2018 MDA Clinical Conference Highlight Report: Day 2 Morning Sessions

On Tuesday morning, MDA’s 2018 Clinical Conference sessions focused on best practices in cardiac care, physical therapy, bone health, technology and nutrition.

Among the highlights:

Cardiac management for the muscular dystrophy lifespan

Elizabeth McNally, M.D., Ph.D., from Northwestern University Feinberg School of Medicine, noted that to best manage the heart in neuromuscular disease, a genetic diagnosis is key as it provides information about cardiac risks, which can include cardiomyopathy, heart failure and arrhythmia.

Some neuromuscular diseases that have associated cardiac involvement include Duchenne and Becker muscular dystrophies (DMD/BMD), Emery-Dreifuss muscular dystrophy (EDMD), some limb-girdle muscular dystrophy (LGMD) subtypes, myotonic dystrophy (DM), Friedreich’s ataxia (FA) and subtypes of congenital, myofibrillar and mitochondrial myopathies.

Special considerations when monitoring and managing cardiac function in the context of neuromuscular disease include the following:

  • Individuals can be exercise intolerant because of their disease, so that won’t be a presenting symptom.
  • Hypotension is common and will limit the use of some medications.
  • Serum creatinine is not an informative measure because its value is low if muscle mass is low.

Cardiomyopathy occurs in a subset of neuromuscular disease and can also be associated with arrhythmias. For other neuromuscular diseases, arrhythmia risk is increased even if there is no left ventricular dysfunction. Therefore, cardiac management requires regular imaging for both left ventricular function and arrhythmia surveillance.

Adequate pulmonary support is also essential to maintaining good cardiac function, and care coordination for advanced muscular dystrophy patients should include both cardiologists and pulmonologists on the multidisciplinary care team.

Cardiac imaging in muscular dystrophy

Jennifer Strande, M.D., Ph.D., from the Medical College of Wisconsin, noted that the American Heart Association published guidelines for managing cardiac involvement in neuromuscular disease in 2017.

Underlying mechanisms in types 1 and 2 myotonic dystrophy (DM1 and DM2) can have adverse effects on the heart and other organs. Common heart conditions in these patients include mitral valve prolapse, cardiomyopathy, bradyarrhythmias and tachyarrhythmias. The first cardiac incident often results in sudden death.

Imaging modalities used to detect and follow cardiac manifestations of neuromuscular disease include:

  • Trans-thoracic echocardiogram (TTE); 2-D image measurements for left ventricle volume, ejection fraction, wall thickness and wall motion; and doppler assessment of diastolic function.
    • Contrast enhancement allows for measurement of thickness of the endocardial border.
    • Strain and strain rate can indicate subclinical systolic dysfunction.
      • With speckle tracking, a computer uses dots to draw the border of the heart and then measurements can be made of the distance between the dots as the muscles contract and relax. Earlier detection of cardiac involvement using this technique requires a skilled sonographer to get good images, and limitations include diminishment of imaging windows because of disease progression and scoliosis or obesity with advancing age.
  • Cardiac MRI can be used to assess function and structure, including left ventricular volume, wall motion, ejection fraction, strain and characterization of tissue.
    • Late gadolinium (contrast) enhancement can reveal interstitial fibrosis, infiltration, infarction and necrosis. The normal heart is very compact with no space for gadolinium, but with defects accumulation and leakage can be seen.
    • Patients who are not good candidates for this technique include those with tachycardia, arrhythmias, high respiratory rates and those who are unable to remain still; patients with older pacers and ICDs made of metal; and patients with rod implants for scoliosis. In patients for whom an MRI is contraindicated, a cardiac CT is an alternative option.

Specific recommendations by disease are as follows:

DM: Screen with TTE at diagnosis and then every one to three years. Mitral valve problems may mask cardiomyopathy, and timing of valve replacement is tricky. With older patients, cardiac MRI should be performed first in order to rule out cardiomyopathy.

DMD: Use echocardiogram for patients in wheelchairs who are unable to transfer to the exam table.

EDMD: TTE annually.

LGMD: TTE every one to two years in types 1B, 2D, 2F and 2I; every three to five years in types 1C and 1E. Perform cardiac MRI to assess fibrosis in types 2D, 2E and 2F.

Management of neuromuscular-associated cardiomyopathy

These findings were presented by Pradeep PA Mammen, M.D., FACC, FAH, UT Southwestern Medical Center.

Advances in respiratory care for patients with muscular dystrophy have increased survival but have unmasked cardiomyopathy.

For the management of cardiomyopathy, all at-risk patients should be treated with ACE inhibitors. Beta blockers and aldosterone blockers are associated with longer life span.

Heart transplants are an option for some patients with neuromuscular diseases, but there’s a 10-year median survival rate for all cardiomyopathies, and they’re associated with risks such as infection, cancer and acute cardiac rejection.

The best predictive measure of sudden cardiac death is the presence of left ventricular fibrosis. Left ventricular assist devices (LVADs) are helpful for some individuals with muscular dystrophy. The HeartWare and Heartmate III do not disrupt diaphragm function, which is critical. These devices can help bring blood tests back to within normal ranges and result in improved ejection fraction. Drawbacks include risks for infection, bleeding, strokes and device malfunction.

Management for type 1 spinal muscular atrophy (SMA)

Allan M. Glanzman, P.T., D.P.T., PCS, from the Children’s Hospital of Philadelphia, noted that the emergence of new treatments for type 1 SMA means clinicians are now seeing patients who are able to achieve a broad spectrum of functional abilities they otherwise would not have been expected to achieve — and this is resulting in a new natural history for the disease.

“It’s a little like working without a natural history,” Glanzman says. “So, do what you can to give everyone as many options as possible — cast a wide net.”

The standards of care for SMA are meant to help optimize function and tolerance to various physical positions.

Rehabilitation goals and treatments should be conducted in the context of emerging patterns of development and the evolution of impairment typical in this population — “think natural history with treatment.”

Mobility training, along with stretching, exercise and range of motion, positioning (posture control to help with sitting tolerance and avoid scoliosis, hip dislocation and chest deformity), bracing and other equipment may be used to assess the degree of impairment and motor function in these babies, and may incorporate movements both with and against gravity. Water and overhead suspension (such as slings and springs) may be used for external support or resistance.

Biofeedback can be incorporated through biofeedback-activated switch toys and computer games (joysticks).

Low-load prolonged stretching, standing and serial casting may be used to prevent contractures. It is useful in standing to ensure a supported posture, keeping pulmonary considerations in mind. KAFOs may be used in the stander to improve knee position and ankle stability, accommodate contractures, and provide support for valgus forces.

Postural control may be assessed using the Hammersmith infant neurologic exam and WHO motor milestones and should be considered when working to achieve sitting tolerance.

Importantly, training should be matched to an activity-specific goal. Play can be used as motivation.

Best practices in rehabilitation for SMA in patients with later-onset SMA

Leslie Nelson, P.T., UT, from Southwestern Medical Center, addressed rehabilitation with regard to patients with later-onset SMA.

With new and emerging treatments, some of the stronger SMA type 1 patients could carry over and fall into some of the same rehabilitative categories as weaker type 2 patients. The paramount question is how will the treatments change the natural history of the disease and what we do?

Evaluations to assess function in infants able to sit include: postural control assessment, HFMSE, ROM/goniometry, strength assessment, pain scale and caregiver burden. Functional evaluations for infants able to stand may include timed function tests, a six-minute walk test, mobility/gait evaluation, ROM/goniometry and exercise tolerance.

Rehabilitation strategies for these patients can include the following.

For sitters:

  • Stretching ROM: These exercises can be done five to seven times per week, with aims to improve length (sustain stretch for greater than 60 minutes) and maintain length (end range held at least 30 seconds)
  • Mobility equipment
  • Play/toys
  • Bracing
  • Postural support and positioning
  • Standers
  • Transfer training
  • Mobile arm supports
  • Aquatic therapy

For standers:

  • Exercise
  • Stretching/ROM
  • Aquatic therapy
  • Balance exercises
  • Bracing
  • Fatigue management
  • ADL management
  • Ambulation devices

“It’s really about using what you have to get the activity you need,” Nelson says. “Don’t forget — it needs to be interesting and fun.”

Stretching exercises should be conducted frequently, and duration should vary by age and type. The goal is to maintain range in order to, in turn, maintain mobility and promote function.

Accelerating discovery in neurological disorders with cognitive computing

Jane Yu, M.D., Ph.D., from Watson Health Life Sciences Solutions, shared information about new technology from IBM Watson Health to help researchers in the search for treatments.

Understanding the genetic causes of disease is critical to the discovery and development of treatments and, eventually, cures.

IBM Watson Health’s new discovery platform is designed to help scientists pinpoint links between genes, diseases and drugs. The platform, which has been tested in a number of projects designed to show proof of concept, employs cognitive computing and artificial intelligence, and draws on Medline abstracts. Predictive analytics enable the identification of genes, proteins and drugs for further analysis and evaluation.

Today we are seeing an explosion in the growth of data, with the rate of biomedical data growth expected to double every 73 days by 2020. There are advances and updates coming online every day in next generation sequencing, biomedical imaging, EMRs, diagnoses, clinical history, labs, medications, exogenous data, socioeconomic data, data around behaviors and choices, time-varying sensors (e.g., Fitbits), and scientific literature.

With new applications coming online, intelligent systems will be able to determine how a unique combination of intrinsic traits, behaviors and environmental factors impact a clinical or biological response. This will generate insights into population health and personalized or precision medicine.

Watson for drug discovery helps researchers answer key questions to discover new drug targets and mine scientific literature to link common concepts. It can draw from domain entities, genes, proteins, drugs and diseases and generate visualizations that depict associations between the entities.

The application has been used to discover five new proteins associated with ALS. There are 15 RNA binding proteins known to affect ALS; when Watson was asked if there are others, it generated a list of 10. Eight out of those 10 were validated with histological staining for mRNA expression and five of these were previously unreported.

The fundamental problem to be solved is, the genome is finite and the environment is infinite. What information are we hoping to find with genes that don’t segregate with the disease?

Telemedicine in health care

James D. Berry, M.D., M.P.H., from Massachusetts General Hospital, discussed telemedicine in ALS (amyotrophic lateral sclerosis) clinical care.

Remote delivery of health-related services and information via telecommunications technologies can supplement and/or replace what we are able to do in person.

Technology is in widespread use on the consumer side, but challenges to using it extensively on the health care side include privacy, legal concerns, institutional rules, caution when it comes to making changes and reimbursement.

ALS is particularly amenable to telemedicine, as travel to Care Centers can be a substantial barrier to care, particularly in the later stages of the disease.

The TelePALS ALS telemedicine program placed a heavy emphasis on video televisits in which ALS teams could be connected to ALS patients in their homes. The program aimed to establish close collaborations between home care providers and health care providers through the use of webinars, videos and in-person meetings.

Challenges — many of which have since been overcome — included difficulty with getting medical insurance to cover televisits, state regulations around providing video care when providers and patients live in different states, technological problems with software and slow internet connections, and a hesitancy on the part of physicians to provide care over video.

Upsides to the program were relief from the burden of travel for individuals with ALS and their families, increased access for the medical professional and patient, geographic equality, and improved connectedness. Sometimes a televisit is easier — it may require less time and be easier for people with ALS. For certain discussions, televisits can be more effective than clinic visits.

There has been good correlation of in-person ALSFRS-R score to results obtained over the phone, although a bias toward higher scores with self-administration has been detected. And while the average daily distance traveled over time (walking, wheelchair, car, etc.), GPS data and ALSFRS-R indications appear to be highly correlated.

These data are promising, but further questions remain about how best to incorporate research into telemedicine. A mobile version of standard clinic outcome measures may need to be developed — perhaps measures that can be deployed to mobile devices that can perform passive data collection.

Precision brain health: Answer ALS is a population-based multi-omics program to identify ALS subgroups, biomarkers and druggable pathways

Jeffrey D. Rothstein, M.D., Ph.D., Johns Hopkins University, School of Medicine, discussed attempts to stratify ALS patients who need different approaches to care management and therapy.

Answer ALS, sponsored by Johns Hopkins University School of Medicine, is a multi-omics approach launched in 2016 to follow 1,000 ALS and ALS/FTD patients, along with a group of matched controls. The goal is to identify subgroups of people with different ALS subtypes, as well as to uncover new clues into the causes of ALS, find new therapeutic targets and identify biomarkers.

Researchers derived iPS motor neurons from the blood of each patient who enrolled in the study. These cells were subjected to a battery of tests including whole genome sequencing, proteomics and imaging. In addition, biofluids and tissue were collected, as well as information about ALSFRS-R scores and ALS symptoms and progression including motor function, speech and breathing. Big-data and machine-learning technologies have been used to integrate the data points.

Data from the study is made available in real-time to enable community-based data analytics.

To date:

  • More than 690 people have enrolled in the study and provided a standard medical history
  • More than 250 iPS cell lines have been generated
  • More than 350 whole genomes have been sequenced

Early analysis of a trial subset of participants identified biological subgroups.

These studies demonstrate distinct reliably identifiable subgroups among the sporadic and familial patients, and the great utility in iPS-based approaches to disease pathophysiology and therapy discovery.

MDA is grateful to the following companies for their support of the 2018 Clinical Conference:

  • Strength for Life supporters — Biogen, PTC Therapeutics
  • Muscle Champion supporters — AveXis, Santhera Pharmaceuticals, Inc., Sarepta Therapeutics