http://www.youtube.com/watch?v=HMGIbOGu8q0&

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How marvelously clever of you to attack the construction of my website when you cannot think of anything to add to the discussion at hand. I suggest that you take a moment to read the thread and perhaps add something constructive.

But if you’d like, you can be the first “Maloneyite” and make up your own religion around my website. Have fun, and be sure to wear a funny hat.

http://www.maloneymedical.com/

For a second I thought it was TimeCube related (http://timecube.com/), due to the haphazard HTML, the copypasta wall-of-texts and bizarre linguistic constructions.

And then as looked closer at it, I noticed the smoothing sunsets, emotional appeals and existentialist questions. Are you a medical doctor or attempting to start a new-age eastern religion?

I tried to interest Dr. Novella in pursuing a possible cause, but he denies any possibility of effect without taking any investigatory steps. I contacted the Seattle neurologists, but no one has followed up on their hypothesis. Dr. Novella is ideally suited to pursue studies in this area. His credentials as a skeptic make any possibility of bias on his part a non-issue, and he has both the staff and the expertise to do some real good here.

Given Dr. Novella’s dismissal of any possible bacterial link, I’ve moved on nutritional supplements as support for ALS patients. Given the short term data on Vitamin E and the study on creatine, I would think a short three month trial combining the two would be useful. If it is negative, it would refute the short term outcomes of the German study, and might convince patients not to experiment personally with vitamin megadoses.

As I point out, over half of Dr. Novella’s ALS patients are likely to be using some form of alternative medicine so engaging in this sort of study would only involve organizing those who are already experimenting on their own.

My point in bringing up the range of nutritional supplements is that a number of things considered “alternative” have some data to support their use in ALS. We are talking about a disease process with a miserable outcome and a minimally effective drug protocol. I am truly interested if Dr. Novella is using any of the supplements in clinical practice, but I suspect that he is dismissive of any supplementation.

If Dr. Novella is consistently discouraging patients to try alternatives, and those patients are still using those alternatives without his knowledge, then the situation is not optimal. A much more functional doctor/patient relationship would be for Dr. Novella to engage in trials, so that he can say: “we tried that, but it doesn’t help.” As a skeptic, Dr. Novella can combine his hatred for quackery with his love of neurology and serve all of us by providing definitive data.

And, your collection of studies show another trend – the bigger and better the study, the weaker the effect. That’s a classic characteristic of useless treatments.

So which are you advocating for ALS? Which do you use for your ALS patients?
Creatine monohydrate?
Vitamin E?
Folic acid?
Alpha lipoic acid?
Lyophilized red wine?
Coenzyme Q10?
Epigallocatechin gallate?
Ginkgo biloba?
Melatonin?
Cu chelators?

Or are you just advocating ANY substance that didn’t come from a pharmacist?

Please unmoderate my responses unless you have decided to moderate all blog responses. It made me very concerned that you had simply blocked my response and had no intention of engaging in a dialogue. After days of delay, I had given up on you. I just checked back for the first time today.

Before you read further, do you know that over half your patients are likely to be using alternative medicine? How open are you about that discussion?

Do you really expect me to produce high quality studies that you would even consider from the Naturopathic journals? The information we both can use is readily available on medline. But the question is whether or not ALS patients are currently receiving the following:

Megadoses of vitamin E- good safety profile and short term benefits, no long term benefits or long term side effect picture.

Antibody screening for celiac disease- several reports of celiac mimicking ALS

Any of the following supportive therapies: creatine, folic acid, alpha lipoic acid, lyophilized red wine, coenzyme Q10, epigallocatechin gallate, Ginkgo biloba, or melatonin?

If you’re doing all of the above, great, but if not, please tell me which ones aren’t in current use. I have attached the creatine information. Surely you are supplying patients already?

J Neurol Sci. 2001 Oct 15;191(1-2):151-4.
The use of alternative medicine by patients with amyotrophic lateral sclerosis.
Wasner M, Klier H, Borasio GD.
Department of Neurology and Interdisciplinary Palliative Care Unit, Ludwig Maximilians University, University Hospital, Grosshadern, D-81366, Munich, Germany.
The use of complementary and alternative medicine (CAM) is increasing in all industrialised countries, especially in patients with chronic and incurable diseases. However, no data are available on the use of CAM by patients with amyotrophic lateral sclerosis (ALS). The German Association for Neuromuscular Diseases (DGM) mailed out a questionnaire on CAM to 350 ALS patients, 171 of whom completed and returned the survey (response rate 49%). The use of CAM was reported by 92 patients (54%). There were no significant demographic differences between users and nonusers. The patients used 73 different methods or substances; some tried up to 11 different treatments. The most widely used methods were: acupuncture (47%), homeopathy (40%), naturopathy (24%) and esoteric treatments (20%). The lower the patients’ expectations from CAM, the better was the subjectively perceived effect. In most cases (60%), alternative treatments were performed by a physician. Patients spent on average 4000 (approximately US$4500) on CAM, generally without reimbursement. CAM is most often used in addition to conventional treatments and may be part of the patients’ coping strategy. Open communication between patients and physicians is essential to warn the patients of medically or financially hazardous treatments. Future research should look at the possible palliative effects of CAM on symptom control and quality of life of patients and families.
PMID: 11677007
J Herb Pharmacother. 2005;5(3):23-31.
The use of herbal supplements and alternative therapies by patients with amyotrophic lateral sclerosis (ALS).
Vardeny O, Bromberg MB.
University of Winconsin-Madison School of Pharmacy, Madison, WI, USA.
OBJECTIVES: Alternative medicine is widely used in all industrialized Western countries. However, there are no published data regarding the use of botanical or herbal supplements in Ayotrophic Lateral Sclerosis (ALS). Our goal was to survey patients with ALS in our clinic regarding their use of herbal supplements, vitamins, and other therapies or compounds. METHODS: Study subjects participated in the University of Utah Motor Neuron Disease Clinic. An anonymous questionnaire was mailed and designed to assess the following: disease duration and onset site, use of riluzole, alternative therapies (i.e., homeopathy, acupuncture), vitamins, herbal supplements, and other compounds, sources of information about herbal supplements or vitamins, estimated monthly expenditure on vitamins, herbal supplements, and other compounds, and expectations from herbal supplements/vitamins. RESULTS: Fifty-three subjects participated; mean age 60 years old (range 39-83 years), 15 females, 38 males. Symptom duration averaged 1-5 years (45 limb onset, 8 bulbar onset). Thirty-two percent took riluzole and 42% used herbal supplements, 70% took vitamins, and 21% used other compounds (prescription medications used for ALS, but not indicated for ALS). Fifteen percent used alternative therapies. Information about herbal medicines was obtained mostly via friends and relatives (n = 17), a physician (n = 20), and the Internet (n = 9). Our patients selected improvement of general well being and slowing of disease progression most often as reasons for using these therapies. CONCLUSIONS: Our study demonstrated that almost half of patients surveyed utilized herbals supplements, and two thirds of ALS study subjects took vitamins. Twenty-one percent used unproven prescription drugs, and 15% used other alternative therapies.
PMID: 16520295
Amyotroph Lateral Scler Other Motor Neuron Disord. 2001 Mar;2(1):9-18.
A double-blind, placebo-controlled randomized clinical trial of alpha-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol Study Group.
Desnuelle C, Dib M, Garrel C, Favier A.
Service Médecine Physique et de Réadaptation, Maladies Neuromusculaires, CHU de Nice Hĵpital, France. desnuelle.c@chu-nice.fr
INTRODUCTION: Increasing evidence suggests that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E (alpha-tocopherol) has been shown to slow down the onset and progression of paralysis in transgenic mice expressing a mutation in superoxide dismutase found in certain forms of familial ALS. The current study was designed to determine whether alpha-tocopherol (500 mg b.i.d.) may be efficacious in the treatment of ALS. METHODS: Two hundred and eighty-nine patients with ALS of less than 5 years duration, treated with riluzole, were enrolled in this study, and were randomly assigned to receive either alpha-tocopherol or placebo daily for one year. The primary outcome measure was the rate of deterioration of function assessed by the modified Norris limb scale. Patients were assessed at entry, and every 3 months thereafter during the study period. Survival was also recorded. Biochemical markers of oxidative stress were measured in a subset of patients on entry and after 3 months of treatment. RESULTS: After 12 months of treatment, alpha-tocopherol had no effect on the primary outcome measure. Survival was not influenced by treatment. Among secondary outcome measures, patients given alpha-tocopherol were less likely to progress from the milder state A to the more severe state B (P=0.046) of the ALS Health State scale. After 3 months treatment, analysis of oxidative stress markers showed an increase in glutathione peroxidase activity in plasma (P = 0.0389) and a decrease in plasma levels of thiobarbituric acid reactive species (P = 0.0055) in the group of patients given alpha-tocopherol in combination with riluzole. CONCLUSION: Although alpha-tocopherol did not appear to affect the survival and motor function in ALS, patients receiving riluzole plus alpha-tocopherol remained longer in the milder states of the ALS Health State scale and showed, after 3 months, changes in biochemical markers of oxidative stress. Further studies are required to confirm the greater sensitivity of the ALS Health State scale over other clinical endpoints.
PMID: 11465936
J Neural Transm. 2005 May;112(5):649-60. Epub 2004 Oct 27.
High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study.
Graf M, Ecker D, Horowski R, Kramer B, Riederer P, Gerlach M, Hager C, Ludolph AC, Becker G, Osterhage J, Jost WH, Schrank B, Stein C, Kostopulos P, Lubik S, Wekwerth K, Dengler R, Troeger M, Wuerz A, Hoge A, Schrader C, Schimke N, Krampfl K, Petri S, Zierz S, Eger K, Neudecker S, Traufeller K, Sievert M, Neundörfer B, Hecht M; German vitamin E/ALS Study Group.
michael.graf@psl.ap-hop-paris.fr
Increasing evidence has suggested that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E (alpha-tocopherol) has been shown to slow down the onset and progression of the paralysis in transgenic mice expressing a mutation in the superoxide dismutase gene found in certain forms of familial ALS. The current study, a double blind, placebo-controlled, randomised, stratified, parallel-group clinical trial, was designed to determine whether vitamin E (5000 mg per day) may be efficacious in slowing down disease progression when added to riluzole. METHODS: 160 patients in 6 German centres with either probable or definite ALS (according to the El Escorial Criteria) and a disease duration of less than 5 years, treated with riluzole, were included in this study and were randomly assigned to receive either alpha-tocopherol (5000 mg per day) or placebo for 18 months. The Primary outcome measure was survival, calculating time to death, tracheostomy or permanent assisted ventilation, according to the WFN-Criteria of clinical trials. Secondary outcome measures were the rate of deterioration of function assessed by the modified Norris limb and bulbar scales, manual muscle testing (BMRC), spasticity scale, ventilatory function and the Sickness Impact Profile (SIP ALS/19). Patients were assessed at entry and every 4 months thereafter during the study period until month 16 and at a final visit at month 18. Vitamin E samples were taken for compliance check and Quality Control of the trial. For Safety, a physical examination was performed at baseline and then every visit until the treatment discontinuation at month 18. Height and weight were recorded at baseline and weight alone at the follow-up visits. A neurological examination as well as vital signs (heart rate and blood pressure), an ECG and VEP’s were recorded at each visit. Furthermore, spontaneously reported adverse experiences and serious adverse events were documented and standard laboratory tests including liver function tests performed. For Statistical Analysis, the population to be considered for the primary outcome measure was an “intent-to-treat” (ITT) population which included all randomised patients who had received at least one treatment dose (n = 160 patients). For the secondary outcome measures, a two way analysis of variance was performed on a patient population that included all randomised patients who had at least one assessment after inclusion. RESULTS: Concerning the primary endpoint, no significant difference between placebo and treatment group could be detected either with the stratified Logrank or the Wilcoxon test. The functional assessments showed a marginal trend in favour of vitamin E, without reaching significance. CONCLUSION: Neither the primary nor the secondary outcome measures could determine whether a megadose of vitamin E is efficacious in slowing disease progression in ALS as an add-on therapy to riluzol. Larger or longer studies might be needed. However, administration of this megadose does not seem to have any significant side effects in this patient population.
PMID: 15517433
AJNR Am J Neuroradiol. 2009 Nov 12. [Epub ahead of print]
White Matter Lesions Suggestive of Amyotrophic Lateral Sclerosis Attributed to Celiac Disease.
Brown KJ, Jewells V, Herfarth H, Castillo M.
Department of Radiology and Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina.
SUMMARY: CD is an autoimmune-mediated disorder of the gastrointestinal tract. Initial symptom presentation is variable and can include neurologic manifestations that may comprise ataxia, neuropathy, dizziness, epilepsy, and cortical calcifications rather than gastrointestinal-hindering diagnosis and management. We present a case of a young man with progressive neurologic symptoms and brain MR imaging findings worrisome for ALS. During the diagnostic work-up, endomysium antibodies were discovered, and CD was confirmed by upper gastrointestinal endoscopy with duodenal biopsies. MR imaging findings suggestive of ALS improved after gluten-free diet institution.
PMID: 19910450
Nat Clin Pract Neurol. 2007 Oct;3(10):581-4.
A case of celiac disease mimicking amyotrophic lateral sclerosis.
Turner MR, Chohan G, Quaghebeur G, Greenhall RC, Hadjivassiliou M, Talbot K.
Department of Neurology, John Radcliffe Hospital, Oxford, UK.
BACKGROUND: A 44-year-old male presented to a general neurology clinic with a 6-month history of progressive right-sided spastic hemiparesis without sensory symptoms or signs. The thigh muscle in the affected leg showed signs of wasting. The patient had a remote family history of celiac disease. INVESTIGATIONS: Neurological examination, neurophysiological studies, brain MRI scan, routine blood tests, duodenal biopsy, cerebrospinal fluid analysis including polymerase chain reaction test for JC virus DNA, serological testing for HIV and for the presence of serum antibodies to endomysium, gliadin and tissue transglutaminase. DIAGNOSIS: Celiac disease with neurological involvement, mimicking amyotrophic lateral sclerosis. MANAGEMENT: Strict gluten-free diet.
PMID: 17914346
Clin Nutr. 2009 Dec;28(6):604-17. Epub 2009 Sep 25.

Nutritional and exercise-based interventions in the treatment of amyotrophic lateral sclerosis.
Patel BP, Hamadeh MJ.
School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada M3J 1P3.
BACKGROUND & AIMS: Disease pathogenesis in amyotrophic lateral sclerosis (ALS) involves a number of interconnected mechanisms all resulting in the rapid deterioration of motor neurons. The main mechanisms include enhanced free radical production, protein misfolding, aberrant protein aggregation, excitotoxicity, mitochondrial dysfunction, neuroinflammation and apoptosis. The aim of this review is to assess the efficacy of using nutrition- and exercise-related interventions to improve disease outcomes in ALS. METHODS: Studies involving nutrition or exercise in human and animal models of ALS were reviewed. RESULTS: Treatments conducted in animal models of ALS have not consistently translated into beneficial results in clinical trials due to poor design, lack of power and short study duration, as well as differences in the genetic backgrounds, treatment dosages and disease pathology between animals and humans. However, vitamin E, folic acid, alpha lipoic acid, lyophilized red wine, coenzyme Q10, epigallocatechin gallate, Ginkgo biloba, melatonin, Cu chelators, and regular low and moderate intensity exercise, as well as treatments with catalase and l-carnitine, hold promise to mitigating the effects of ALS, whereas caloric restriction, malnutrition and high-intensity exercise are contraindicated in this disease model. CONCLUSIONS: Improved nutritional status is of utmost importance in mitigating the detrimental effects of ALS.
PMID: 19782443
CNS Drugs. 2004;18(14):967-80.
The role of creatine in the management of amyotrophic lateral sclerosis and other neurodegenerative disorders.
Ellis AC, Rosenfeld J.
Carolinas Neuromuscular/ALS Center, Charlotte, North Carolina 28203, USA. amy.ellis@carolinahealthcare.org
Creatine is consumed in the diet and endogenously synthesised in the body. Over the past decade, the ergogenic benefits of synthetic creatine monohydrate have made it a popular dietary supplement, particularly among athletes. The anabolic properties of creatine also offer hope for the treatment of diseases characterised by weakness and muscle atrophy. Moreover, because of its cellular mechanisms of action, creatine offers potential benefits for diseases involving mitochondrial dysfunction. Recent data also support the hypothesis that creatine may have a neuroprotective effect. Amyotrophic lateral sclerosis (ALS) is characterised by progressive degeneration of motor neurons, resulting in weakening and atrophy of skeletal muscles. In patients with this condition, creatine offers potential benefits in terms of facilitating residual muscle contractility as well as improving neuronal function. It may also help stabilise mitochondrial dysfunction, which plays a key role in the pathogenesis of ALS. Indeed, the likely multifactorial aetiology of ALS means the combined pharmacodynamic properties of creatine offer promise for the treatment of this condition. Evidence from available animal models of ALS supports the utility of treatment with creatine in this setting. Limited data available in other neuromuscular and neurodegenerative diseases further support the potential benefit of creatine monohydrate in ALS. However, few randomised, controlled trials have been conducted. To date, two clinical trials of creatine monohydrate in ALS have been completed without demonstration of significant improvements in overall survival or a composite measure of muscle strength. These trials have also posed unanswered questions about the optimal dosage of creatine and its beneficial effects on muscle fatigue, a measure distinct from muscle strength. A large, multicentre, clinical trial is currently underway to further investigate the efficacy of creatine monohydrate in ALS and address these unresolved issues. Evidence to date shows that creatine supplementation has a good safety profile and is well tolerated by ALS patients. The purpose of this article is to provide a short, balanced review of the literature concerning creatine monohydrate in the treatment of ALS and related neurodegenerative diseases. The pharmacokinetics and rationale for the use of creatine are described along with available evidence from animal models and clinical trials for ALS and related neurodegenerative or neuromuscular diseases.
PMID: 15584767
Amyotroph Lateral Scler. 2008 Oct;9(5):266-72.
Creatine monohydrate in ALS: effects on strength, fatigue, respiratory status and ALSFRS.
Rosenfeld J, King RM, Jackson CE, Bedlack RS, Barohn RJ, Dick A, Phillips LH, Chapin J, Gelinas DF, Lou JS.
The Carolinas Neuromuscular/ALS Center, Charlotte North Carolina, Carolinas Medical Center, USA.
Our objective was to determine the effect of creatine monohydrate on disease progression in patients with amyotrophic lateral sclerosis (ALS). One hundred and seven patients with the diagnosis of probable or definite ALS, of less than five years duration from symptom onset, were randomized to either treatment with daily creatine monohydrate (5 g/d) or placebo. In this multicenter, double-blinded study we followed changes in disease progression: using quantitative measures of strength via maximal isometric voluntary contraction, forced vital capacity, ALSFRS, quality of life, fatigue and survival. Patients were followed for nine months. The results showed that creatine monohydrate did not significantly improve motor, respiratory or functional capacity in this patient population. The drug was well tolerated and the study groups well balanced, especially considering the absence of forced vital capacity criteria for entrance into the study. There was a trend toward improved survival in patients taking daily creatine monohydrate and this was identical to the trend seen in another recently published report of creatine in ALS patients 1. In conclusion, creatine monohydrate (5 g/d) did not have an obvious benefit on the multiple markers of disease progression measured over nine months. We measured fatigue during isometric contraction and found no significant improvement despite anecdotal patient reports prior to and during the study. The trend toward improved survival was also found in another recently completed blinded trial using creatine monohydrate. Further investigation on the possible survival benefit of creatine in this patient population is ongoing.
PMID: 18608103

There are many speculations about possible causes of ALS, and perhaps several will turn out to be correct as ALS is a syndrome made up of several, perhaps many, diseases. Many options are being explored, and generally those of us who treat ALS use the one proven therapy (riluzole) while adding 2-3 experimental treatments either as part of a clinical trial (preferable) or as compassionate use. We use treatments with some rationale and positive evidence and at least evidence of safety, and with full informed consent. But we also study them, and if they fail in clinical trials we stop using them.

The clostridium paper was published 5 years ago (and not in a reputable journal) with no follow up research that I can find. This is very problematic, and may reflect the fact that it is a dead end. In any case – this is a naked hypothesis with nothing close to the data we would need to use as a compassionate treatment. Maybe someone is working on a clinical trial somewhere, but if so I have not heard (there is no buzz), but I will ask at the next meeting.

Antibiotic and anti-inflammatory approaches to ALS have already been tried and failed in the past. The only antibiotic recently studied for ALS is minocycline, but that was due to its pharmacological non-antibiotic properties. In any case – patients did worse on minocycline than placebo – it had a net negative effect. Which is another cautionary tale against prematurely using experimental treatments – they can do harm, even when the animal and preliminary data looks positive (the same thing happened with topiramate).

The bottom line is that you have nothing new to add or any useful treatments beyond what is already being used by neurologists or being studied. Naturopathy has nothing unique to offer.

For other readers, I’m attaching the current status of treatments for ALS to get a sense of what you deal with and other options. But I think I may have something helpful.

Turns out your colleagues in Seattle already came across the same idea, but I don’t think you’re using it yet. It involves Clostridium difficile causing a portion of the ALS cases. I came across this idea when I was researching possible ALS support and I found a small study on stool analysis of ALS patients. About 1/3 had significant Clostridium overgrowth, but I can’t find the study on medline listed under Clostridium. I assume the Seattle neurologists must have found the same study.

So here’s the thought: if a portion of ALS patients (peripheral onset?) are genetically susceptible to the relatively mild Clostridium difficile toxins then a stool analysis would give a possible treatment option: systemic antibiotics and the addition of Sacchromyces boulardii. Previous trials with antibiotics and ALS haven’t focused on the possibility of an antibiotic resistant organism causing the problem. I think the addition of S. boulardii is essential to provide competition to C. difficile regrowth.

So, trash away. But maybe have a discussion with Seattle about why they have the same crazy, quacky idea I do. If you don’t want to put ALS patients through the systemic antibiotics, what about a simple trial of S. boulardii for patients? Keep patients on oral feeding and add S. boulardii with every meal. It has a good safety profile.

I’ve got some other ideas, but I want to get this one out to you quickly. Please at least talk to Seattle about it.

Med Hypotheses. 2005;64(6):1153-6.

Hypothesis: a motor neuron toxin produced by a clostridial species residing in gut causes ALS.
Longstreth WT Jr, Meschke JS, Davidson SK, Smoot LM, Smoot JC, Koepsell TD.

Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, USA. wl@u.washington.edu

Comment in:

Med Hypotheses. 2006;66(2):438-9.

We hypothesize that a yet-to-be-identified motor neuron toxin produced by a clostridial species causes sporadic amyotrophic lateral sclerosis (ALS) in susceptible individuals. This clostridial species would reside undetected in the gut and chronically produce a toxin that targets the motor system, like the tetanus and botulinum toxins. After gaining access to the lower motor neuron, the toxin would be transported back to the cell body, as occurs with the tetanus toxin, and destroy the lower motor neuron – the essential feature of ALS. Again like the tetanus toxin, some of the toxin would cross to neighboring cells and to the upper motor neuron and similarly destroy these motor neurons. Weakness would relentlessly progress until not enough motor neurons remained to sustain life. If this hypothesis were correct, treatment with appropriate antibiotics or antitoxins might slow or halt progression of disease, and immunization might prevent disease.

PMID: 15823706

Ann Neurol. 2009 Jan;65 Suppl 1:S3-9.

Current hypotheses for the underlying biology of amyotrophic lateral sclerosis.
Rothstein JD.

Department of Neurology and Neuroscience, Brain Science Institute, Johns Hopkins University, Baltimore, MD 21287, USA. jrothstein@jhmi.edu

The mechanisms involved in selective motor neuron degeneration in amyotrophic lateral sclerosis remain unknown more than 135 years after the disease was first described. Although most cases have no known cause, mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) have been implicated in a fraction of familial cases of the disease. Transgenic mouse models with mutations in the SOD1 gene and other ALS genes develop pathology reminiscent of the disorder, including progressive death of motor neurons, and have provided insight into the pathogenesis of the disease but have consistently failed to predict therapeutic efficacy in humans. However, emerging research has demonstrated that mutations and pathology associated with the TDP-43 gene and protein may be more common than SOD1 mutations in familial and sporadic ALS. Putative mechanisms of toxicity targeting motor neurons include oxidative damage, accumulation of intracellular aggregates, mitochondrial dysfunction, defects in axonal transport, growth factor deficiency, aberrant RNA metabolism, glial cell pathology, and glutamate excitotoxicity. Convergence of these pathways is likely to mediate disease onset and progression.

PMID: 19191304

Neuropsychiatr Dis Treat. 2009;5:577-95. Epub 2009 Nov 16.

Current and emerging treatments for amyotrophic lateral sclerosis.
Zoccolella S, Santamato A, Lamberti P.

Azienda Ospedaliero-Universitaria Ospedali Riuniti, Department of Medical and Neurological Sciences, Clinic of Nervous System Diseases, University of Foggia, Italy;

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a relatively rare neurodegenerative disorder of both upper and lower motoneurons. Currently, the management of ALS is essentially symptoms-based, and riluzole, an antiglutamatergic agent, is the only drug for the treatment of ALS approved by the food and drug administration. OBJECTIVE: We reviewed current literature concerning emerging treatments for amyotrophic lateral sclerosis. METHODS: A Medline literature search was performed to identify all studies on ALS treatment published from January 1st, 1986 through August 31st, 2009. We selected papers concerning only disease-modifying therapy. RESULTS: Forty-eight compounds were identified and reviewed in this study. CONCLUSIONS: Riluzole is the only compound that demonstrated a beneficial effect on ALS patients, but with only modest increase in survival. Although several drugs showed effective results in the animal models for ALS, none of them significantly prolonged survival or improved quality of life of ALS patients. Several factors have been implicated in explaining the predominantly negative results of numerous randomized clinical trials in ALS, including methodological problems in the use of animal-drug screening, the lack of assessment of pharmacokinetic profile of the drugs, and methodological pitfalls of clinical trials in ALS patients.

PMID: 19966906

Cochrane Database Syst Rev. 2007 Jan 24;(1):CD001447.

Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).
Miller RG, Mitchell JD, Lyon M, Moore DH.

California Pacific Medical Center, Department of Neurosciences, 2324 Sacramento Street, Suite 150, San Francisco, California 94115, USA. millerrx@sutterhealth.org

Update of:

Cochrane Database Syst Rev. 2002;(2):CD001447.

BACKGROUND: Riluzole has been approved for treatment of patients with amyotrophic lateral sclerosis in most countries. Questions persist about its clinical utility because of high cost and modest efficacy. OBJECTIVES: To examine the efficacy of riluzole in prolonging survival, and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Register for randomized trials in December 2004 and made enquiries of authors of trials, Aventis (manufacturer of riluzole) and other experts in the field. We searched MEDLINE (January 1966 to August 25 2006) and EMBASE (January 1980 to September 30th 2006). SELECTION CRITERIA: Types of studies: randomized trials. Types of participants: adults with a diagnosis of amyotrophic lateral sclerosis. Types of interventions: treatment with riluzole or placebo. Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 100 mg. Secondary: per cent mortality with riluzole 50, 100 and 200 mg; neurologic function, muscle strength and adverse events. DATA COLLECTION AND ANALYSIS: We identified four eligible randomized trials. MAIN RESULTS: The four trials examining tracheostomy-free survival included a total of 974 riluzole treated patients and 503 placebo treated patients. The methodological quality was acceptable and three trials were easily comparable, although one trial included older patients in more advanced stages of amyotrophic lateral sclerosis and one had multiple primary endpoints. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (P value = 0.042, hazard ratio 0.80, 95% confidence interval 0.64 to 0.99) and there was no evidence of heterogeneity (P value = 0.33). When the third trial (which included older and more seriously affected patients) was added, there was evidence of heterogeneity (P value < 0.0001) and the random effects model, which takes this into account, resulted in the overall treatment effect estimate falling just short of significance (P value = 0.056, hazard ratio 0.84, 95% confidence interval 0.70 to 1.01). This represented a 9% gain in the probability of surviving one year (57% in the placebo and 66% in the riluzole group). There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. A threefold increase in serum alanine transferase was more frequent in riluzole treated patients than controls (weighted mean difference 2.62, 95% confidence interval 1.59 to 4.31). AUTHORS' CONCLUSIONS: Riluzole 100 mg daily is reasonably safe and probably prolongs median survival by about two to three months in patients with amyotrophic lateral sclerosis.

PMID: 17253460

Clin Infect Dis. 2000 Oct;31(4):1012-7. Epub 2000 Oct 25.

The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii.
Surawicz CM, McFarland LV, Greenberg RN, Rubin M, Fekety R, Mulligan ME, Garcia RJ, Brandmarker S, Bowen K, Borjal D, Elmer GW.

Division of Gastroenterology, Department of Medicine, University of Washoington, Seattle, WA USA. surawicz@u.washington.edu

Recurrent Clostridium difficile disease (CDD) is a difficult clinical problem because antibiotic therapy often does not prevent further recurrences. In a previous study, the biotherapeutic agent Saccharomyces boulardii was used in combination with standard antibiotics and was found to be effective in reducing subsequent recurrences of CDD. In an effort to further refine a standard regimen, we tested patients receiving a regimen of a standard antibiotic for 10 days and then added either S. boulardii (1 g/day for 28 days) or placebo. A significant decrease in recurrences was observed only in patients treated with high-dose vancomycin (2 g/day) and S. boulardii (16.7%), compared with those who received high-dose vancomycin and placebo (50%; P=.05). No serious adverse reactions were observed in these patients. Comparison of data from this trial with data from previous studies indicates that recurrent CDD may respond to a short course of high-dose vancomycin or to longer courses of low-dose vancomycin when either is combined with S. boulardii.

PMID: 11049785

Can J Gastroenterol. 2009 Dec;23(12):817-21.

Prevention of Clostridium difficile infection with Saccharomyces boulardii: a systematic review.
Tung JM, Dolovich LR, Lee CH.

Department of Pharmacy, St. Joseph's Healthcare, Hamilton, Ontario.

BACKGROUND: Clostridium difficile is a major cause of antibiotic-associated diarrhea within the hospital setting. The yeast Saccharomyces boulardii has been found to have some effect in reducing the risk of C difficile infection (CDI); however, its role in preventive therapy has yet to be firmly established. OBJECTIVE: To review the effectiveness of S boulardii in the prevention of primary and recurrent CDI. Benefit was defined as a reduction of diarrhea associated with C difficile. Risk was defined as any adverse effects of S boulardii. METHODS: A literature search in MEDLINE, EMBASE, CINAHL and the Cochrane Library was performed. Included studies were English language, randomized, double-blind placebo controlled trials evaluating S boulardii in CDI prevention. RESULTS: Four studies were reviewed. Two studies investigated the prevention of recurrence in populations that were experiencing CDI at baseline. One trial showed a reduction of relapses in patients experiencing recurrent CDI (RR=0.53; P<0.05). The other demonstrated a trend toward reduction of CDI relapse in the recurrent treatment group of patients receiving high-dose vancomycin (RR=0.33; P=0.05). Two other studies examined primary prevention of CDI in populations that had been recently prescribed antibiotics. These studies lacked the power to detect statistically significant differences. Patients on treatment experienced increased risk for thirst and constipation. CONCLUSION: S boulardii seems to be well tolerated and may be effective for secondary prevention in some specific patient populations with particular concurrent antibiotic treatment. Its role in primary prevention is poorly defined and more research is required before changes in practice are recommended.

PMID: 20011734

Neurology. 2009 Oct 13;73(15):1218-26.

Practice parameter update: The care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.
Miller RG, Jackson CE, Kasarskis EJ, England JD, Forshew D, Johnston W, Kalra S, Katz JS, Mitsumoto H, Rosenfeld J, Shoesmith C, Strong MJ, Woolley SC; Quality Standards Subcommittee of the American Academy of Neurology.

Department of Neurology, California Pacific Medical Center, San Francisco, California, USA.

Erratum in:

Neurology. 2009 Dec 15;73(24):2134.
Neurology. 2010 Mar 2;74(9):781.

OBJECTIVE: To systematically review evidence bearing on the management of patients with amyotrophic lateral sclerosis (ALS). METHODS: The authors analyzed studies from 1998 to 2007 to update the 1999 practice parameter. Topics covered in this section include slowing disease progression, nutrition, and respiratory management for patients with ALS. RESULTS: The authors identified 8 Class I studies, 5 Class II studies, and 43 Class III studies in ALS. Important treatments are available for patients with ALS that are underutilized. Noninvasive ventilation (NIV), percutaneous endoscopic gastrostomy (PEG), and riluzole are particularly important and have the best evidence. More studies are needed to examine the best tests of respiratory function in ALS, as well as the optimal time for starting PEG, the impact of PEG on quality of life and survival, and the effect of vitamins and supplements on ALS. Recommendations: Riluzole should be offered to slow disease progression (Level A). PEG should be considered to stabilize weight and to prolong survival in patients with ALS (Level B). NIV should be considered to treat respiratory insufficiency in order to lengthen survival (Level B) and to slow the decline of forced vital capacity (Level B). NIV may be considered to improve quality of life (Level C) [corrected].Early initiation of NIV may increase compliance (Level C), and insufflation/exsufflation may be considered to help clear secretions (Level C).

PMID: 19822872

Your criticisms are not even substantive – is the abstract wrong, or is this an uncontrolled study?

This study is clearly a pragmatic study – the purpose of which is to look at the application of proven therapies in practice – it is not to provide evidence of efficacy. So you linked to a non-efficacy study as if it were evidence of efficacy. And you wonder why we are not impressed.

Your other comments were just incoherent. Is it really your claim that I need you to tell me what effective treatments there are for the conditions I treat? Such hubris.

But if you want to play – let’s focus on ALS. Tell me what magical new treatments you have for ALS that I have somehow missed.