International Symposium on ALS/MND: Clinical Update

Joint Opening Session

Steve Ringel, M.D., USA
Using Guidelines to Change Practice

“Studies have shown that there is a significant gap between medical care known to be effective and the actual care delivered. One strategy for quality improvement has been the development of practice guidelines.”

Dr. Ringel discussed strategies to advance guidelines to change clinical practice behaviors and improve clinical care. Guidelines must be based on data that are valid and the guidelines must be realistic and sensitive, not punitive. Benchmarking, timeliness and feedback will all increase physician acceptance. Other factors tied to positive responses from physicians toward practice guidelines are agreement and understanding, awareness, incentives, planned implementation, monitoring, and assurance of professional autonomy. Additional strategies that assist with guidelines acceptance and use include: involve opinion leaders early, educate all audiences, establish periodic reminder systems, audit practices and provide feedback, utilize computer systems to the maximum extent possible, promote rule-based behaviors, standardize data collection, provide incentives, include multiple interventions and set up the guidelines as collaborative models.

The Burden of Care

S.M. Albert, Ph.D., USA
The Burden of ALS on the Caregiver and Family

Based on data from caregiver research, this session explored the extent to which patients and caregivers agree in their perception of: 1) the disease and its effects, 2) the relationship between distress in patients and distress in caregivers, 3) the course of caregiver burden and adaptation over the course of the disease, and 4) the mental health of caregivers after patients begin using mechanical ventilation and 5) the mental health of caregivers following patients' deaths.

Family caregivers are key figures in ALS care. They provide the bulk of support to patients and play a central role in clinical decision making. Families vary in how well they are able to meet the challenges of the progressing disease. In families that are well-informed and supported, the patients tend to report a better quality of life than in families that are less well-informed and where there is little or no support.

A. Gauthier, Italy
ALS Caregivers and Quality of Life and Burden of Care

The investigators assessed the quality of life reported by patients and caregivers, together with other factors such as depression and care burden in a cross-sectional and longitudinal study.

ALS involves the caregivers as well as the patients. Caregivers must be supported in a similar manner to patients, considering the suffering that they experience. Couples represent a unique entity whose components cannot be considered separately. Therefore, the caregiver’s physical and psychological health is important for the acceptance of their caregiving role and for improving the quality of their relationship with the patient.

Leo F. McCluskey, M.D., USA
Breaking the News

Breaking the news of the diagnosis of ALS is a difficult task and is the first step in the palliative care of patients. A report was presented of findings from a study designed to determine the overall satisfaction of patients and caregivers with the way they were given the diagnosis and which aspects had the greater satisfaction.

Results from the respondents (65% response rate from 250 mailed surveys), indicate the following distribution of response to the physician’s presentation of the ALS diagnosis: 16% poor; 9% below average; 31% average; 19% good and 25% excellent. By improving how physicians break the news of an ALS diagnosis, patient and caregiver perceptions can be positively impacted.

Dr. McCluskey noted both the ALS Practice Parameter and Buckman’s SPIKES protocol as useful tools the physician can use in breaking the news. Items that must be taken into consideration include: the Setting, patients' Perceptions, an Invitation to provide the news, Knowledge provided to the patient, Exploration of the patients' feelings and development of a Strategy to move forward with treatment and care.  Results of this study indicated that physicians breaking the news of the diagnosis of ALS can improve the process and positively impact the perceptions of patients and caregivers.

M.A. Ciechoski, R.N., M.S.N., USA
Differences in Intimacy in Non-Ventilator and Ventilator Dependent Patients

Intimacy in spousal relationships is a nurturing component for both caregiver and patient. An ALS diagnosis affects a fundamental human longing for intimacy and physical expressions of love. As losses grow in depth, patients increasingly long for life enhancing experiences of intimacy.  Caregivers also struggle with their feelings and barriers to intimacy.  Healthcare professionals can enhance the quality of intimate relationships for couples living with ALS.

The study results focused on how ALS affected spousal intimacy, scores on function and quality of life and differences between couples where the patient was and was not using tracheostomy ventilation. As ALS progresses, patients and caregivers report an increase in social isolation and an increase in the desire for intimacy. Healthcare professionals can enhance the quality of spousal intimacy through education and skill development that includes insight, respect and compassion.

E.J. Kasarskis, M.D., USA
ALSFRS-R validity on phone

It’s not unusual for it to be increasingly difficult for patients to come into clinic as their disease progresses. Bulbar involvement impacts the patient’s ability to respond to questionnaires over the telephone. These changes in mobility and communication can impact research when studies are implemented at an ALS clinic or even by telephone. As part of the Veteran’s Affairs Registry, Dr. Kasarskis and colleagues evaluated the potential of using the ALSFRS-R over the telephone with spouses and caregivers. It has previously been determined by other investigators that it is feasible and valid to administer the ALSFRS-R to patients directly over the telephone.

The data from this study support the accurate assessment of the patient’s functional status using the ALSFRS-R with the patient’s spouse/caregiver by telephone. This work needs to be validated by other investigators and using a longitudinal approach. If further validated, clinical trials could utilize this technique and, potentially, increase the number of patients who can participate in research studies.

Communication

S. Bloch, UK
Communication and ALS/MND: From the Individual to Interaction

Successful communication management shifts the emphasis from the individual to interaction.  Communication is experienced through every social encounter, not just at a professional level, and it is used to display our social competence as it is more than just speech. Communication problems draw attention to the hidden mechanisms of social action. The challenge is to establish practical ways of understanding interaction and learning how to work at an interactive level. Interventions to help people with ALS who have difficulty communicating should include the traditional strategy of overcoming the physical impairments as well as using AAC devices and the interactive and social participation that makes communication much more than the transfer of information.

S. Carroll-Thomas, Canada
Augmentative and Alternative Communication (AAC) in ALS/MND: A Report of 100 Patients

The objectives of the study were to determine if there is a relationship between the severity of activity limitations in ALS/MND and the patient’s participation in the selection or rejection of a device, to identify the main factors influencing device selection and to report on sustained use and satisfaction with the communication aid use.

Results from the first 50 patients indicate that the patient’s perception of their own degree of communication difficulty is a better predictor of their acceptance of a communication aid than the professional’s evaluation of the communication disability. The most important selection feature for patients is the voice output, although integration with life style and access methods were also identified as important.

When AAC strategies and technology are applied effectively to communication in ALS, deficits are reduced. This allows patients the means to retain control and direct their lives, to establish and maintain social closeness and to promote improved quality of life.  Clinicians are challenged with identifying those strategies and devices that will benefit each patient.

M. Nicolelis, USA
Computing with Neural Ensembles

The investigator reported on experiments with real-time computational models to evaluate how ensembles of neurons encode motor information. Results demonstrate that brain-machine interfaces can be used to control a robotic arm and raise the question of whether the neuronal functioning can be utilized as extensions of a patient’s body for communication, environmental control, leisure and daily living activities.

Quality of Life

Z. Simmons, M.D., USA
Key Determinants of Quality of Life in ALS

Dr. Simmons reported on a program of research examining quality of life in people with ALS. There are several tools commonly used to evaluation quality of life patients, but there is no consensus as to which is the most useful and effective measure. The investigators developed an ALS-specific tool, the ALSSQoL, based on the McGill tool, factors patients identify as having the greatest effect on their quality of life, and data from previous studies suggesting a role for spirituality and religion in ALS patient’s quality of life. A multi-center, 342-patient study of the ALSSQoL resulted in six important factors in quality of life and confirmed that physical symptoms are only one domain among several identified as key determinants in these patients.

Quality of life in ALS patients is determined by an array of factors which include emotions, psychological factors, relationships and other support factors, religion and spirituality, and strength and physical function. This information is important when assessing the needs of individuals for care purposes and when evaluating the effects of interventions in both individuals and groups.

L.J. O'Doherty, Ireland
Challenges to the Interpretation of Quality of Life in ALS

This research of 42 patients examined prospective changes in patients’ functional abilities and sought to determine if there was a relationship between function and both health-related and individual quality of life measures.

Using health related quality-of-life measures to assess quality of life can lead to conclusions that functional ability is a strong indicator of quality of life. Individualized quality of life assessments show that quality of life does not necessarily decline alongside disease progression. If measures of health related quality of life are used in isolation, it is possible that overall patient quality of life may be underestimated and may provide misleading information. 

Clinical Trials

W.G. Bradley, D.M., USA
Pilot Study of Hyperbaric Oxygen Therapy (HBO) for ALS

“Abnormalities of the mitochondria have been noted in ALS and its animal models. Theoretically HBO might improve or worsen damage due to mitochondrial disorders. HBO has been reported to delay the onset of weakness in the Wobbler mouse.”

This study of five patients exposed to HBO for one hour, five days per week for four weeks, showed that maximum isometric voluntary contraction (MVIC) improved significantly in some muscles. However, there was no change in measures of neuromuscular function. A controlled trial with a larger number of patients and a control group will be needed to rule out the placebo effect and to determine if the improvements in muscle strength are conclusive. This therapy is not recommended to patients at this time.

K.L. Ferrante, USA
Coenzyme Q10 (Co Q10)

Participants in the nine-month, 31 patient study to test the safety and tolerability of increasing doses of Co Q10 tolerated the higher does well. There were no serious side effects or adverse events related to its use.  Some participants experienced gastrointestinal problems; however, all participants completed the study. A small dose of Vitamin E was taken by the study participants, as it has been reported to increase the uptake of Co Q10 by the body.

This study did not address whether CoQ10 had an effect on the ALS disease process. It was designed to determine what doses could be used in a large, randomized controlled trial in the future.

H. Yoshino, Japan
Randomized, Placebo-Controlled Double Blind Study of free Radical Scavenger, Edaravone, in ALS

(From the web site of the Motor Neuron Disease Association of the UK and Northern Ireland )

“Dr. Hiide Yoshino reported on a small trial in 40 patients of the free radical scavenger Endaravone. Motor neurons which are very active cells, use up a lot of energy, which in turn creates a lot of waste in the form of molecules called free radicals. If levels of these molecules are not kept in check, they can start to corrode the various components of the cell – this is commonly known as oxidative stress. Free radical scavengers can bind to and inactivate free radicals and have been shown to reduce damage to neurons in laboratory studies. Dr. Yoshino reported that patients taking the compound had lower levels of free radicals (measured by a chemical marker of oxidative stress in the cerebrospinal fluid) and although there was no overall benefit in the total patient population taking the drug compared to placebo, those patients in the earlier stages of the disease did appear to show some small but significant improvement over the eight-week study period. As with the hyperbaric oxygen study, larger trials are needed to determine whether this is a real effect or just a statistical ‘blip' and Dr. Yoshino announced his intention to take this research forward to multicenter studies in Japan.”

Dysphagia and Nutritional Management

D.R. Harris, USA
Quantitative Sensory Testing in the Assessment of Deglutition and Laryngeal Sensory Dysfunction in a Subset of ALS Patients

The purpose of this study of 27 patients was to determine if sensory dysfunction contributes to dysphagia in patients with ALS. Evaluation included a dysphagia questionnaire and endoscopic sensory testing and swallowing assessment. Abnormal sensation was observed in 44% of the subjects.

The sensory deficits are present in a great proportion of ALS patients. It is usually assumed that ALS patients develop pharyngeal dysphasia in the course of the disease secondary to muscle weakness. Results of this study indicate that sensory deficits may be a significant contributing factor to the risk of aspiration.

A. Wright, USA
VitalStim™ for the Treatment of Dysphagia in Patients with Motor Neuron Disease

VitalStim™ is a product that provides electrical stimulation to the weakened swallowing muscles of people with ALS. It is being used experimentally and this speaker presented the experience at one ALS center. The treatment course was 10 one-hour sessions during which surface electrodes were placed over the swallowing muscles. Cues were given for swallowing training during the sessions. Outcomes of time, amount of liquid and puree swallowed, coughing frequency and modified barium swallow were assessed. Investigators are encouraged by the results of this initial study showing that there was benefit from the treatments. This was not a randomized controlled trial and more research is needed.

E.J. Kasarskis, USA
Early Treatment of ALS with Nutrition and NIPPV

Dr. Kasarskis presented plans for an NIH-funded pilot study that is planned to precede a larger phase III study of early intervention of PEG and noninvasive ventilation. The specific aims of the 11 study site pilot will be to:

• Develop and validate strategies to improve tolerability of NIPPV and to identify factors that influence acceptance of NIPPV
• Evaluate measures of early respiratory dysfunction
• Develop and validate methods to determine energy balance in ALS

The results of this pilot will be able to help patients immediately as well as serve as the basis of the phase III study which is designed to measure the efficacy of early intervention of both NIPPV and PEG.

Cognitive Changes

(From the web site of the Motor Neuron Disease Association of the UK and Northern Ireland )

It is often widely believed that MND damages only the motor neurons. In reality the motor neurons bear the brunt of the disease, but other parts of the CNS can be affected as well, in particular a part of the brain called the frontal lobe, which is involved with behavioral and cognitive (‘thinking') processes. Prof. Bruce Miller outlined the similarities and differences between MND and a condition called frontotemporal lobe degeneration (FTLD), both in pathology and in some of the clinical symptoms. He focused particularly on a rare familial condition where the two diseases are seen together. In these cases, the cognitive symptoms are apparent some time before the motor system is affected.

Three further speakers in the session went on to present their studies looking for evidence of cognitive changes in general MND populations. Using a variety of tests, changes in verbal fluency, verbal memory and social judgment were frequently seen in patients. Of course, people with MND do not normally undergo such a battery of neuropsychological testing, so whether the bulk of these observed changes actually reflect ‘real life' changes for the majority of people with MND is uncertain. It is clear, however, that a greater understanding of the different types of cognitive changes would allow healthcare professionals to better understand the needs of people with MND and their families.

Trends in Care Management

P.L. Ingles-Allred, Canada
Adhesive capsulitis: A Profile of Patients with ALS

Adhesive capsulitis, or frozen shoulder, is a condition that affects some people with ALS causing pain and reduced range of motion limiting function. The investigator reported on a study to determine the incidence of adhesive capsulitis and the demographic and disease characteristics associated with the condition at one ALS center.

This retrospective reviewed 87 patients – 63 men and 24 women – which was greater than the incidence of the condition in the general public, but lower than in other diseases with shoulder weakness or spasticity. The finding of more men than women with adhesive capsulitis in the ALS population differs from the higher predominance of the condition in women among the general population. More research is needed to have a better understanding of the development of this condition and treatment strategies that prove effective in managing or prevention adhesive capsulitis.

Miller, R.G.; Mitsumoto, H.; Brooks, B.; USA
ALS CARE Database Findings

Results from the North American ALS CARE Database included the following:

• Temporal trends in the management of ALS have been prospectively evaluated through the ALS CARE Database from 1997. Since 1997, 5,309 patients have enrolled in the Database. In the six years between 1997 and 2003 there has been an increased use of Riluzole (from 35% to 59%), and NIPPV (from 4% to 24%), PEG (from 2% to 16%). Despite these encouraging trends toward greater utilization of effective treatments, there is more work to be done to assure that every person with ALS is afforded the opportunity to utilize these common therapies.
• Disturbingly, there is an increase over the six year interval in the amount of time between the onset of symptoms and the time of diagnosis (from 9.2 months to 11.1 months).
• Interest in improving end-of-life care in ALS prompted the following review and findings:
  • From October 1995 through February 2004, 5,529 patients enrolled in the Database from 107 clinical sites; 34% of them have died.
  • Based on follow up data, the investigators report that the median age at the time of death was 65 years; 67% of deaths were attributed to respiratory causes, 5% were sudden or unexpected and seven suicides were reported (0.06).
  • Death was reported as peaceful for 60%, not peaceful for 7% and unknown in 30%. 92% of patients had advance directives in place and they were reported to have been followed 97% of the time.
• The ALS CARE Database includes 1,093 US military veterans and it is the largest prospectively-collected, clinic-confirmed database of ALS patients. It was designed to measure management techniques and health outcomes with a primary aim to raise the stand of care for ALS patients through North America .
• The investigators used the Database to study the treatment and management off U.S. military veterans with ALS following the publication of the ALS Practice Parameter manuscript. Since the publication in 1999, the use of Riluzole increased, the use of OT, speech therapy and PT increased, PEG and respiratory support both increased as well.

Poster   S.J. King #156 Living with ALS: Ongoing Change and Adaptation Model (Victoria, Australia)
People with ALS have different illness experiences. Living with the disease and navigating health care services change as the disease progresses. There is lack of research about the illness experience as reported by people living with the disease. Those living with the disease perceive their quality of life differently than health care professionals do. Generally, patients seem to have a more positive experience than health professionals think they do. 

Poster   M. D'Amour #157 - Availability of Services for Patients with ALS (Montreal, Canada)
Patients with ALS require several services over a short period of time.  Little is written on how easy or difficult it is to obtain these services. OT, physiotherapists, nutritionists, nurses, social workers, psychologists, domestic helps and ventilation technicians are generally available at government local community health services centers throughout the province. Health professionals see patients at the centers or through home visits. 

Study Looks at ALS Among Italian Soccer Players

Questions about the frequency of ALS among Italian soccer players have been in the news in the past two years since the diagnosis of several players became public.

Dr. Adriano Chio, Italy, reported on a retrospective study his research team conducted into the question of incidence of ALS among Italian soccer players one of several new and interesting clinical presentations made during the closing session of the 15^th Annual International Symposium on ALS/MND.  

This large study included 7,325 Italians who played professional soccer between 1970 and 2001. Chio's group found that 15 players developed ALS which is about a six-fold increase above the number that would be expected in this group of soccer players.

Chio noted that the study was designed to answer the question of whether or not there were more soccer players with ALS than was expected, and not to identify what possible causative factors might be.

This study cannot confirm an association between soccer playing and ALS; however, there are questions about the following factors that are topics for further research.  

• Athleticism or a mutation of a gene that makes one person more naturally athletic than another person, which may be specifically linked to ALS
• Physical injury or trauma experienced while playing soccer
• Environmental toxicants that players may have long-term exposure to on the playing field or with other aspects of the sport
• Drugs – legal or illegal – that soccer players may use

Encouraging News About Tamoxifen

Also during the closing session, Dr. Benjamin Brooks, USA, presented findings from the ongoing 60-person clinical trial of Tamoxifen, a FDA-approved drug used to treat breast cancer.

The study, supported by the ALS-division of the Muscular Dystrophy Association and the National Institute of General Medical Sciences through the University of Wisconsin General Clinical Research Center, evaluated as a safety endpoint, length of survival between groups that were taking different doses of Tamoxifen plus Riluzole [Rilutek].

Results from this Phase 2B study demonstrated an increase in survival by the end of two years in the groups taking the higher doses of Tamoxifen.

The two lower dose groups had a survival experience similar to that reported in the placebo groups of other ALS clinical trials. 

The three higher dose groups experienced a four to six month prolongation of survival compared with the two lower dose groups. No significant side effects were observed.

Brooks is recommending additional clinical trials with larger groups of patients with ALS in order to confirm this observation and to define the future role of Tamoxifen, or other Selective Estrogen Receptor Modulator [SERM] drugs as adjuvant therapies for ALS patients. 

FDA officials attending the 15^th Annual International ALS-MND Symposium noted that a randomized multiple dose ranging clinical trial of a treatment for ALS is an acceptable trial design that permits each patient to receive some dose of a potentially active medication.

ALS Research Update - What's New and What's on the Horizon.
Pamela Shaw, M.D. – United Kingdom

Dr. Shaw provided an overview of recent advancements in the scientific knowledge about ALS and new technologies that are expanding the tools scientists can use in understanding the complex factors involved in ALS. A summary of Dr. Shaw’s comments follows.

1) Gene abnormalities: 

Dr. Shaw reviewed the scientific knowledge about which gene mutations are known to cause motor neuron injury and death. Identifying more genetic abnormalities associated with developing ALS will increase the overall understanding of the disease for both the familial and sporadic forms. Significant scientific efforts are underway to identify more genetic mutations that are linked with ALS.

There are now five genes identified that, when mutated, cause ALS or similar disorders. 

The superoxidide dismutase (SOD1) protein mutation was discovered in 1993 and much of our understanding of ALS came from this discovery which led to the development of a mouse model of the disease for study and testing of potential treatments. This particular mutation is responsible for 20% of familial cases of ALS.  Normally, SOD1 is an important factor in antioxidant defense and fights free radicals that are produced in the motor neuron. This gene is found in the cytosol of the cell and in the mitochondria. 

More recently, Dynactin 1, another gene mutation, was found that is very rare.  It has only been found in one family.  This gene's function is to move molecules from the cell junction to the cell body.  This genetic mutation leads to a slow progressing lower motor neuron disorder and is not typical ALS.

Mutation of the gene, Alsin, causes a rare form of ALS that affects those at young ages.  Generally this is found in Arabian countries. Senataxin mutation is responsible for a juvenile onset form of ALS.

VAPB (vesicle associated membrane protein) - mutation of this protein causes various motor neuron degeneration and is found in people living in South America .  

An abnormality in the gene that controls vascular endothelial growth factor (VEGF) has been linked to ALS.  Normally, VEGF helps the body respond to low oxygen levels; however, in animals, it was noted that mutations in the gene that control VEGF resulted in a motor neuron disease in the mice. In further experiments, providing VEGF has had a protective effect on motor neurons in cell cultures and was shown to slow progression of the disease in the SOD1 mouse model when injected into the muscles.  

2) Mitochondria

Dr. Shaw noted that scientists now know that mitochondrial function within the motor neuron is not healthy in people with ALS.  The mitochondria are responsible for supplying the motor neuron with energy. The cells become swollen and are biochemically abnormal.  They begin to generate less energy than they should. How this disruption in the motor neuron’s energy supply may contribute to ALS is under further investigation.  

3) Neighborhood cells

Motor neurons are surrounded by other cells (astrocytes and microglia) which normally keep motor neurons healthy.  When these neighbor cells are unhealthy, they secrete substances that may damage the motor neurons. Recent research discoveries reveal that cells surrounding the motor neurons are not normal in models of ALS. More research is underway to learn more about how and why these cells begin to act abnormally and how they may be having a harmful effect on motor neurons.  

4) Scientific approaches and how advances may lead to treatments

Scientists are identifying subtypes of motor neuron disease/ALS so they can establish various types of new treatments.  Greater understanding of the subtypes of ALS is needed to know how to protect the mitochondria, utilize gene therapy techniques, improve the function of the neighborhood cells, and develop combination therapies. 

5)  Technology tools

New technology is allowing scientists to study motor neurons, genes and proteins in new ways that will lead to a better understanding of ALS. Dr. Shaw described efforts using laser capture microdissection which allows researchers to remove just the motor neurons from the spinal cord without the contamination of other cell groups. Using microarray and proteomic technology, scientists can study genes and proteins within specific cells in new ways.

Dr. Shaw concluded by commenting on the vast increase in understanding about ALS within the past decade and the enormous efforts world wide in the fight against ALS/MND.

A Plan for Treatment in ALS: Small Molecules, Gene Therapy and Stem Cells.
Jeffrey Rothstein, M.D., Ph.D. – USA

Dr. Rothstein noted that there are multiple disease pathways that may be occurring in ALS and scientists need to focus on all of them in the development of treatments. Multiple approaches to all of the possible disease pathways should be explored. Studies from other disorders involving the motor neurons have suggested that as many as 40 different proteins or pathways may be involved in cell death leading to ALS.

Motor neurons may not be dying on their own. Their neighboring cells are likely contributing to the motor neuron injury and death; this complicates the task of discovering the cause of ALS and developing effective treatments. 

Models used to study the disease and learn more about therapeutic approaches include:

• The SOD1 mouse model
• Spinal cord culture
• Virus induced motor neuron injury model system

A number of potential therapeutic approaches are listed below. Research efforts are underway to develop all of these therapeutic approaches.

• Neuroprotective - an attempt to delay or stop disease progression.  One example, IGF-1 or myotrophin, is being evaluated in a clinical trial now. A gene therapy trial of myotrophin is in the planning stages. Neuroprotective agents would help protect surviving neurons.  
• Restorative – an attempt to develop agents that would replace dying motor neurons – a more challenging task.  
• Small molecule therapies that can cross the blood-brain barrier.
• Stem cell therapy
• Gene therapy
• RNAi technology

The delivery of small molecules and trophic (growth) factors, such as IGF-1 and GDNF, remains a challenge as the brain is surrounded by a protective barrier. This blood-brain barrier separates the blood and the brain and prevents access to the brain and motor neurons for many of these compounds.

Dr. Rothstein described many studies in the laboratory involving stem cell research. He emphasized the many different sources of stem cells and he cautioned that, although very promising, there are many challenges scientists are working to overcome before stem cells can move into successful therapies in the laboratory.

To overcome delivery issues for drugs, and encouraging them to pass the blood-brain barrier, technologies such as gene therapy are being developed for ALS.

As a result of screening efforts using FDA-approved compounds and a partnership between The ALS Association and the National Institute of Neurological Diseases and Stroke (NINDS), Ceftriaxone will enter clinical trials. Originally prescribed for its antibiotic properties, this compound has shown an effect in model systems of ALS and is acting through properties other than its antibiotic function.

Dr. Rothstein noted that patients should be aware of three potential outcomes when taking drugs or participating in a clinical trial. Each of these outcomes is possible.

1) The compound may slow disease.

2) The compound may do nothing.

3) The compound may speed up disease progression.

ALS Therapies - How do we find a cure?
Merit Cudkowicz, M.D. – USA

Dr. Cudkowicz discussed the importance of first identifying the causes or disease mechanisms responsible for ALS, and then moving to therapy development and human trials.  The last 10 years have provided advances for ALS treatment development that have been developed from increasing knowledge of the disease pathogenesis, drug screening assays and experience with clinical trials. 

Compounds currently in human clinical trials:

ONO 2506 – almost completed

IGF-1 (Myotrophin) - enrolling

Minocycline - enrolling

Tamaxofin

Copaxone

TCH386

AEOL10150 - enrolling

Compounds planned for trials to begin within the next few months:

Ceftriaxone (phase I-III)

Coenzyme Q10 (phase II)

Sodium Phenylbutrate (phase I)

AAV IGF-1 (phase 1) trial of Myotrophin using gene therapy as a delivery system

Brief descriptions:

Celebrex – originally prescribed as an arthritis drug.  This study has shown no benefit in the recent ALS trial.

Minocycline – an antibiotic that has central nervous system penetration.  Has proven effective in the SOD1 mouse model.  NINDS has funded a trial in humans.

Coenzyme Q10 – A larger trial is set t be launched by early 2005.

AEOL 10150 – an antioxidant that has had a large effect on survival in one animal study. This study starts with a single dose to test safety, and requires a short hospitalization.

Ceftriaxone  – the study is planned to begin in early 2005 and is funded by NINDS.  This is an antibiotic and no long term safety data exists.  They are looking for a small number of patients for the safety study and will then recruit a larger sample to test efficacy.  Although originally prescribed for its antibiotic properties, this compound has shown an effect in model systems of ALS and is acting through properties other than its antibiotic function.

Sodium Phenylbutrate – the compound is used in other neurodegenerative diseases.  This trial is funded by the U.S. Department of Veterans Affairs, and the Phase I safety and dose testing trial is planned for early 2005.

ALS - A Treatable Disease
Daniel Newman, M.D. – USA

Dr. Newman's presentation focused on dispelling the fears of progressive disability and a progressively worsening quality of life.  Survival for people with ALS is improving, due to advances made in patient care. These include use of riluzole, patients being seen at multidisciplinary clinics, early nutrition support (PEG) and respiratory (noninvasive and invasive ventilation) interventions.  Use of noninvasive ventilation has been shown in studies to improve survival and quality of life and reduce fatigue. Good clinical care has a potent effect on survival.  Mobility and communication advances have also improved the quality of life for those living with ALS. 

Dr. Newman commented that it is legitimate to view ALS as treatable.  In a study, 96 patients were asked to rate their quality of live on a scale of 1-10, with 10 being the best.  For patients living with ALS for 2-1/2 years, an average score of seven was reported.  Even with declining function, patients reported as a positive that their quality of life remained constant. In another study of quality of life in the terminal phase of ALS, 121 patients in Germany and 50 in the UK, 88% of those caregivers in Germany and 98% of those in the UK reported that their loved one died peacefully.

In conclusion, Dr. Newman remarked that supportive and palliative care for people living with ALS has only begun to receive the attention it deserves.