want up to date information
 

Muon Do you have any follow up on on the DPS in use today or not.


DPS in ALS: Clinical Trial Under Way at
University Hospitals Case Medical Center
UH physicians involved in the Diaphragm Pacing
Center and the Neuromuscular Center of the
Neurological Institute proposed using the DPS system
in an attempt to maintain respiratory muscle function
in ALS patients. A pilot study conducted between
March 2005 and March 2006 demonstrated the DPS
system can be safely implanted in ALS patients, with
a documented decrease in the decline of respiratory
function leading to increased survival.14
In the pilot study, 16 patients (13 men and 3
women with an average age of 50 years; age range
32-70) received implants and no adverse events were
observed or reported. The mean time between the
onset of symptoms and enrollment in the trial was
45 months. All patients had a 2-month lead-in period
prior to implantation. The median forced vital capacity
(FVC) at implantation was 57%. In all pilot-study
patients, more fluoroscopically observed diaphragm
excursion occurred with diaphragm stimulation than
under maximal voluntary effort. DPS significantly
increased diaphragm muscle thickness when assessed
with ultrasound (P=0.02). After conditioning the
diaphragm with the DPS, preliminary results showed
an average rate of decline in FVC of 1.3% per month
from the pre-implantation decline of 3.1% per
month. This extrapolates to an additional 24 months
of ventilator-free survival

Greetings again, Thelma!

You posted a message from the first pilot study involving the DPS. Several Phase II studies have occurred since and at least one remains open to the best of my knowledge and belief.

There are about fifty sites in the US where one can obtain the implant, provided they meet the qualification criteria. I have found at least five patients who have 'internet disclosed' they obtained the implant this year.

A report from the UK went to press recently, reflecting on a study of 74 patients who were LESS successful than expected . . . about half of these patients underwent the implant. The reports indicates the implant may be harmful to patients but admits some patients might benefit. I have not completed my evaluation of the report but will comment further upon doing so.

". . . the qualification criteria . . ." my previous post this thread probably should read ". . . the HUD/HDE qualification criteria . . . ."

URL for DiPALS report in Lancet Neurology
 

Safety and efficacy of diaphragm pacing in patients with respiratory insufficiency due to amyotrophic lateral sclerosis (DiPALS): a multicentre, open-label, randomised controlled trial

http://www.thelancet.com/journals/la...152-0/fulltext

An issue clearly reflected in the data is asperation pneumonia . . . does the noninvasive ventilation increase risk of asperation pneumonia . . . does the pacer increase the risk of asperation pneumonia?:confused:

There may be an increase in asperation pneumonia risk with these technolgies, so be sure to incorporate routine use of pulse oxygen meter with the use of this equipment.

Here is the appendix for the Lancet DPS report:

http://www.thelancet.com/cms/attachm...10528/mmc1.pdf

The French study has resumed, US NIH Clinical Trails database now reports, "This study is ongoing, but not recruiting participants" whereas, previously reported "suspended."

While I continue to review the Lancet report I am convinced the writers ought to have identified gastronomy tube usage among the patients included in the study. Very little data on this issue appears in the report . . . one of the major reasons patients use gastronomy tubes is to decrease the risk of aspiration pneumonia.

The Lancet report also indicates 'no stimulation' is a possible 'sham stimulation,' whereas, in my estimation, 'sham stimulation' means stimulation other than 'no stimulation' or 'intended stimulation.' Its possible the complete absence of stimulation might be harmful in the presence of the implants because the implants may, in effect, cause short-circuits and thus increase the energy neurons must produce to sufficiently activation the synapse. The change in stress neurons may undergo might increase their load and thereby possibly reduce the neuron's longevity. A stimulation offsetting this effect ought to be possible - if it is needed.

The limited amount of French comment on the studies might in fact only be in reference to the Lancet report and thus the remarks implying the French study encountered trouble too is possibly only a rumor.

Possibly the most worrisome issue in the report are the two pulmonary embolisms. Until this report, I was aware of only one case, ending badly. Was this one of those two or are there now three . . . what happened of these two?

My understanding is pulmonary embolisms are always a surgical risk and people who live a sedentary lifestyle have a greater risk. So far no clear connection between the pacer and these embolisms are evident in the documentation I can find on the web. The first occurred within the thirty day surgery period; I can only find they occurred in the report, but not when, as yet.

The DiPALS report may be a study incurred of a false negative sample; In ALS a treatment group may appear to fair less successfully than the control group when the patient count is small. I have seen cases where a patient lasts only six months from disease onset to cases where a patient remains alive after fifty years from disease onset. So the patients lived less long in the treatment group; did they live longer than they would have? Efficacy is about whether they lived longer with than without the treatment.

Given a group of 37 ALS patients, we might expect to see seven slow regressors and presumably seven fast regressors (yet I know of very little literature on fast regressors).

censored?
 

This note pertains to Figure 2 of the DiPALS report in Lancet Neurology. There are tic marks on both lines in the chart: the upper line has about twenty of them and the lower line about ten. The caption regards them as indicating censored patients. The term censored is sometimes used to indicate cases excluded from consideration because of missing criterion(s): the report suggests some datums were instead interpolated because they were not received. I have wondered whether the tic marks indicate a patient passed the point where their speech was no longer intelligible? Such an indication would be scientifically valuable. Surely they do not mean they told the patient to shut up.

Journal papers free online
 

Prognostic factors in ALS: A critical review
Chio, et alia (Torino-Italy, Harvard, Dublin-Ireland, Dundee-Scotland, Preston-UK, Milano-Italy, NIH-USA)
Published 2009, "Amyotrophic Lateral Sclerosis"
http://www.tandfonline.com/doi/abs/1...82960802566824

Respiratory effects of amyotrophic lateral sclerosis: problems and solutions.
Lechtzin, Noah (Johns Hopkins)
Published August 2006, "Respiratory Care" Vol 51 No 8
http://www.ncbi.nlm.nih.gov/pubmed/16867198

status change on French study . . . :
 

A new status is posted on the ClinicalTrials.gov database for the French study:

"This study has been terminated.

(in the absence of benefits and because of a statistically significant excess mortality in the group of patients receiving active stimulation.)"

Further to my review of The Lancet Neurology report . . . :

The report ". . . patient population in the present study is characteristic of the ALS population in terms of age, sex, site of onset, and proportion with a clear family history . . ." is erroneous insofar as gender is concerned . . . no publication I am aware of has males nearly four times more likely to acquire ALS than females. The idea of randomization in the context of these kind of trials is to produce what could be called 'fair teams' in the groups undergoing treatment in consideration of whether there is efficacy against the disease(s) processes . . . one of the problems of ALS research is the unpredictability of each particular patient's likely survival. Would equal unfairness improve the reliability of a result? Variances as high as those found in ALS are quite rare among diseases, if there are any existing at all. The easiest tactic to compensate for this problem is to make the 'teams' larger, probably much larger; in a group of thirty-seven patients one would expect about seven whose regression rate is slow. "The Lancet Neurology's" report indicates five plus one patients had effectively abandoned the DPS branch of the trial. Could all of these have been slow regressors? How vulnerable are these trials to disruption . . . "to death from any cause."

Why did they call it ALS rather than MND (in the UK they call it MND)?

I have no print copy of the report . . . although I am searching for one. To the best of my knowledge and belief the French have not yet published a full report.

Health care codes used in the DiPALS trial report:
 

These URLs the assessments included in the DiPALS report.

SAQLI (Sleep Apnoea Quality of Life)
http://www.thoracic.org/members/asse...ires/saqli.php

SF-36 (Short Form Health Survey)
http://www.sf-36.org/tools/sf36.shtml

EQ-5D
http://www.euroqol.org/about-eq-5d.html

EQ-5D-3L (Euroqol 5D questionaire 3-level format)
http://www.euroqol.org/eq-5d-products/eq-5d-3l.html
Patient
Health State
Thermometer scale
Carer
Health State
Thermometer scale

Audio commentary related to the DiPALS report
 

I thought I should suggest listening to the audio commentary associated with the DiPALS report . . . you might have overlooked the audio recording of Chris McDermott and Richard Lane discussing the DiPALS study. The interesting audio commentary is found adjacent to the report on The Lancet Neurology's web site and adds content not found in the report:

http://www.thelancet.com/journals/la...152-0/abstract

UK's MNDA comments on DiPALS results
 

UK's MNDA comments on DiPALS results:

https://mndresearch.wordpress.com/20...mnd/#more-3701

I am nearing the completion of my review of the DiPALS Writing Committee report . . . sorry for the delay.

I would like to encourage SiTraN's DiPALS Writing Group to conduct a study on the " . . . web-based randomisation system. . . " using the remainder of their applicants . . . their report indicated there were 759 applicants, whereas they only needed 108 for their study. Such would result in about a dozen or so groups, wherefrom one can derive survival statistics . . . then consider whether the several groups developed similar or dissimilar survival profiles. Generally, PREDICTING the survival of patients is considered difficult to do, some researchers even say impossible and such is a primary issue in the development of sound treatment trials. Will the ". . . web-based randomisation system . . ." produce groups with similar or dissimilar survival profiles? Such study may produce a basis for a journal paper all by itself:confused:.

Although I continue reviewing the DiPALS report from SiTraN, I have another observation to note:

Again reviewing the numbers along the lower horizontal edge of the graph:

37 36 26 13 6 4
37 29 14 06 4 1

These appear to be the number of patients remaining alive at the start and then at end of each six month period thereafter. The lower numbers are regarded as the DPS stimulation group. Consider the following:

-7 -5 +5 +5 -1

These numbers are the differences in the number of patients who left the study (passed away) at each six month interval. Two things to note:

1. In the six month periods ending at eighteen months and two years the DPS stimulation group had five more survivors than the NIV only group.

2. The -7 in the first six months probably includes the five who opted out and the one found during surgery not to be able to accomodate the DPS device (total of six). They didn't immediately die.

So adjusted, the numbers would be:

-1 -5 +5 +5 -1

. . . far closer than you would think (the DPS stimulation group clearly prevailed in two of the five periods) . . . . Important question is: the stati of those six are (were they still alive at thirty months)? A difference of only one in a period is probably too close to call but two such periods leaned to the NIV only group and in the second period the NIV only group was clearly ahead.

Further, Table 4 lists one DPS stimulation patient as dying of hypothermia . . . correct me if I am wrong, isn't hypothermia freezing to death? How can the DPS device cause one to freeze to death, stimulation or no stimulation?

One further comment on the UK's MNDA comments on DiPALS results . . . :

Their MNDA says the DPS harmed patients but the DiPALS writing committee report only says such patients might have been hurt AND their MNDA says the DPS ". . . was not beneficial . . ." whereas the DiPALS writing committee regarded the efficacy as 'low' rather than non-existent. Apparently the MNDA is not careful in its choice of words.

Please further note
 

I have only accessed ELECTRONIC editions of these documents, I continue to search for authentic print editions. It is very easy to manipulate electronic documents.

what is ethical about death that would require contemplation
 

on witholding care or treatment. the end is not debatable



Can we see your final draft and not wait

Thelma, I am not sure whether your apparent question is directed to the MNDA or myself?

I continue to wonder whether the data they are analyzing is the French data; one might say, since their study was challenged on the basis of ethics by a researcher in the U.S., they would be wise to allow an independent authority to do the analysis. Such authority may have never met ANY of the patients . . . there are not many authorities in this area to begin with . . . imagine you were one and they gave you 'all the data,' via computer, and asked you to do the analysis. So you do the best you can . . . .

Such would improve the ethics posture of the trial but may opportune errors unlike those discoverable in nearly venues of research. You likely would only know the patients by some code rather than name.

(¿Thelma?) . . .

This year is likely the first where the number of patients who began using the patients and could be discovered via the web are fewer than the number of patients who were using the pacer but died . . . at this moment, the numbers are 10 new, 22 passed for 2015 . . . in the several prior years they today are:

2015 10 22
2014 26 13
2013 30 13
2012 34 05
2011 12 04 (not a full year . . . fda approval was in September).

survival brief for pacing patients we've lost this year
 

Survival (in months) of those pacing ALS patients we've lost this year:


all 23:median38

14 14 22 25 27 27 29 29 35 37 38 38 40 41 48 52 55 56 56 57 63 81 84


bulbarOnset

14 25 38 41 52 56


unknownOnset

27 29 35 37 38 40


infoNeeded

14 14 27 27 29 29 35 37 38 38 40 48 56



dataComplete

22 25 41 52 55 56 57 63 81 84


Thirteen patients have one or more unspecified dates (usually onsetDate). Their survival period is likely six to twelve months or more the currently specified here.


In this small group of bulbar onset also sees median of 38, much higher than medians of 20 (pre-riluzole) and 27 (post-riluzole). Medians for 'complete' sets have tended to be less than 36 months, here we see 38 plus likely at least six months. Note the dataComplete set shows median as 55-56 . . .19 to 20 months better than upper level studies (they sometimes show as high as 36 months) . . . even though thirty percent of cases are bulbar!


I believe we will see further {modest} improvements. Of the 150 patients I have found, I saw three blood clots reports and one stroke after implant. One of the blood clots was fatal. The investigation reported no link to the pacer though and I have seen no report regarding FDA changes to the requirements for the procedure.

Three UK pacer users have remarks in the web . . .
 

Liz Pick
'Pulses' help motor neurone disease patient breathe
http://www.bbc.com/news/uk-england-21663483

Mohan of www.alsforums.com
http://www.alsforums.com/forum/members/mohan.html

Malcolm Chattle
Major trial gives hope to motor neurone disease sufferers
https://www.sheffield.ac.uk/news/nr/...field-1.174450
http://medicalxpress.com/news/2012-0...e-disease.html

In depth report on DPS in ALS (Onders et alia)
 

Identification of unexpected respiratory abnormalities in patients with amyotrophic lateral sclerosis through electromyographic analysis using intramuscular electrodes implanted for therapeutic diaphragmatic pacing

http://www.americanjournalofsurgery....598-4/fulltext

selected excerpts:
"Control of respiration is incompletely understood in normal subjects and even less in ALS. . . .

"Some patients had minimal or absent dEMG activity but strong diaphragm contraction when the electrodes were stimulated. . . .

" . . . With disuse, the intact motor units of the diaphragm will rapidly convert to Type IIb fast-twitch muscle fibers . . . .

" . . . There is a growing evidence that ALS patients have sleep-disordered breathing that is most often because of central mechanisms. . . .

". . . dEMG burst activity improved for some patients after DP conditioning or a rhythmic breathing pattern would continue when DP was not being used. Fig. 1 highlights the dEMG improvement in burst activity. . . .

". . . DP may improve automatic respiratory control. . . .

". . . Death can occur within hours of DP withdrawal indicating that there can be a rapid loss of control leading to respiratory failure with DP cessation. . . .

"(evidence of) NIV causing diaphragm activitiy suppression; (4) identification of unilateral abnormalities with a loss of control of the diaphragm from respiratory control centers in the brainstem; (5) DP improves diaphragm burst activity and helps in maintaining the respiratory pacemaker. . . .

"(DP may) also delay the death of those motor neurons. . . .

"The fifth finding is a growing area of research in respiratory physiology. There is evidence that the respiratory system is able to "fight back" and trigger spontaneous compensatory plasticity that can maintain respiration in the face of motor neuron loss. . . .

"The plasticity although somewhat persistent was shown to wane when DP is discontinued. For example, in one case a patient with DP became intubated secondary to aspiration pneumona and DP was stopped for several days at an outside hospital. Prior to the event the patient had large dEMG burst activity and was using DP as the primary mode of ventilation even though he was late in his disease. When re-evaluated, the patient had no dEMG volitional burst activity and DP could no longer maintain ventilation. The plasticity seen from DP may rapidly degenerate when DP is stopped in ALS patients. . . .

"Because DP prevents diaphragm atrophy from NIV suppression, DP can decrease the need for NIV during the day. . . .

"If the dEMG shows no burst activity but the diaphragm was stimulable then the patient requires 24 hours pacing to maintain diaphragm function. . . .

"DP therapy is optimum when the patient has unused motor units that DP can drive and dEMG shows the patient has instability of control of those units. . . .

"In conclusion, these dEMG findings demonstrate that ventilatory dysfunction in ALS is likely much more complex than just denervation atrophy of the diaphragm. Significant areas of central dysregulation were seen along with interesting observations of apparent asymmetric central dysfunction."

Onders recommends patients should have DP active whenever they are on BiPAP . . . "We've now realized that just being on the ventilator in your intensive care unit, if you get pneumonia, actually changes your brain stem control of respiration. There's actually adverse effects in your pre-Botzinger complex."

high variance
 

Quick note, re: DiPALS report . . . :

Even though implanting but not activating the DPS may be a mistake, such trial might well be scientific . . . I say I would not have approved because a need to compensate for the 'short-circuit' effect of the probe may exist. Yet I remain uncertain as to whether such would matter. It might not. The issue may be unknown . . . unknown from my perspective certainly - maybe someone knew. However, the issue might be moot . . . variance from 'norm' in pilot samples in ALS is not well study to the best of my knowledge and belief. Are there any researchers who would doubt variance in pilot samples is large in ALS, more likely larger in ALS than many other diseases? Most would have to admit substantial variance in pilot samples is likely but there is very little discussion of sample variance in the recent papers. The high variance may partially explain the results the DiPALS writing group reports. Its 20-20 hindsight though.

How difficult would disturbing an ALS clinical study be . . . How frail is the effect being exploited in the DPS treatment?

One area where the DiPALS report may be flawed involves their discussion of whether ALS patients ought to undergo surgery, a reference being made to a paper by Pinto, et alia, published in 2004 suggested disease progression may increase in ALS patients who undergo surgery. They do not suggest constraining gastronomy tube surgeries, et alia or tracheostomy surgeries, however. Since I began observing remarks by ALS patients in 1999, the pacer was unanimously regarded as the least difficult of those who underwent same and expressed their opinion in on-line remarks I discovered. The DiPALS authors express an interest in the full set of data used by the FDA in support of the HUD/HDE determination; indeed I also wish this data, but even if such were available there are likely not enough cases to support conclusions needed to perfect medical opinion on the pacer. The symptom variance in ALS patients is very large and as a result, I estimated the number of cases needed to complete the medical review is likely more than 5,000 to 10,000 cases.

Their analysis was by intent to treat; Sandeep Gupta describes here:

Intention-to-treat concept: A review
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159210/

According to Sandeep Gupta "Intent to Treat" analysis usually produces more conservative estimates of efficacy because the ". . . estimate of treatment effect is generally conservative because of dilution due to noncompliance. Also, heterogeneity might be introduced if noncompliants, dropouts and compliant subjects are mixed together in the final analysis."

In a normal pilot sample one would expect about two patients who regress slowly, in the referenced study each group had about two pilot samples wherefore, about four patients in each group, were the pilot samples normal, would be expected to last at least five years. Such may have been the case in the NIV group as, at the close of the study, approximately thirty months, four patients remained alive but only one did in the DPS group and they decided to undergo tracheostomy. A slow regression patient would likely not need to do so for some time, hence, either the DPS group was not normal or the slow regression patients left the study early.

Quick note, at present I have so far found 38, 31 and 34 pacing ALS patients in 2012, 2013 and 2014 respectively. Only 13 for 2015 so far but not too unusual as many patients do not immediately disclose their medical strategy.

I saw a report in only one apparent news source indicated about 6,400 patients had died in 2014 several months into 2015 . . . recently ALSA apparently updated their statistics to say the expected number of diagnoses each year is now 6,400 . . . up from 5,600 . . . known since at least 1999.

I think the DiPALS report might be best thought of as a minimus . . . within the report, a statement implies an informal per-protocol analysis was made and showed 'low efficacy.' Their report covers much 'territory,' often with very limited depth. Centers ought to at least meet and should exceed their results. Each of their centers administered less than a pilot study of implants (less then about sixteen). Patients are more likely to obtain an implant at their nearest center . . . patients are more likely to be later in their 'implant opportunity window' in the early period of a center's initiation of implants.

I keep trying to remind myself to note the several cases were remarks exist regarding incomplete happiness with the pacer . . . these are:

regarding Harrell of PatientsLikeMe.com by their care provider.
regarding llbjgb of inspire.com by their care provider.
by Susan F., an M.D. regarding their spouse in response area of a notice.
(will try to rediscover the notice).

and

Knudson in http://dailylifewithals.blogspot.com/
noting '. . . sleeps better without the pacer . . .' but uses during the day. In contrast, "Tom M" of PatientsLikeMe.com could not use the pacer during the day (due to asynchronization issues) but was able to use while sleeping.

Many patients have commented on discomfort associated with feeling electrical sensations during the period the pacer is being adjusted but I know of none persisting after calibration was complete.

The DiPALS report refers to this paper:

Does surgery accelerate progression of amyotrophic lateral sclerosis?
http://www.ncbi.nlm.nih.gov/pubmed/2...?dopt=Abstract

by Pinto et alia, wherein some fifty patients experience noticeable drop in ability shortly after surgery . . . of these approximately two thirds were for surgeries appearing to be unnecessary because the condition the patient was believed to have before the surgery was not found to be the case during surgery. In my experience observing the remarks of patients suffering from ALS I recall several patients who noted a sudden change in the rate of their regression; HarryAZ of BrainTalk communities after they underwent an umbilical cord blood procedure (the dozen or so fellow patients who also underwent the procedure did not). A patient who was participating in a fundraiser by 'driving' the full length of New York's Long Island in their power wheelchair while nearing the end of the trek. Another I don't clearly recall at this moment . . . resulted in my hypothesis patients under a drop in their supposedly 'linear' regression for some unknown reason - (currently unknown). Patients often report a 'trigger' to their ALS symptoms. I further hypothesize patients didn't need the surgery but may have felt they did due to this 'drop' and thus the Pinto report may have gotten the 'cart before the horse' so to speak. MORE on this issue later.

I am hoping we will hear of Knudson soon, they were planning on moving into their new home and where having trouble with their computer's adaptive components (as way too many patients have). We have not heard from them since New Years Eve.

One quick note before the long weekend . . . be careful about the difference between Average and Median: In most cases, in ALS papers, average will be higher than median . . . because slow regressors can pull these datums up more forcefully than rapid regressors can pull them down. Median is the 50:50 point . . . a randomly chosen patient 'ordinarily' has a fifty percent chance of making the median . . . in most cases, at this time, the chances of a randomly chosen patient making the Average is significantly less than making the Median (less than fifty percent).

Happy Valentines and President's day weekend.

Breaking in the 9th year . . . :
 

Quick note to advise several pacing patients are in or breaking into their ninth year of pacing.

I am inclined to believe the report of the DiPALS committee is intended primarily as an alert to a possible problem and not a referendum on the pacer because they do not criticize the lead surgical team, only the United States Food and Drug Administration (possibly because their HUD/HDE approval did not take into account the possibility the pacer might be implanted but not activated).

Are females in greater danger once affected?
 

Upon the news of djbailey's death (of alsforums.com) In at least two ways I continue to see gender bias in my review of ALS cases . . . In cases were patients are alive nearly nine years after initiating pacing I have found about a dozen cases, only two are female . . . unclear how real those two cases are . . . ; in this list of studies, only five studies found bias against females but no study has found bias against males:

http://neurotalk.psychcentral.com/sh...29#post1203229

Although females are much less likely to incur ALS, when they have, they may be less successful in fight off the disease. djbailey apparently had a more aggressive form of the disease, as they became unable to move their eyes only three years in from symptom onset of limb onset ALS. Ocular immobolization is rare in ALS, occuring late in the disorder's process.

Further, of the eight apparently least successful cases wherein full data is available, five are female and three are male . . .

Thanks, MuonOne
 

MuonOne
I appreciate your taking the time to keep ALS patients and caregivers so very well informed. I do not have ALS, but have been diagnosedwith Parkinson's for 20+ years.

There are many similarities between ALS and PD. By studying all neurological illnesses, I believe we will come closer to finding therapies that work. I want to thank Thelma for her work in this area, also.
Peggy