain in patients with weakness. Non steroidal anti-inflammatory medications are useful for acute pain, and antidepressants or antiepileptics for chronic musculoskeletal pain.
Treating physicians should routinely inquire about pain in patients with FSHD. Referral for a physical therapy evaluation may prove helpful as an initial nonpharmacologic intervention. In patients with persistent pain and no contraindications, a trial of nonsteroidal anti-inflammatory medications is appropriate for acute pain and antidepressants or antiepileptics for chronic pain (Level B).
Treatment of FSHD
As of this writing, no evidence exists for any effective pharmacologic interventions that improve strength or slow disease progression in FSHD. Randomized, controlled trials of albuterol were negative. Uncontrolled, open-label trials of corticosteroid and diltiazem showed no benefit. A controlled early phase II study of MYO-029, a myostatin inhibitor, also failed to show benefit.
In patients with FSHD, clinicians should not prescribe albuterol, corticosteroid, or diltiazem for improving strength (Level B).
Surgical Scapular Fixation
In patients with FSHD, limited shoulder range of motion due to periscapular muscle weakness is a major source of functional limitation. Moreover, in many patients, bedside manual scapular fixation can result in significant improvement in shoulder range of motion. Postoperative complications are infrequent but include hemothorax or pneumothorax, pain, infection, nonunion, and reduced lung capacity. Scapular fixation appears to be generally safe and may be effective for improving shoulder range of motion.
Surgical scapular fixation might be offered cautiously to selected patients after careful consideration of the overall muscle impairment in the involved arm, assessment of potential gain in range of motion by manual fixation of the scapula, the patient's rate of disease progression, and the potential adverse consequences of surgery and prolonged postsurgical bracing (Level C).
Aerobic exercise in FSHD appears to be safe and potentially beneficial, as has been shown in many other muscle diseases. Aerobic fitness is important for overall health. To minimize injury from falls or overuse, the type of aerobic exercise should be tailored to the patient's particular distribution of weakness. For example, a stationary bicycle rather than a treadmill should be recommended for patients with leg weakness. Although no data exist to suggest that strength training is detrimental in FSHD, further research is needed to determine whether such strength training will result in clinically meaningful long-term functional improvement.
Clinicians might encourage patients with FSHD to engage in low-intensity aerobic exercise. An experienced physical therapist can help guide development of individualized exercise programs. Clinicians might also use the practical physical activities guidelines for individuals with disabilities, provided by the US Department of Health and Human Services, when counseling patients about aerobic exercise (Level C).
In patients interested in strength training, clinicians may refer patients to physical therapists to establish a safe exercise program using appropriate low/ medium weights/resistance that takes into consideration the patients' physical limitations (Level C).
American Academy of Neurology (AAN) Rules for Classification of Evidence for Risk of Bias
For Questions Related to Screening (Yield)
- Study of a cohort of patients at risk for the outcome from a defined geographic area (i.e., population based)
- The outcome is objective
- Also required:
- Inclusion criteria defined
- At least 80% of patients undergo the screening of interest
- A non-population-based, nonclinical cohort (e.g., mailing list, volunteer panel) or a general medical, neurology clinic/center without a specialized interest in the outcome. Study meets criteria a b (see Class I)
- The outcome is objective
A referral cohort from a center with a potential specialized interest in the outcome
- Did not include persons at risk for the outcome
- Did not statistically sample patients, or patients specifically selected for inclusion by outcome
- Undefined or unaccepted screening procedure or outcome measure
- No measure of frequency or statistical precision calculable
For Questions Related to Prognostic Accuracy
- Cohort survey with prospective data collection
- Includes a broad spectrum of persons at risk for developing the outcome
- Outcome measurement is objective or determined without knowledge of risk factor status
- Also required:
- Inclusion criteria defined
- At least 80% of enrolled subjects have both the risk factor and outcome measured
- Cohort study with retrospective data collection or case-control study. Study meets criteria a and b (see Class I)
- Includes a broad spectrum of persons with and without the risk factor and the outcome
- The presence of the risk factor and outcome are determined objectively or without knowledge of one another
- Cohort or case-control study
- Narrow spectrum of persons with or without the disease
- The presence of the risk factor and outcome are determined objectively, without knowledge of the other or by different investigators
- Did not include persons at risk for the outcome
- Did not include patients with and without the risk factor
- Undefined or unaccepted measures of risk factor or outcomes
- No measures of association or statistical precision presented or calculable
For Questions Related to Therapeutic Intervention
- Randomized, controlled clinical trial in a representative population
- Masked or objective outcome assessment
- Relevant baseline characteristics are presented and substantially equivalent between treatment groups, or there is appropriate statistical adjustment for differences
- Also required:
- Concealed allocation
- Primary outcome(s) clearly defined
- Exclusion/inclusion criteria clearly defined
- Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias
- For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*:
- The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority
- The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose, and dosage adjustments are similar to those previously shown to be effective
- The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment
- The interpretation of the study results is based on a per-protocol analysis that accounts for dropouts or crossovers
- Cohort study meeting criteria a–e above or a randomized, controlled trial that lacks one or two criteria b–e
- All relevant baseline characteristics are presented and substantially equivalent among treatment groups, or there is appropriate statistical adjustment for differences
- Masked or objective outcome assessment
- Controlled studies (including studies with external controls such as well-defined natural history controls)
- A description of major confounding differences between treatment groups that could affect outcome**
- Outcome assessment masked, objective, or performed by someone who is not a member of the treatment team
- Did not include patients with the disease
- Did not include patients receiving different interventions
- Undefined or unaccepted interventions or outcome measures
- No measures of effectiveness or statistical precision presented or calculable
*Numbers 1–3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.
**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data)
Assigning a Level of Strength to the Recommendation
When there is sufficient evidence to support an inference for the use of an intervention (i.e., the balance of benefits and harms favors the intervention), the author panel assigns one of three recommendation designations: A, B, or C. Each designation corresponds to a helping verb that denotes the level of strength of the recommendation. Level A is the strongest recommendation level and is denoted by the use of the helping verb must. Must recommendations are rare, as they are based on high confidence in the evidence and require both a high magnitude of benefit and low risk. Level B corresponds to the helping verb should. Should recommendations tend to be more common, as the requirements are less stringent but still based on the evidence and benefit–risk profile. Finally, Level C corresponds to the helping verb may or might. May and might recommendations represent the lowest allowable recommendation level the American Academy of Neurology (AAN considers useful within the scope of clinical practice and can accommodate the highest degree of practice variation.
Level A denotes a practice recommendation that "must" be done. In almost all circumstances, adherence to the recommendation will improve health-related outcomes. A Level B indicates a recommendation that "should" be done. In most circumstances, adherence to the recommendation will likely improve health-related outcomes. A Level C represents a recommendation that "might" be done. In some circumstances, adherence to the recommendation might improve health-related outcomes.
When there is insufficient evidence to support an inference for the use of an intervention (i.e., the balance of benefits and harms is unknown) a Level U or Level R designation is appropriate.
A Level U indicates that the available evidence is insufficient to support or refute the efficacy of an intervention. A Level R is assigned when the balance of benefits and harms is unknown and the intervention is known to be expensive or have important risks. A Level R designates that the intervention should not be used outside of a research setting. Non-evidence-based factors that need to be transparently and systematically considered when formulating recommendations include the following:
- The relative value of the benefit as compared with the risk; this is derived from consideration of:
- The importance to patients of the health related-outcomes (both benefits and harms)
- The size of the intervention's effect
- The risk of harm of the intervention (i.e., tolerability and safety)
- The feasibility of complying with the intervention (e.g., the intervention's availability)
- The cost of the intervention
- The expected variation in patient preferences relative to the risks, burdens, and benefits of the intervention