Categories: Fresh Air

Clearing the air on the DPS?

clock May 7, 2013

NeuRX DPS diaphragm pacing ALS

 

Plugging in A surgeon plugs the electrodes of the NeuRX DPS into the diaphragm using a special light-guide microscope called a laproscope.  Image: University of Florida.

Breathing is essential to life. But for many people with ALS, breathing can be difficult to do.

In 2005, Case Western University School of Medicine’s Ray Onders MD introduced the NeuRX diaphragm pacing system (DPS) in hopes to help people with ALS breathe better. The electrical device, originally developed for people with spinal cord injuries, aims to help keep the diaphragm moving longer by boosting the stamina of these respiratory muscles.

The treatment strategy, FDA-approved for humanitarian use in 2011, might help slow respiratory decline and boost survival according to clinical studies.  But a growing group of neurologists say more studies are needed to demonstrate that diaphragm pacing is an effective treatment for people with ALS.

Now, a US team led by State University of New York’s Kirsten Gruis MD hopes to clear the air by putting the NeuRX DPS to the test in a randomized controlled clinical trial. The study is expected to help clinicians best meet the respiratory needs of people with ALS. 

”ALS clinicians would really like to have more information,” says Gruis, “to know whether to recommend this therapy to their patients.”

The phase II clinical trial is expected to begin in the summer of 2013.

Case Western School of Medicine's Ray Onders MD implanted the first diaphragm pacer into a person with ALS in March 2005. Nearly a decade later, however, neurologists remain unsure whether to recommend the treatment strategy to their patients.

NeuRX DPS diaphragm pacer ALS

 

Resetting the pace? The diaphragm pacer aims to boost the stamina of the diaphragm by electrically conditioning these breathing muscles. Image: Synapse Biomedical.

One of the biggest concerns according to California Pacific Medical Center's Jonathan Katz MD is whether healthier people with ALS are in some way being selected for the procedure.  People who would live longer with the disease – with or without the device.

”We have to do a randomized trial,” says Katz, co-principal investigator of the study. “There is still an open question whether the procedure works.”

Many neurologists simply do not know whether to recommend diaphragm pacing. A decision that is all the more difficult due to the growing number of clinical trials of emerging ALS medicines that excludes patients that use them.

Now, a US team is gearing up to put the NeuRX DPS through its paces in people with ALS.  Clinicians will compare the breathing abilities, quality of life and survival rates of people with ALS using the NeuRX DPS to those being treated by the standard of care alone (non-invasive ventilation).

The clinical trial, run by the Northeast ALS (NEALS) Consortium and Western ALS (WALS) study group, will take place at 20 ALS clinics in North America. Sites include the State University of New York’s Upstate Medical University in Albany and California Pacific Medical Center in San Francisco.  180 people with ALS are expected to participate.

The results will help clinicians determine whether diaphragm pacing is effective and identify certain subsets of people with ALS most likely to benefit from the procedure. 

"For the first time in the history of ALS, we have an intervention that is possibly very powerful. But we don't have the evidence we would like to have supporting its use," says Duke University School of Medicine's Rick Bedlack MD. "It is critically important for us to confirm that it really does work."

***

To learn more about the NeuRX DPS including the upcoming clinical trial, tune into our podcast with Kirsten Gruis MD, DPS Point Blank.

References

Onders, R.P., et al. (2009) Complete worldwide operative experience in laparoscopic diaphragm pacing: results and differences in spinal cord injured patients and amyotrophic lateral sclerosis patients. Surgical Endoscopy, 23(7), 1433-1440Abstract | Full Text (Subscription Required)

Further Reading

Gonzalez-Bermejo, J., et al. (2012) Diaphragm pacing improves sleep in patients with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis 13(1), 44-54.   Abstract | Full Text (Subscription Required)

Scherer, K. and Bedlack, R.S (2012) Diaphragm pacing in amyotrophic lateral sclerosis: a literature review. Muscle and Nerve 46(1), 1-8. Abstract | Full Text (Subscription Required)

 

 

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Categories: Fresh Air

The DPS point blank

clock May 7, 2013

 

Breathing Coach. The diaphragm pacer aims to boost the stamina of the weakening breathing muscles in people with ALS by electrically conditioning them. Video: Synapse Biomedical.

Breathing is a precisely choreographed dance of the diaphragm and intercostal muscles. An electric slide of the diaphragm enables the chest to contract or expand - allowing air to enter and exit the lungs. But in people with ALS, these breathing muscles gradually weaken and atrophy- leading to respiratory distress and failure.

Scientists are developing treatments that aim to strengthen the respiratory muscles in hopes to help people with ALS keep breathing longer. One emerging therapy called diaphragm pacing uses an electrical device (the NeuRX DPS) to regularly stimulate the diaphragm. The strategy strives to boost the stamina of these breathing muscles by conditioning them.

A phase II clinical trial of the NeuRX DPS for ALS is expected to begin in the US in the summer of 2013. The randomized controlled study aims to determine whether the device can improve the quality of life and boost the survival of people with ALS.

ALS Today’s Michelle Pflumm PhD talked to principal investigator Kirsten Gruis MD of the State University of New York to learn more about diaphragm pacing and its potential benefits for people with ALS going forward.

To  learn more about diaphragm pacing, check out Clearing the air on the DPS? and DPS sleep.  To find out about ongoing clinical trials of the NeuRX DPS around the globe, read UK team gears up to put the DPS through its paces and French team rethinks the potential of the DPS.

References

Gonzalez-Bermejo, J., et al. (2011) Diaphragm pacing improves sleep in patients with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis. doi:10.3109/17482968.2011. 597862  Abstract | Full Text (Subscription Required)

Onders, R.P., et al. (2009) Complete worldwide operative experience in laparoscopic diaphragm pacing: results and differences in spinal cord injured patients and amyotrophic lateral sclerosis patients. Surgical Endoscopy, 23(7): 1433-1440.  Abstract | Full Text (Subscription Required)

Further Reading

Scherer, K. and Bedlack, R.S (2012) Diaphragm pacing in amyotrophic lateral sclerosis: a literature review. Muscle and Nerve 46(1), 1-8. Abstract Full Text (Subscription Required)

Gruis, K.L. and Lechtzin, N. (2012) Respiratory therapies for amyotrophic lateral sclerosis: a primer. Muscle and Nerve 46(3), 313-331.  Abstract  Full Text  (Subscription Required)

Patient Resources

Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation (RespiStimALS). Contact | ALS TDI Website 

Diaphragm Pacing in Motor Neuron Disease (DiPALS) Study  Contact  |  ALS TDI  Website 

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Categories: Fresh Air , Watchlist

French team rethinks potential of the DPS

clock April 30, 2012

 

The NeuRX Diaphragm Pacing System. Image: Synapse Biomedical.

One of biggest challenges treating ALS is breathing difficulties which occur due to the gradual weakening and decline of the respiratory muscles.  Researchers nevertheless are working hard to develop treatment strategies to keep these respiratory muscles moving to help people with ALS breathe easier.

One potential strategy called phrenic pacing hopes to keep the diaphragm moving by boosting the stamina of the respiratory muscles through the implantation of a device that regularly stimulates the connecting nerves. The FDA-approved device, called the NeuRX diaphragm pacing system (DPS), is available by prescription for patients experiencing frequent trouble breathing (chronic hypoventilation).

But a group of physicians from Assistance Publique – Hôpitaux de Paris led by respiratory specialist Thomas Similowski MD PhD thinks that the NeuRX DPS could benefit a lot more people with ALS.  They suspect the device, introduced at the very first signs of breathing difficulties, might jump start the training of these muscles to keep the diaphragm moving even longer - postponing the need for non-invasive ventilation.

Now, the French team is gearing up to put their treatment strategy to the test in people with ALS.  The double-blind randomized clinical trial, called RespiStimALS, is to be conducted at the Pitié-Salpêtrière Hospital in Paris.  All participants are to be monitored three times monthly for 2 years.  Outcomes include: reductions in respiratory decline (forced vital capacity), improvements in sleep quality and overall survival.  74 people with ALS are expected to participate.

The trial is scheduled to begin in June 2012.

To learn more about the NeuRX DPS and how the device might help people with ALS, read DPS Sleep.  To read about the ongoing NeuRX DPS trial in the UK, check out UK Gears Up To Put DPS Through Its Paces.  To find out about other strategies to help people with ALS breathe easier, read CK-357, helping pALS live strong?

References

Gonzalez-Bermejo, J., et al. (2011) Diaphragm pacing improves sleep in patients with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis. doi:10.3109/17482968.2011. 597862  Abstract Full Text (Subscription Required)

Onders, R.P., et al. (2009) Complete worldwide operative experience in laparoscopic diaphragm pacing: results and differences in spinal cord injured patients and amyotrophic lateral sclerosis patients. Surgical Endoscopy, 23(7): 1433-1440.  Abstract | Full Text (Subscription Required)

Further Reading

Ducko, C. (2011) Clinical advances in diaphragm pacing. Innovations: Technologies and Techniques in Cardiothotacic and Vascular Surgery 6(5), 289-297. Abstract | Full Text (Subscription Required)

Marion, D.W. (2011) Diaphragm Pacing.  UpToDate.  Excerpt |  Full Text (Subscription Required)  

Patient Resources

Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation (RespiStimALS). Contact | ALS TDI Website 

Diaphragm Pacing in Motor Neuron Disease (DiPALS) Study. Contact | ALS TDI Website 

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Categories: Fresh Air , Watchlist

CK-357, helping pALS live strong?

clock March 6, 2012

 

Power gain.  CK-357 may boost the power of fast skeletal muscles by increasing their sensitivity to weak electrical impulses generated by deteriorating motor nerves. CK-357 might be particularly useful to boost diaphragm function because these muscles contain nearly 50% fast-twitch muscle fibers. Courtesy of Nature Publishing Group. All Rights Reserved.

In people with ALS, the diaphragm and intercostal muscles gradually weaken often leading to respiratory distress and failure.  In hopes to keep these muscles moving, Case Western University School of Medicine surgeon Raymond Onders MD FACS introduced a device, now approved by the FDA for people with ALS with breathing difficulties, called the NeuRX DPS which may boost the stamina of these muscles.  

But researchers from San Francisco’s Cytokinetics Inc. think that they might have a simpler solution: the experimental drug CK-2017357 (CK-357). Introduced in 2008, CK-357 might increase the strength of certain skeletal muscles including those needed for breathing. Now, Cytokinetics scientists reveal just how CK-357 works: the drug promises to make the most of weakening neuromuscular junctions by helping fast twitch fibers in skeletal muscles hold on to calcium, enabling more powerful contractions.  These so-called fast skeletal muscles are needed in part, to maintain a healthy breathing rate.

The Cytokinetics’ team anticipates that the drug could be beneficial in the treatment of number of neuromuscular diseases including ALS.

CK-357 increases the calcium affinity of fast skeletal muscle troponin

 

Sensitive muscle? Electrical signals from the motor nerves enable skeletal muscles to move by pulling the wrench out of the muscular works - troponin - through the release of calcium. CK-357 may strengthen muscles by increasing the affinity of fast skeletal troponin for calcium, boosting the power of these contractions. Adapted from Nature Education. Original source: Lehman, W. et al. (1994). Courtesy of Nature Publishing Group. All Rights Reserved.

Performance testing

Physicians are currently evaluating the safety and tolerability of multiple doses of CK-357 in people with ALS.  The multi-institutional US team, led by State University of New York neurologist Jeremy Shefner MD PhD, are also checking for improvements in patients’ muscle function including breathing ability.  The two 14 day placebo-controlled phase II clinical trials are expected to be completed by the end of March 2012. About 48 ALS patients are participating.

Meanwhile, researchers in England and France are gearing up to put the NeuRX DPS to the test to determine whether the device improves the quality of life and extends survival of people with ALS. The first results of these clinical trials are expected in early 2015.

Reference

Russell, A.J. et al. (2012) Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases. Nature Medicine doi:10.1038/nm.2618. Abstract | Full Text (Subscription Required)

Further Reading

Hardiman, O., van den Berg, L.H. and Kiernan, M.C. (2011) Clinical diagnosis and management of amyotrophic lateral sclerosis. Nature Reviews Neurology 7(11), 639-649. Abstract | Full Text (Subscription Required)

Hardiman, O. (2011) Management of respiratory symptoms in ALS. Journal of Neurology 258(3), 359-365. Abstract | Full Text (Subscription Required)

Patient Resources

Please note: These clinical trials are ongoing but are not recruiting.

A Study to Evaluate the Effects of Multiple Doses of CK-2017357 in Patients With Amyotrophic Lateral Sclerosis (ALS)  ALSTDI | Website | Contact

Dose Titration Study to Test Safety and Effects of CK-2017357 in Patients With Amyotrophic Lateral Sclerosis (ALS)  ALSTDI | Website | Contact 

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Categories: Fresh Air

DPS Sleep

clock December 6, 2011

 

The NeuRX Diaphragm Pacing System. The NeuRX DPS phrenic pacer, developed by Case Western’s; Ray Onders MD, FACP, may condition the diaphragm muscles in people with ALS by stimulating the phrenic nerve that controls these muscles through implanted electrodes.  Recently approved by the FDA, the device is available by prescription to people with ALS that are battling chronic hypoventilation. Image: Synapse Biomedical.

Over 75% of people with ALS ultimately lose the battle with the disease due to respiratory failure.  To combat the decline of the diaphragm muscles, physicians at Case Western Reserve University School of Medicine introduced a phrenic pacer called the NeuRX  DPS in hopes to strengthen these muscles to bolster diaphragm function.  Recently approved by the FDA, this device according to anecdotal evidence may delay the need for mechanical ventilation.

But some ALS experts argue that the NeuRX DPS has not yet been sufficiently demonstrated through clinical studies to slow respiratory decline or even improve the quality of the life of people with ALS.  And with a cost of upwards of $20,000 USD, insurance providers may therefore be reluctant to cover this device for patients.

Now, University of Paris’ Groupe Hospitalier Pitié-Salpêtrière physicians in a preliminary study report that the NeuRX DPS may increase the stamina of the diaphragm muscles, helping people with ALS sleep more soundly.

The team found that patients implanted with the device after four months of diaphragm conditioning experienced a median increase in sleep efficiency of 9%, dropping the time awake after falling asleep by 40%, about one hour.  18 patients participated.

“Even if we would have shown a maintenance in sleep quality would have been a surprise,” says Thomas Similowski, Groupe Hospitalier Pitié-Salpêtrière Chief of Respiratory and Intensive Care Medicine who led the study. “Showing that we actually improve sleep efficiency is very spectacular.”

A larger study is now ongoing.

Keeping Pace

Phrenic pacemakers substitute for brain centers that become decoupled due to injury or disease from the neuronal circuitry controlling respiratory muscles by electrically signaling at regular intervals the diaphragm to contract, allowing patients to breathe without mechanical ventilation.

 

Just breathe. Phrenic nerve (red) impulses trigger the contraction of the muscles (blue) in the diaphragm, enabling us to breathe air in. Here, only slow muscle fibers and their attachments to nerve terminals called neuromuscular junctions (yellow) are shown. Image: Gary Sieck PhD, Mayo Clinic.  Copyrighted and used with permission from the Mayo Foundation for Medical Education and Research. All rights reserved.

Harvard cardiologist Stanley Sarnoff MD first introduced the idea of phrenic pacing in 1944 to support breathing of a 5 year old boy who suffered from paralysis of the diaphragm.  And in 1968, Yale cardiologists William Glenn MD and John Judson MD demonstrated that these devices can help regulate the breathing of a patient suffering from chronic hypoventilation – the inability to bring enough air into the lungs to support respiration.  Introduced into routine clinical practice in the early 1970s, phrenic pacemakers are typically prescribed to support ventilation of people who suffer from spinal cord injuries or experience certain chronic sleep or breathing difficulties.

But physicians remained skeptical about whether or not phrenic pacemakers could benefit people with ALS.  This is because the phrenic nerves in patients are deteriorating making it more difficult for these electrical impulses to reach the diaphragm.  And at the same time, these nerves are inflamed and may be inadequately myelinated in places in people with ALS resulting in the inefficient delivery of these impulses, making it harder to stimulate the contraction of these respiratory muscles.

Physicians at Case Western Reserve University School of Medicine nevertheless suspected that phrenic pacemakers may help people with ALS.  Their idea: these devices could strengthen the muscles in the diaphragm and thereby slow respiratory decline. 

“They are applying stimulation not to produce ventilation,” explains Similowski, “but to train the diaphragm muscles.”

In 2007, a multinational team led by Case Western surgeon Ray Onders MD, FACP, launched a clinical trial in the United States and France to evaluate the potential benefits of the NeuRX DPS phrenic pacemaker in people with ALS with chronic hypoventilation.  86 patients participated.   

The physicians found according to results submitted to the FDA that the device extended the median survival of participants 16 months than those in a comparable study supported by noninvasive ventilation alone.  But the team was unable to definitively demonstrate that this device slowed respiratory decline in people with ALS – at least as determined by monitoring participants’ forced vital capacities.

”It looks like it may be helpful but the scientific evidence is truly lacking,” says Methodist Neurological Institute neurologist Stan Appel MD.  “We just don’t know.”

Goodnight DPS

 

Take a deep breath. Breathing is powered by a choreographed dance of respiratory muscles featuring the diaphragm and intercostal muscles. Video: Tutor Vista.

But breathing is powered by much more than a diaphragm during waking hours.  And forced vital capacity therefore evaluates the health of other respiratory muscles in the chest that are also deteriorating in people with ALS. 

Groupe Hospitalier Pitié-Salpêtrière physicians decided therefore to take a look at people with ALS after bedtime.  This is because the diaphragm alone powers breathing during sleep.  By evaluating sleep quality of patients, the physicians could compare the function of the diaphragm before and after being conditioned. 

“A decrease in breathing during sleep is a very sensitive marker of diaphragm dysfunction in ALS,” says Similowski.  “That’s a very early marker of the disease.”

The team found that people with ALS stayed asleep longer and slept more soundly.  But surprisingly, the team found that key indicators of diaphragm strength continued to decline such as Sniff Nasal Inspiratory Pressure (SNIP) – about 8% on average during the duration of the study.

The team speculates that this is because the device does not make the diaphragm stronger but instead boosts the stamina of these muscles by promoting the conversion of the fibers to so-called slow twitch ones that are designed for endurance.   Typical tests such as those the team used according to Similowski predominately evaluate fast twitch fibers in the diaphragm which are designed for speed.  Studies to test this idea are ongoing.

Before NIV?

Physicians at the University of Paris however suspect that phrenic pacemakers such as the NeuRX DPS can make more of difference for people with ALS.  Anecdotal evidence suggests that the device may prolong the need for a mechanical ventilator up to 24 months.  And suspects Similowski, conditioning the diaphragm just as these respiratory muscles start to deteriorate might even delay the time when noninvasive ventilation is needed.

Starting in 2012, Similowski’s team is launching a clinical trial to test just that.  People with ALS experiencing the first signs of respiratory dysfunction with or without the NeuRX DPS implanted will be monitored for two years and compared.  About 75 patients are expected to be enrolled.  Results are expected in early 2015.

References

Gonzalez-Bermejo, J., et al. (2011) Diaphragm pacing improves sleep in patients with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis. doi:10.3109/17482968.2011. 597862  Abstract Full Text (Subscription Required)

Onders, R.P., et al. (2009) Complete worldwide operative experience in laparoscopic diaphragm pacing: results and differences in spinal cord injured patients and amyotrophic lateral sclerosis patients. Surgical Endoscopy, 23(7): 1433-1440.  Abstract Full Text (Subscription Required)

Sarnoff, S.J., Hardenbergh, E., and Whittenberger, J.L. (1948) Electrophrenic respiration. Science, 108(2089), 482.  Full Text (Subscription Required)

Judson, J.P. and Glenn, W.W. (1968) Radio-frequency electrophrenic respiration. Long-term application to a patient with primary hypoventilation. Journal of the American Medical Association, 203(12), 1033-1037.  Abstract Full Text (Subscription Required)

Further Reading

Marion, D.W. (2011) Diaphragm Pacing.  UpToDate.  Excerpt Full Text  (Subscription Required)  

 

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