Corpus cavernosum EMG in erectile dysfunction

Cel

A. BACKGROUND
A.1. Introduction
Corpus Cavernosum ElectroMyoGram (ccEMG) is the measurement of the electrical activity of the smooth muscle cells of the Corpus Cavernosum of the penis. Neural input causes relaxation of the smooth muscle cells, which results in a strong increase in arterial blood flow, that is necessary for an erection. Thus, the proper functioning of the smooth muscle cells is one of the key issues in erectile function. The ccEMG measurement of the smooth muscle cells activity and the propagation of the activity to the surface, is therefore one of the ideal (non-invasive) tools that can be used in the diagnosis, treatment and follow-up of erectile dysfunction.
Most (oral) drugs for the treatment of erectile dysfunction influence the smooth muscle cells activity. ccEMG can be used to evaluate these drugs and to develop safer and more efficacious drugs.
A.2. Erectile Dysfunction
Erectile dysfunction (ED) is defined as an inability to obtain an erection sufficient for intercourse. Causes for ED may vary between patients. Although clinicians and scientists try to distinguish causes of ED mainly between psychological and organic, this distinction has proven to be illusive. Nowadays, one comes to the perception that ED is an example of a multifactoral disease, in which psychological and/or organic factors are involved. Moreover, one realises that ED, irrespective of its cause, augments itself by negative performance anxiety and hypoxia of the cavernous bodies. This perception has led to a more multidisciplinary approach and prevention of ED in which urologists, psychologists, sexologists, and internists are involved.
Among the organic causes of ED are vascular impairment (arteries, veins, but also the endothelial function itself), neuropathy (peripheral sensory-motor, autonomic nervous system, and probably the central nervous system), myopathy (especially trabecular and vascular smooth muscle cells in the cavernous bodies), and hormonal disturbances. Recently, the geometry of the penis was introduced as an additional organic factor. Less directly an organic cause, but not less important, are medicinal drugs. Although it may be difficult to distinguish between drug effects (as pharmacodynamic effect or as adverse drug event) and the disease itself as cause for ED, it is believed that many drugs (antidepressants, antihypertensives, serotonin uptake inhibitors, H2 receptor antagonists, hormones) do influence the sexual response.
ED combined with comorbidity, and (co-) medication, is a field that is gaining interest. Patients with a chronic disease like diabetes mellitus, renal insufficiency, cardio-vascular diseases or psychiatric illnesses form groups in the population that are at risk to suffer from ED to a large extent. Patients with transient comorbidity form another important group. Especially, following pelvic surgery, a temporary form of ED may develop; artificially (pharmacological) induced erections gain interest to prevent hypoxic damage to the cavernous tissue during this period. The outcome of studies on the prevalence of ED may differ considerably, due to methodological differences (how is ED objectivated) and differences in study populations (cultural, comorbidity, co-medication). Today, the best study is the Massachusetts Male Ageing Study, concerning males aged 40 - 70. The chance to have any (mild, moderate, complete) ED at the age of 40 is 40%, which increases to 67% at the age of 70. In the Netherlands, the prevalence of sexual problems in the general male population, aged 20 - 65 years, is about 10%. The difference with the Massachusetts Male Ageing Study is caused by the different endpoints: dysfunction versus problem, the latter being a subjective appraisal of erectile function. It is clear that ED is a numerical and substantial disease.
Due to these methodological problems, the impact of ED on quality of life has yet not been studied. But clinicians consider its impact as very important. ED is directly related to the self-esteem of men, and consequently, men often wait many years to "come out". The estimated average patient's delay in seeking medical care for ED in the Netherlands is about 2 years. During this period, quality of life is severely diminished. This is demonstrated by the increase in quality of life with successful treatment of ED.
A.3. Role of ccEMG
The diagnostic array for ED is large, and its choice depends on the specific question to be answered, taking the limitations of each methodology into account. Next to ccEMG, the diagnostic tools available are:
- Questionnaires to assess psychological issues, to differentiate between organic and psychological ED, and to assess the quality of the sexual response. The limitations are validity, references values, and often of a time consuming nature.
- The quality of erections at night can be assessed by the Rigiscan(r), a computerised device to measure tumescence and rigidity at night. The need of 3 consecutive nights, and the costs and vulnerability of the device limit this method.
- Visual erotic stimulation is a psychophysiological investigation. The response can be measured with the Rigiscan(r). However, the nature of the erotic stimulation limits its applicability.
- A pharmacotest is the intracavernous injection with a vasodilating drug to induce an erection. The absence of an erection favours an organic, mainly vascular cause for ED. If sufficient erection occurs, auto-injection therapy may be a therapeutical strategy. Although not regarded as an invasive method, this test requires an intracavernosal injection, being its limitation.
- A duplex scan is a pharmacotest with simultaneous ultrasonography with Doppler measurement. The duplex scan assesses the quality of the arterial response and the veno-occlusive function. Limitations are comparable with the pharmacotest (see above).
- Arteriography can be used to localise an arterial stenosis. Very invasive and indicated only if a localised stenosis is expected.
- Cavernosometry/graphy is a method to assess the veno-occlusive function by measuring and visualising venous leakage during maximal smooth muscle relaxation. Very invasive.
- Neurological testing is mainly limited to somatic-motor nerves, which play a minor role in pathophysiology of ED.
In conclusion: The main limitations of the mentioned diagnostics are: lack of specificity and sensitivity with regard to a well defined component of the erectile mechanism, lack of validity, or limited indication to use it. Moreover, physicians prefer to perform as little as possible diagnostics, and this is only achievable with a diagnostic tool that measures directly the final common pathway of the erectile mechanism, being autonomic innervation of the vascular and trabecular smooth muscle cells within the cavernous bodies, as possible with ccEMG.
Advantage of ccEMG: ccEMG is a (non-invasive) measurement that is able to evaluate directly the characteristics of the autonomic nervous signals and of the smooth muscle cells, being the final common pathway of the erectile mechanism. A normal result identifies the problem at a higher level, for which appropriate tests are available. An abnormal result (autonomic neuropathy or smooth muscle cell damage) limits the need for other diagnostic tests. The effect of oral medication like sildenafil (Viagra(r)) can be evaluated. It is an ideal test with respect to research, prevention, diagnosis and treatment of ED. If ccEMG can be developed to a clinical useful test, it is expected that it will play an important role in the diagnosis and treatment of erectile dysfunction. Furthermore, ccEMG can play an important role in the development and evaluation of new drugs that influence the smooth muscle cells activity.
A.4. Current status
Wagner et al introduced the ccEMG technique in 1989. Since then, different groups have performed clinical research in this field, resulting in several scientific publications. Most of the publications are from European groups.
At the moment, ccEMG is not used in the daily routine clinical practice, due to technical, practical and other problems. First of all, there is no standard regarding the measurement technique. Different settings of the equipment are used, and different electrodes and electrode locations are used. Furthermore, different measurement protocols are used. The result is that it is very difficult to compare the results of the different centres. There is a lack of basic understanding, resulting in problems with the interpretation of the signals.
During meetings in Madrid in September 1997 and in Amsterdam in August 1998, it was concluded that the bottlenecks at the moment are the standardisation and basic understanding of ccEMG. All researchers present at this meeting felt that it is time for a well coordinated project.
The introduction of new oral drugs for the treatment of ED resulted in a revival of interest for ED and in particular ccEMG.
A.5. European coordination
Europe plays a key role in ccEMG measurements. Most of the scientific results published during the last 10 years are from European groups. Lack of standardisation and basic understanding urge for a well coordinated European project. The first step in such a European project is to make sure that all research projects are well coordinated. Therefore, we think that the COST action is the best action to improve the ccEMG research.
The (pharmaceutical) industry is supporting some national basic and clinical research projects. For example, in Nijmegen Pfizer the Netherlands is supporting a research project focussed on ccEMG computer modelling. However, it is almost impossible to get industrial or national grants for such a European coordination of research. Therefore, a COST action is a perfect solution for the lack of coordination in ED and ccEMG research. Both the research groups and the industry will benefit from such a European coordination.
B. OBJECTIVES AND BENEFITS
The main objective of the Action is to determine the value of ccEMG in the investigation and management of erectile dysfunction. The action should improve the clinical significance of ccEMG as a non-invasive test in erectile dysfunction. The objective is to make the ccEMG test available for (pharmaceutical) research and daily routine clinical use.
The secondary objectives are:
- basic understanding of ccEMG
- standardisation of ccEMG measurement
- interpretation of ccEMG
- role of ccEMG in diagnosis and treatment monitoring
C. SCIENTIFIC PROGRAMME
C.1. Groups
In Europe, 15 groups are active in the field of cc-EMG. Furthermore, a few companies are developing equipment for ccEMG measurement. Several pharmaceutical companies are active in the ED market. The industry has shown their interest in this proposal, as can be seen in the list of experts involved in the preparation of this proposal. Further, the European Society of Impotence Research (ESIR) has shown its interest in a coordinated cc-EMG project.
The 15 research groups can be divided into:
- 3 groups that are performing basic research, with a special interest in animal models,
- 3 groups with a special interest in research on signal analysis and interpretation (e.g. Fourier analysis and knowledge based interpretation),
- 1 basic research group with a special interest in computer modelling of cc-EMG
- 5 University Clinics interested in clinical research and
- 3 peripheral Hospitals interested in the collection of patient data.
Several companies have shown their interest in this proposal. Three pharmaceutical companies and one equipment company want to play an active role in this COST action.
All research groups and companies present in the list of experts have signed a form in which they declare that they are willing to actively participate in this COST action.
C.2. Scientific program
The scientific program of the COST action is focused on increasing the knowledge on ccEMG. The final outcome of the coordinated research should be that ccEMG can be used as a test to localise the cause of ED at the level of the final common pathway of the erectile mechanism. Therefore ccEMG can be a crucial tool in the routine diagnostic work up of ED, and as a test to evaluate the effects of intervention (e.g. drugs like sildenafil, intracavernous prostaglandin).
The basis of the action is the basic research. Animal experiments combined with a computer modelling study are used to increase the basic understanding of ccEMG. Furthermore, based on this increased understanding, the interpretation research is essential for making ccEMG useful as a test in erectile dysfunction. The clinical research, the coordinated collection and interpretation of data measured in many patients are necessary to validate the test. The influence of different (drugs) treatments on the ccEMG can be evaluated in clinical research programs.
The coordination by an expert team consisting of researchers and industry will ensure that the coordinated research will have an impact on ED in general.
C.3. Research tasks
Research task 1: Well-defined animal experiments
Animal experiments are necessary to test hypotheses and to increase the basic knowledge of ccEMG. Measurement in patients can be influenced by artefacts as for example electrodes artefacts due to the movement of the patient or due to movements induced by the erection itself. Further, artefacts or disturbances can be induced by other electric activity of muscles and skin. In these animal experiments well-controlled measurements can be performed to investigate the influence of these artefacts. The results can be used to define measurement protocols and interpretation algorithms that minimise the artefacts.
By using in vitro experiments of for example isolated tissue samples, the origin of the electrical activity of the smooth muscle cells can be investigated in detail. This information is essential for the computer modelling study.
The exact specification of the ccEMG signals in amplitude and frequency domain can be determined in these animal experiments.
The effect of drugs on the activity of smooth muscle cells and on the ccEMG signals can be investigated in detail.
During the COST action, results from the animal studies should be translated to the clinical protocols. Furthermore, questions from the clinicians can be answered by well-defined animal experiments.
Research task 2: Computer modelling
To understand the generation process of the ccEMG and to simulate the effect of different abnormalities, a computer model is used. The results of animal experiments and the knowledge found in literature are the basis of such a computer model. The electrical sources together with the volume conductor (anatomy) are modelled. Such a computer model is an ideal tool to understand for example all geometric and electrical parameters that influence the ccEMG. The results can be used to adapt the measurement methods, the equipment (hardware) and the interpretation algorithms.
Research task 3: Equipment, measurement protocols
Based on the characterisation of the ccEMG, the basic understanding of ccEMG and the computer model simulations the measurement protocols are defined. The kind of electrodes, the location and the specifications of the measurement equipment have to be defined in detail.
Research task 4: Interpretation of ccEMG, algorithm development
To be able to interpret the ccEMG signals in a clinical environment, algorithms have to be defined. The characteristics of the ccEMG related to abnormalities have to be defined. Algorithms have to be developed to automate the interpretation for routine clinical use.
One of the important goals of the interpretation algorithms is the detection of possible artefacts in the measured signals. This is very important for a practical clinical application. The results of the animal experiments, the computer modelling and the clinical measurements should result in algorithms that can identify and eliminate these artefacts.
Research task 5: Clinical testing, evaluation and validation
For the clinical testing, well-defined measurement protocols are necessary. The strict clinical protocols allow the combination of the measurements of all different clinics, resulting in one large database with standardised measurements. These are used to evaluate the results of the animal experiments, the computer simulation results and the interpretation algorithms. During the action, the protocols might need to be adapted from time to time, based on the results achieved. The standardised measurements are used to evaluate the effect of (drug) treatments. In this phase, the input of the companies is essential. In several clinical trials, new treatments can be evaluated. The information collected can be used by the companies to develop new strategies for treatments for ED. The ccEMG measurements are compared to traditional diagnostic evaluations.
Research task 6: standardisation
The final research task is the standardisation. The action should result in a standardisation report. This report should contain the results of all different elements of the COST action: it should describe the ccEMG measurement in such detail, that it can be used in a standardised manner in research and the daily routine clinical practice.
D. ORGANISATION AND TIME TABLE
D.1. Coordination
The different European groups and companies working in the field of ccEMG all have their own speciality (see C:Groups). From the scientific program and the different research tasks, it can be concluded that a well-defined coordination of the COST action is not only beneficial, but it is essential to improve the diagnosis and evaluation of ED and in particular to introduce ccEMG as a well defined test in erectile dysfunction. The coordination is together with the expertise of all groups and the industry necessary to reach the goal of an improved ccEMG test.
On a European level the input of the different equipment manufacturing and pharmaceutical companies are coordinated during the COST action. The results of the ccEMG research are translated into specifications for ccEMG equipment. The ccEMG as a diagnostic test and for treatment monitoring can be defined together with the pharmaceutical companies. As already mentioned, funding by industry or national grant of such a coordination project is very difficult if not impossible. Therefore, a COST action is an ideal tool to coordinate the national research projects from research groups and industry. The industry is and will support several research projects on a national scale.
We feel that next to the coordination on a management level (COST management), a well-defined coordination program focussed on the experts and researchers of research groups and industry is essential. An expert team (~ 8) should discuss achieved results and based on the discussion, new goals can be defined. Furthermore, the expert team should make strategic decisions about future research and the (national/European) financing of the different research projects. The cooperation between the expert groups and the companies is performed by the expert team. The expert team should perform this very important coordination twice a year.
Next to the expert team, coordination between the research groups and the researchers of the industry in the form of workshops is also essential. During these workshops, the results of all projects are presented and discussed. One workshop a year is planned. To keep the scientific community informed about the progress of the COST action, the results of the projects are presented once a year during a major scientific meeting. Furthermore, next to the scientific publications of all different research groups, the combined research is published once a year in a major scientific journal by the expert team. The final results of the COST action are published in ccEMG standardisation reports. In conclusion: The clinical and basic research efforts and the participation of the industry have to be coordinated. The following sub-items are of utmost importance in the coordination:
CLINICAL RESEARCH:
- Standardisation of (different) clinical protocols. This will ensure that all researchers are measuring the cc-EMG in the same manner, and that the results from the different centres can be combined. Furthermore, different protocols are defined, each of them focused on one well defined clinical question.
- Standardisation of the measurement technique. This has to make sure that all centres are measuring the same signals in the same way. Furthermore, it is a requisite to compare the results of the different centres. The standardisation includes the type of electrodes, the location and the specifications of the measurement equipment. The cooperation with companies is of utmost importance for the implementation of the standardised measurement technique.
- Standardisation of the interpretation of the cc-EMG. The measured signals should be interpreted in a standardised manner.
- Combining the efforts in generating multi-centre studies. This is the only way to include the large number of patients necessary for the final clinical validation of the technique. During these studies, the effect of different (drug) treatments can be evaluated.
BASIC RESEARCH:
- Well-defined animal experiments, necessary to improve the basic knowledge of the ccEMG. Within the project, detailed clinical and basic questions are defined, and tested in animal experiments. In these animal experiments the influence of drugs on ccEMG can be studied. The relationship between the changes in the ccEMG and for example new drugs can be studied in animals in detail.
- Computer modelling. To increase the basic knowledge about the generation of cc-EMG signals, a computer modelling study will be performed. In such a model, the electrical sources together with the volume conductor are modelled.
- Method of interpretation. Methods, algorithms and the implementation in software are developed for the (standardised) clinical interpretation of the signals.
D.2. Time frame
YEAR 1:
- Set-up of the cooperation. During the start of the project it is very important to define the expert team.
- Exact definition of research topics. After setting up the expert team, it has to define the exact research questions. The first important step is the definition of the clinical protocols for the different clinics, to make sure that the data collection will begin as soon as possible. The measurement techniques have to be discussed with industrial partners. Furthermore, the research topics related to the animal experiments and the computer modelling have to be defined in a close cooperation between clinicians, basic researchers and the researchers of the pharmaceutical industry.
YEAR 2:
- Year 2 will start with the evaluation of the first clinical measurements.
- If necessary, the clinical protocols and/or the measurement techniques will be adapted. Based on the experience, the literature and the first results of the clinical measurements, the interpretation algorithms will be discussed. The result of the discussion will be a well-defined interpretation protocol, which has to be implemented in software, for use in the measurement equipment.
- The computer model will be implemented, and the first results will be presented at the end of year two. * Animal experiments will be performed.
YEAR 3/4:
- Year 3 will start with the evaluation of the clinical measurements, the computer simulations and the animal experiments. This discussion will result in new adapted clinical protocols, adaptations in the computer model, and new research topics for the animal experiments.
- The results of the interpretation algorithms will be correlated to the clinical diagnosis. If necessary, the algorithms will be adapted.
- If necessary, the measurement protocols will be adapted. The industrial partners have to implement these new protocols in the measurement hardware/software.
- A large multi-centre study will be started to validate the developed techniques.
YEAR 5:
The last year of the COST action.
- The results of the clinical and basic research together with the multi-centre validation of the technique will lead to:
1. Standardisation of the measurement technique, interpretation and clinical protocols. The result will be written down in a standardisation report and the results will be published in several scientific journals.
2. The determination of the exact clinical value of ccEMG: the diagnostic accuracy.
3. The role of the ccEMG test in the diagnosis and treatment of erectile dysfunction.
D.3. Organisation time schedule
1. The members of the expert team can be divided in basic, clinical, interpretation and industrial experts. During the meetings of the expert team, separate meetings of the different groups are planned, together with a final meeting of the complete expert team.
2. The workshops are planned to take place before/during scientific meetings.
3. If possible, the second meeting of the expert team is planned at the same time and location as the workshops.
4. During the last year, a standardisation committee will meet on regular bases to finalise the standardisation report.
5. During the last part of the action, the multi centre validation will take place.
E. ECONOMIC DIMENSIONS
The following COST countries have actively participated in the preparation of the Action or otherwise indicated their interest:
- The Netherlands - Belgium
- France - Spain
- Italy - Germany
- Denmark - Norway.
On the basis of national information provided by representatives of these countries, the overall cost of the activities to be carried out under the Action has been estimated, in 2000 prices, at roughly EUR 7 million, about 4% for the coordination being expected.
This estimate is valid under the assumption that all the countries mentioned above but no other countries will participate in the Action. Any departure from this will change the total cost accordingly. The exact calculation of the national costs still has to be made.
F. DISSEMINATION PLAN
This COST action is focused on a well coordinated European project to improve the ccEMG research. The final result of the action is a standardisation report. This report contains the results of all different elements of the COST action, and it describes the ccEMG measurements in detail. The report is the basis for the use of ccEMG in the daily routine clinical practice.
During the COST action the scientific, clinical and industrial community involved in the diagnosis and treatment of erectile dysfunction will be informed about the progress of the COST action. This will be done by:
- A WWW-site will be created with a public and a protected section. The protected section is only accessible for the organisations involved in this COST action; the public area will be used to present the results of this COST action to the general public.
- At least one scientific publication a year in a major scientific journal. The expert team will publish the results of the combined research.
- The final result of the COST action, the standardisation report, will also be published in a major scientific journal.
- The workshops and expert team meetings (one a year) are planned to take place before/during scientific meetings. The results of the COST action will therefore be presented during at least one major scientific meeting a year.
- During the last year of the COST action, the final results will be presented during a scientific meeting. It is planned that during this last meeting a ccEMG scientific (sub)meeting will take place. One of the results of this meeting will be an international acceptation and implementation of a standard protocol for the use of ccEMG in the daily routine clinical practice.
- Next to all publications and presentations as mentioned above, the individual researchers will publish and present their scientific results.

Program(-y)

IC-COST - European cooperation in the field of scientific and technical research (COST), 1971-

Temat(-y)

7 - Medical Research

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N/A

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