Early Identification of Neuromuscular Disorders

Topic Suggestion

1. What is the decision or change you are facing or struggling with where a summary of the evidence would be helpful?

Early identification, diagnosis, and provision of treatment has substantial impact on clinical outcomes and life-expectancy across various neuromuscular disorders. Infant onset hypotonia is a frequent nonspecific presenting symptom of an underlying neuromuscular disorder (Leyenaar et al, 2005). However, further evaluation of hypotonia is frequently delayed due to multiple reasons including a large number of possible diagnoses, perceived inconsistent symptom profile of cognitive and social alertness with motor weakness, and uncertainty about whether the observed or reported hypotonia is significant enough to alarm parents (Leyenaar et al, 2005). Although once considered dire, the advent of effective treatments offers hope to children with neuromuscular disorders, and early treatment plays a significant role in the optimization of outcomes (Chien et al, 2009; Kishnani et al 2009; Chien et al, 2013; Kishnani et al, 2013; Finkel et al, 2016; Dowling et al, 2017; Finkel et al, 2017; DeVivo et al, 2018; Finkel et al, 2018; DeVivo et al, 2019).

Since the early identification of developmental concerns leads to further evaluation of underlying etiology, pediatricians are encouraged to incorporate developmental screening within structured well visits (Council on Children with Disabilities et al, 2006). Current guidelines recommend the use of developmental screening tools at 9-, 18-, 30-, and 48-months; ongoing surveillance at all remaining well visits and use of screening tools at the discretion of the provider and as elicited by parental concerns (Noritz et al, 2013; Hagan et al, 2017). However, surveillance alone has proven less effective than developmental screening tools to identify developmental delays (Rydz et al, 2005; Marks et al, 2011; Guevara et al 2013; Carroll et al, 2014). Children screened using the developmental screening tools recommended by Bright Futures are more likely to receive a timely diagnosis and treatment than those receiving developmental surveillance alone. Physicians have a higher likelihood of recognizing early signs of delays, without the overidentification of false positives, when screening tools are utilized in clinical settings (Palfrey et al 1987; Dulcan et al 1990; Horwitz et al, 1998; Shevell et al 2001; Rydz et al, 2005; Carroll et al, 2014).

Our topic suggestion seeks to examine the potential impact of the implementation of universal developmental screening tools at 2- and 4-month well visits, on the early identification of motor delays and hypotonia in children before the age of 6 months. Are developmental screening tools at 2- and 4- months more effective than developmental surveillance, in successfully identifying a higher rate of children with motor delays? Can universal screening at the aforementioned time points speed recognition of infantile hypotonia and narrow the list of possible diagnoses? Additionally, would universal implementation of developmental screening at 2- and 4-months reduce diagnostic delays of disorders presenting as motor delays, with symptom onset prior to the age of 6 months, including those of neuromuscular origin?

2. Why are you struggling with this issue?

Pediatric neuromuscular disorders occurring during infancy often present with hypotonia and weakness (Anderssonn et al, 1999). Assessment of developmental delays assists with the identification of early key concomitant signs of neuromuscular disorders including difficulty swallowing during feedings, failure to thrive, and early gross motor delays such as head lag and slowed movement of limbs when in supine (Leyenaar et al, 2005; Squires & Bricker, 2009). The combination of symptoms and age of onset helps to narrow the differential diagnosis of neuromuscular disorders; a clear clinical picture is required to expedite appropriate evaluation of symptoms and obtain an early and accurate diagnosis. Diagnostic delays place a significant financial and emotional burden on families (Larkindale et al, 2014; Lin et al 2015). As these disorders are progressive, overtime advancing symptom presentation enhances the likelihood that a specific neuromuscular disorder may be identified clinically (Noritz et al, 2013). Yet the FDA approval of treatments and development of robust treatment pipelines offers hope for a variety of neuromuscular diseases, and for many, the timing of administration impacts prognosis (Finkel et al, 2015; Dowling et al, 2017; Finkel et al 2017; DeVivo et al, 2018; Finkel et al, 2018; DeVivo et al, 2019). It is well documented that the use of developmental screening tools impacts the timing at which children with motor delays are identified in practice (Guevara et al, 2013; Carroll et al, 2014). Despite the established impact of developmental screening, and the influence of early diagnosis on clinical outcomes, current utilization of screening tools prior to the 9-month well visit remains variable in practice (Hirai et al 2018). Thus, we seek to examine the potential impact of the implementation of universal developmental screening at 2- and 4-month well visits, on the early identification of motor delays, hypotonia, and underlying neuromuscular disease.

3. What do you want to see changed? How will you know that your issue is improving or has been addressed?

For many neuromuscular disorders, we are in the unique and exciting position to dramatically improve children’s lives with early diagnosis, and the early provision of pharmaceutical treatment and other interventions, such as occupational therapy, physical therapy, speech therapy and others (Dowling et al, 2017). Early identification of at-risk children prior to the age of 6 months encourages early diagnosis of underlying etiology; the additional use of the 2-, and 4-month screening tools may play a significant role in the reduction of diagnostic delays presenting not just in neuromuscular diseases, but all developmental disorders presenting in infancy which ultimately enhances health outcomes including but not limited to (Palfrey et al, 1987; Carroll et al, 2014):

Improved prognosis, quality of life, and in many instances reduced mortality
Achievement of motor outcomes based on timing of identification / treatment (i.e., motor milestones achieved that are not expected based on natural history) and thus alternating the natural history
Decreased burden of disease for patients and families

Reduction of diagnostic delays via improved screening rates may dramatically help to improve said outcomes.

4. When do you need the evidence report?

Thu, 04/30/2020

5. What will you do with the evidence report?

[redacted: organization name] works with health care professionals (HCP), and specialists to ensure that patients affected with spinal muscular atrophy (SMA) have access to available treatments and the recommended standard of care. One of our key educational goals is to reduce the diagnostic delay in SMA and raise awareness about the urgency of early treatment in the most severe of SMA types. [redacted: organization name] recently launched [redacted: organization initiative/website], a new disease awareness and educational campaign to empower parents and healthcare professionals to promptly recognize and diagnose the early signs of SMA. Various stakeholders have hosted similar awareness initiative for other neuromuscular disorders including Pompe disease and congenital muscular dystrophy. Additionally, the National Task Force for Early Identification of Childhood Neuromuscular Disorders, convened in 2009 to address diagnostic delays experienced by patients and families impacted by neuromuscular disorders, developed the Child Muscle Weakness campaign (https://childmuscleweakness.org/). Despite such efforts, diagnostic delays persist. Therefore, although we fully recognize the significance of disease specific resources to enhance pediatrician awareness, universal developmental screening prior to the 6-months may alleviate practice variation, reduce burden on pediatricians unfamiliar with the early signs of neuromuscular disorders, and ultimately support current efforts via the reduction diagnostic delays. To support the efforts of [redacted: organization name] and our advocacy partners, we are proposing the implementation of universal screening at the 2- and 4-month well visits. Should the topic suggestion be approved, we are eager to assist with the expansion of current practice guidelines as well as the dissemination and implementation of materials to providers and families. We look forward to working with our partners at [redacted: organization name] to disseminate report findings across our combined provider/partner network. A working group may be established to discuss opportunities to potentially implement findings at the national and local level; invitations to participate will be extended to representatives of the aforementioned organizations and their constituents. Additionally, we would continue to foster strategic partnerships with groups such as [redacted: organization name] to promote universal utilization of screening tools at the 2- and 4-month well visits, discuss opportunities to update current practice guidelines for pediatricians, and leverage said guideline expansion to support achievement of Title V MCH National Performance Measures. To expedite implementation, we are looking to tap into the current infrastructure developed and supported by Title V MCH block grants.

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Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, Yamashita M, Rigo F, Hung G, Schneider E, Norris DA, Xia S, Bennett CF, Bishop KM. Treatment of infantile-onset spinal muscular atrophy with nusinersen: A phase 2, open-label, dose-escalation study. Lancet 2016;388(10063):3017-3026.

De Vivo DC, Bertini E, Hwu W-L, Foster R, Bhan I, Gheuens S, Farwell W, Reyna SP. (2018, March). Nusinersen in Infants Who Initiate Treatment in a Presymptomatic Stage of Spinal Muscular Atrophy (SMA): Interim Efficacy and Safety Results from the Phase 2 NURTURE Study. Poster session presented at the Muscular Dystrophy Association Clinical Conference, Arlington, VA.

Darryl C. De Vivo, Enrico Bertini , Kathryn J. Swoboda, Wuh-Liang Hwu , Thomas O. Crawford, Richard S. Finkel, Janbernd Kirschner, Nancy L. Kuntz, Julie A. Parsons, Monique M. Ryan, Russell J. Butterfield, Haluk Topaloglu, Tawfeg Ben-Omran, Valeria A. Sansone, Yuh-Jyh Jong, Francy Shu, John F. Staropoli, Douglas Kerr, Alfred W. Sandrock, Christopher Stebbins, Marco Petrillo, Gabriel Braley, Kristina Johnson, Richard Foster, Sarah Gheuens, Ishir Bhan, Sandra P. Reyna, Stephanie Fradette, Wildon Farwell, on behalf of the NURTURE Study Group, Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study, Neuromuscular Disorders (2019), doi: https://doi.org/10.1016/j.nmd.2019.09.007

Finkel RS, Kirschner J, Mercuri E, De Vivo DC, Bertini E, Foster R, Reyna SP, Farwell W. (2018, March). Benefits of Earlier Treatment with Nusinersen in Infants and Children with Spinal Muscular Atrophy (SMA). Poster session presented at the Muscular Dystrophy Association Clinical Conference, Arlington, VA.

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Finkel, R., Chiriboga, C., Vajsar, J., Day, J., Montes, J., De Vivo, D., . . . Bishop, K. (2015). Treatment of infantile-onset spinal muscular atrophy with nusinersen: A phase 2, open-label, dose-escalation study. Lancet, 388, 3017-3026. doi:https://doi.org/10.1016/S0140-6736(16)31408-8

Finkel, RS; Kirschner, J; Mercuri, E; De Vivo, DC; Bertini, E; Foster, R; Reyna, SP; Farwell, W. (2017, January). Primary Efficacy and Safety Results from the Phase 3 ENDEAR Study of Nusinersen in Infants Diagnosed with Spinal Muscular Atrophy (SMA). Poster session presented at the 43rd Annual Congress of the British Paediatric Neurology Association 11-13, Cambridge, UK.

De Vivo, DC; Bertini, E; Hwu, W-L; Foster, R; Bhan, I; Gheuens, S; Farwell, W; Reyna, SP. (2018, March). Nusinersen in Infants Who Initiate Treatment in a Presymptomatic Stage of Spinal Muscular Atrophy (SMA): Interim Efficacy and Safety Results from the Phase 2 NURTURE Study. Poster session presented at the Muscular Dystrophy Association Clinical Conference, Arlington, VA.

Finkel, RS; Kirschner, J; Mercuri, E; De Vivo, DC; Bertini, E; Foster, R; Reyna, SP; Farwell, W. (2018, March). Benefits of Earlier Treatment with Nusinersen in Infants and Children with Spinal Muscular Atrophy (SMA). Poster session presented at the Muscular Dystrophy Association Clinical Conference, Arlington, VA.

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Senior Manager of Clinical Affairs

Effective Health Care Program

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Early Identification of Neuromuscular Disorders