Interviews

Interview with Researchers

Wed, 02 Apr 2008 14:27:47 -0400

The UK MS Society held it MS Life Conference last weekend. Here are interviews with the Researchers that presented. EBV as a possible trigger is raised by Dr Brenda Banwell.

Genes + Environment and Vitamin D Video

art — Tue, 04 Sep 2007 15:45:48 -0400

In this video George Ebers, MS geneticist, talks about gene/environment interaction and vitamin D in particular (warning, he alternately pronounces 'vitamin' with a short 'i' which makes me cringe :-). The video is available via YouTube.

More ECTRIMS Reporting

art — Wed, 22 Nov 2006 07:39:11 -0500

This interview (free reg required) with Mark Freedman covers his take on some of the research presented at ECTRIMS. If you like to hear what people in the MS biz think is important, take a look at this interview.

Protecting and repairing the nervous system

art — Thu, 23 Mar 2006 06:41:03 -0500

As part of the MS Awareness Week, the NMSS has a different webcast each day. Monday's webcast was with Dr Peter Calabresi on repairing damage and protecting the nervous system. Existing drugs are being examined to protect the nervous system. A transcript is here.

As usual the good times are five years away. Lets just hope that in 2011 the good times are not five years away!

Experiences of childrens and teens with MS

art — Wed, 15 Feb 2006 06:18:37 -0500

An interesting study reprinted on Medscape (free registration required) describes the thoughts and feelings of children and teens who are living with MS. This study was authored by two nurses at Toronto's Hospital for Sick Children, one of the few sites in the world with a pediatric MS clinic.

Children and teens with MS have many of the same problems and concerns as adults, but also have unique experiences due to their stage of life, and the purpose of this study was to better understand what young people with MS are going through in order to better support them. The study involved interviewing twelve subjects between the ages of 7 and 18 about how they received their diagnosis, how they are coping with MS, and how MS is affecting various aspects of their lives. The interviews did show that having MS has affected the lives of these young people in many ways, for example through missed school, restrictions on activities, and being treated differently by their peers. However, some of the effects were perceived as positive (e.g., closer relationships and special privileges), and all of the subjects had a hopeful attitude about the future.

Interviews with the creators of AlzGene

mind3 — Tue, 18 Oct 2005 10:38:51 -0400

Here's an interesting interview with two of the creators of AlzGene, an online database of genetic association studies performed in Alzheimer's Disease (AD). AlzGene is a fantastic resource for Alzheimer's researchers, providing data and meta-analyses from hundreds of genetic association studies in an easy-to-use, searchable database. Scientists interested in a particular gene can search for it in AlzGene to see what previous studies have reported, receiving a wealth of information in a very short amount of time. The interview talks about the development of AlzGene and how this resource may be expanding in the future. The interviewees also share their ideas for future Alzheimer's genetic research. Most of these ideas are also applicable to MS, since both diseases have one major susceptibility gene/gene region (APOE in AD, HLA in MS) but probably several other genes that confer moderate or modest risk.

We at the Accelerated Cure Project recognize the value of resources like this, and have put together our own open-access database of MS genetic studies, although it's not nearly as user-friendly or well-curated as AlzGene. Perhaps someday we can help make "MSGene" available for MS researchers!

Larry King Live MS Show

art — Tue, 15 Feb 2005 08:41:00 -0500

Here's the transcript from the CNN LARRY KING LIVE Interview with Panel on Multiple Sclerosis which Aired January 17, 2005 - 21:00 ET. It features Meredith Vieira from "The View" and her husband, Emmy-winning TV journalist Richard Cohen, actress Teri Garr, Alan Osmond, one-time leader of the hit singing group The Osmond Brothers, and one of Larry's friends Mark Barondess.

Interview with LDN researcher Dr. Agrawal

art — Thu, 27 Jan 2005 12:44:55 -0500

The Need for Trials of Low Dose Naltrexone as a Possible Therapy for Multiple Sclerosis
Interview with Dr. Yash Agrawal, M.D., Ph.D., University of Iowa

Boston Cure Project, January 2005
www.bostoncure.org

Note: LDN has not been formally studied as a therapy for MS and is therefore not an approved therapy for the disease. The Boston Cure Project does not endorse or recommend any specific treatment for any disease, and people considering any therapy should consult with their doctor to obtain professional advice.

Rob: Dr. Agrawal, the idea of treating MS with LDN is spreading rapidly among the patient community because of a grass roots effort on the Internet and a large community of enthusiastic lay people. This is obviously very different from the way in which traditional medical research and drug discovery is done. Should this "bottom up" phenomenon concern us, or is it to be welcomed?

Yash: For the "bottom up" approach to succeed, it requires an open-minded physician. Throughout the history of medicine, the best clinicians have made their mark by avidly listening to and observing patients. With the advent of the Internet and easy access to information, patients have become very well informed. The practice of medicine is changing rapidly. Smart physicians should not feel threatened, but instead go back to their roots and listen to what the patients are saying.

Unfortunately, there is an established history of ineffective or even harmful treatments being tried for MS. This has led to a deep skepticism of any new therapy by both the medical establishment and the patient population. Why is that, and what signs are there that LDN could actually be a realistic treatment for MS?

This is a very important point. There are many issues. First, the diagnosis of MS is challenging and misdiagnoses do happen. Thus, in some cases a patient could take virtually any treatment and observe a lack of progression/relapses of their MS. Secondly, the snake-oil salesmen prey on MS patients. Physicians rightly brush aside any thoughts that the patient may have of trying such remedies. Thirdly, the common forms of MS are characterized by waxing and waning of symptoms. So patients may feel that a particular remedy is working, while in reality it is just the natural process of their MS.

You ask - what makes me suspect that LDN is the real thing? At this point, neither I nor anyone else can give a definitive answer. This answer can only be learned after a proper clinical trial. But I ask you, can there be smoke without fire? As a very skeptical person myself, I offer the following for consideration.

Firstly, the main proponents of LDN are not involved in selling the remedy; therefore there is no profit motive for them. Rather, they are the thousands of individual MS patients who have found benefit, and they spread the word due to their own unshakable conviction about LDN. Some of these stories can be read at www.LDNers.org in the US or at the LDN trust site www.ldnresearchtrust.org in the U.K. Highly motivated patients who have failed conventional therapies and were going downhill maintain these web sites. Go through these web sites and consider the effort they have expended in doing all the surveys, establishing a trust, the fund raising efforts, etc. Why would they do it? What might be their motivation?

Secondly, the LDN movement is picking up steam. Consider that one pharmacy alone (Skip's Pharmacy in Boca Raton, Florida) reported dispensing 2508 patient-months of LDN during the period January 1 to August 16, 2004. If one assumes 30 capsules are taken per month, this implies a total of 30 x 2508 = 75,240 capsules. In a prior quote from the same pharmacy dated October 23, 2003, Dr. Skip Lenz reported: "As I have said before, if I had MS, the only drug that I would absolutely be taking is LDN..... In 4 years of dispensing LDN, with over 10,000 patient months, I have heard of only three cases of exacerbation... this is truly a no-brainer. I would find someone to prescribe it no matter the cost or effort." While skeptics would equate this with the extreme gullibility of MS patients, an alternate explanation might be that perhaps it works.

As a third example, www.remedyfind.com collects patient initiated reports, which show an overwhelmingly positive response to LDN. These findings appear to have been independently confirmed in a survey by Samantha Wilkinson of www.LDNers.org. She surveyed hundreds of patients from 16 countries worldwide. She reports a relapse rate of approximately 0.2/year in relapsing remitting MS, as well as benefit in other types of MS. Now I must emphasize, the results should be interpreted with a grain of salt as this study was done by a patient and can in no way be equated with a proper clinical trial (see LDNers.org for survey results).

Finally, it appears that the existing ABCR drugs are no miracle either. The Cochrane Database, after analyzing all published trials, reported: "Glatiramer acetate did not show any beneficial effect on the main outcome measures in MS, i.e. disease progression, and it does not substantially affect the risk of clinical relapses. Therefore its routine use in clinical practice is not currently supported." Regarding the use of interferons in RRMS, they were more charitable: "The efficacy of interferon on exacerbations and disease progression in patients with relapsing remitting MS was modest after one and two years of treatment." (Both quotes are from the Cochrane Database of Systematic Reviews, 4: 2004.)

How widespread do you believe LDN usage is among MS patients? Why do you suppose a fairly large number of MS patients are willing to try LDN, especially given that there have been no formal clinical trials of it?

Precise numbers for LDN usage are hard to come by. I have reported in my article (Medical Hypotheses, in press, 2004) that one pharmacy in the US alone shipped 70,000+ capsules over an 8-month period. LDN is becoming increasingly popular in the U.K and worldwide. A Google search reveals over 30,000 hits for the word "low dose naltrexone," some in a variety of languages besides English. LDN is being used in at least 16 countries (based on the survey by Samantha Wilkinson of LDNers.org). A survey of over 1300 MS patients at www.thisisms.com shows LDN is more commonly used than Betaseron and is running neck and neck in usage with Rebif amongst the survey participants. An important caveat to note when interpreting such surveys is that there might be a "selection bias" in favor of respondents who prefer LDN to other drugs.

LDN is popular because it is inexpensive, oral, has minor side effects, and offers the possibility of stopping progression of MS (at least in some patients). Trying LDN is a no-lose situation for most patients.

As described in your upcoming article, your hypothesis about how naltrexone may be beneficial in MS is based on its ability to prevent oxidative damage, which some researchers now believe to be responsible for neurodegeneration in MS. Could you summarize this hypothesis and explain what oxidative stress is?

The area of free radical biology and oxidative stress is quite complex. A good introduction to oxidative stress and MS is the recent article by Gilgun-Sherki (J Neurol 251:261-68, 2004). At the risk of oversimplification, free radicals are certain chemical species that steal electrons from other molecules. This loss of electrons from the molecule is referred to as oxidation, and the causative free radicals are called oxidizing agents. Free radicals are created in the environment, or may be man-made. For example they may be produced by exposure to cosmic radiation, cigarette smoke, or from cellular metabolic processes. The classic free radicals are the hydroxyl, the superoxide and the nitric oxide radicals. Some other relevant species such as hydrogen peroxide and peroxynitrites are not free radicals but can help produce free radicals. Together, this group of chemical species is referred to as reactive oxygen species (ROS). Neuronal cells are normally able to defend themselves against ROS. However, when the neuronal defense system is overwhelmed by ROS, it results in oxidative stress. Oxidative stress causes damage to protein, lipid and DNA in the cell by this process of oxidation.

The neurotransmitter glutamate is another factor involved in the "excitotoxicity," or toxicity by excitation of neuronal cells. Glutamate stimulates various receptors in the brain, commonly abbreviated as NMDA, AMPA, and KA. This excitatory effect of glutamate can cause neuronal degeneration by oxidative stress and other mechanisms. Usually glutamate is released in the neural cleft, but part of it may also originate from activation of microglial cells.

How does all this fit in with damage to oligodendrocytes and the production of scar tissue in MS?

Oligodendrocytes are the myelin producing cells. Glutamate causes excitotoxic death of oligodendrocytes via the AMPA/KA receptors. This is well established in the experimental mouse models of MS, but less well established in the human model (Wosik K. et al, Brain 2004). Wosik's claim that human oligodendrocytes are not susceptible to excitotoxicity must be taken with a grain of salt. The authors of this paper point out the many caveats in their study (see the last paragraph of the paper, page 2647).

Loss of myelin producing cells will ultimately result in demyelination. The interesting thing is that the demyelinating lesions caused by glutamate are very similar to that observed in MS (see J.Neurol 251; 261-68, 2004 for details). The idea that glutamate and ROS may be important in MS is also suggested by numerous studies that show that peroxynitrites and glutamic acid levels are elevated in the cerebrospinal fluid (CSF) of MS patients. Moreover, direct examination of MS plaques has revealed increased free radical activity and decreased levels of anti-oxidants.

My hypothesis says that stress (including oxidative stress) activates astrocytes/microglial cells. This results in activation of a kinase called the p38 MAPK. p38 MAPK is known to increase the inducible nitric oxide synthase (iNOS), an enzyme required for the production of nitric oxide and ultimately peroxynitrites. Peroxynitrites are known to inhibit glutamate transport in synaptic clefts and adjacent oligodendrocytes by inhibiting the glutamate transporters. Since the transport of glutamate into cells is inhibited, it results in an accumulation of glutamate that causes excitotoxic death of oligodendrocytes. In this eco-system, naltrexone prevents the increase in iNOS, therefore fewer peroxynitrites are produced, and there is less excitotoxic death of oligodendrocytes. The scientific evidence for each of these steps is discussed and can be seen in a diagram, in my article at LDNers.org.

Your hypothesis differs from what the majority of the medical community seems to believe, which is that MS is an autoimmune condition in which the body's immune system mistakenly attacks the myelin sheath. Indeed, the interferon drugs used in MS treatments are thought to suppress the immune system in an attempt to slow the disease process. More recent drugs, including the recently approved Tysabri (natalizumab), are based upon newer research that has suggested that MS is related to disruptions in the blood brain barrier. What do you think about this approach to treating MS?

The idea that MS may not be an autoimmune disease has been propagated by Peter Behan and colleagues (Chaudhuri A and Behan PO. Arch Neurology 61: 1610-12, 2004) in a series of eloquent papers. Dr. Behan's thinking is not mainstream. But, one must ponder, what if he is right? Is this the reason that the standard drugs work so poorly in MS? After all, if the premise for the mechanism of MS is incorrect, one would not expect drugs designed on an incorrect premise to work correctly.

Natalizumab is the latest drug in the MS armamentarium. It is based on the idea that inflammation of brain tissue is an important part of MS pathology. At a simplistic level, natalizumab blocks certain integrin receptors on some types of leukocytes. By blocking these receptors with natalizumab, the inflammatory cells do not reach the brain tissue and/or cannot cause inflammatory damage. With respect to natalizumab, of concern to me are the findings of Barnett and Prineas. They examined brain tissue of MS patients obtained via autopsies and they did not find the typical inflammatory cells (Annals of Neurology, 55:458-68, 2004). Their results imply that MS may not be an inflammatory disease. So if natalizumab works, it may be by mechanisms different from those based on reducing inflammation.

Naltrexone is classified as an opiate antagonist. What does that mean? Much of the Internet based discussion of LDN's usage in MS is centered on the idea that it boosts endorphin production; in fact that is why LDN is supposed to be taken at bedtime. Furthermore, several teams of researchers have found inverse correlations between endorphin concentrations and MS disease severity. One study even found that administration of beta interferon raised endorphin levels. What part do endorphin levels play in your hypothesis, or do you view higher levels of endorphins simply as a (beneficial) side effect of LDN?

Essentially, naltrexone blocks the opiate receptors in the brain. As a result the normally circulating peptides (small proteins) that bind to these receptors can no longer do so. This has two types of effects, firstly that these circulating peptides can no longer stimulate the opioid receptors and mediate their action through it, and secondly their levels probably rise, because they are not being used up by the opioid receptors.

An example of a circulating small peptide is beta-endorphin. It binds to the mu-type of opioid receptor. There are some interesting observations in the literature. For instance, beta-endorphin levels are low in blood cells of MS patients as compared to controls and during relapses (J Neurol Neurosurg Psychiatry 74(4): 495-, 2003). So naltrexone could potentially elevate beta-endorphin levels in MS patients. The problem with the beta-endorphin theory as the sole explanation for the mechanism of action of LDN is, "so what," i.e., it is hard to explain why elevation of beta-endorphins should put a stop to MS. It is possible that beta-endorphins play a role, but the science supporting their role is unclear to me. Also such a hypothesis would imply that other activities that increase beta-endorphins such as eating chocolates, cayenne pepper, exercise, etc. should put a stop to MS.

Endorphin secretion follows a diurnal rhythm, with secretion occurring in the early morning. Taking the drug at night ensures that the naltrexone-induced increase in endorphins coincides with the body's own endorphin secretion. Because the endorphins cannot bind to the opiate receptors which are occupied by naltrexone, the levels of circulating endorphins increase, and they likely mediate their actions by binding to other receptors. Therefore, the elevated beta-endorphins may create a feeling of well being which is observed in many patients, but naltrexone must act on MS by other additional mechanisms.

Naltrexone is used in much higher doses to block opiate receptors when treating substance abuse. Wouldn't we want to use a similar dose in treating MS since this would more fully block the brain's opiate receptors?

As the saying goes: "If it ain't broke, don't fix it." As I have said before, blockage of opioid receptors is only part of the story. LDN has other actions, probably relating to the oxidative damage theory. An important point to note is that usage of higher doses will very likely block multiple receptors other than the mu receptors, leading to undesirable effects. This is well known for opioid antagonists such as naltrexone, where even ultra low dose femtogram (for comparison femto=10-15gm, milligram=10-3 gm) amounts of naltrexone can potentiate the effects of morphine, and different results are seen at higher doses of naltrexone (see Neuroscience. 2004;129(3):733-42). In fact, Pain Therapeutics, a small biotechnology company, is developing such a drug based on the use of ultra low doses of opioid antagonist, PT-901. So the argument that is widely reported on the Internet, i.e. that high doses of naltrexone (5 mg/kg) did not work in the EAE model of MS, therefore, low dose naltrexone cannot work in human MS, is flawed.

The other thing to keep in mind is that the so-called EAE mouse model of MS does not faithfully replicate human MS. So negative results obtained in the mouse model need not correspond to the human situation. Conversely, positive results in the mouse model (e.g. with AMPA antagonists) also do not ensure similar results in humans. The solution is to do a clinical trial, especially since we are fortunate to have an FDA approved drug to begin with.

If naltrexone can alter the mechanisms behind apoptosis in MS, does this potentially explain why so much anecdotal evidence suggests that LDN may be helpful in a wider variety of conditions in addition to MS?

I have not explored in any depth the multiple other diseases where LDN has been reported to be useful. However, apoptosis is a central process in many of the diseases in question, especially cancers. Naloxone, a drug similar to naltrexone, has been tried clinically in stroke and Alzheimer's disease where neuroprotection is needed.

I've read that LDN is already being studied for treatment of autoimmune conditions such as Crohn's disease, IBS, etc.

You are right; LDN has been used for other "autoimmune" diseases. While we like to call these diseases autoimmune, they may not be autoimmune. For example, we have discussed Dr. Behan's work that suggests MS is not an autoimmune disease. Recent work suggests that even Crohn's may not be autoimmune, in fact certain mycobacteria are believed to be the causative agents (Lancet. 364(9439): 1039-44, 2004). I think there is much that we don't know about these diseases, and about LDN. More research is needed.

Dr. Bihari and other doctors who have experimented with LDN in MS feel that it should not be taken with the interferon drugs, but apparently taking it with Copaxone (glatiramer acetate, co-polymer-1) is OK. Can you theorize why this might be the case? Any thoughts on whether or not LDN would be compatible with natalizumab?

As for taking LDN with interferons, I have not investigated it. This is Dr. Bihari's observation. He says that interferons are immunosuppressants, while LDN is a stimulant. So the two drugs work in opposite directions.

In the case of LDN with glatiramer acetate, the effects are synergistic, or at least not antagonistic. The beta-endorphin peptide and other peptides that bind to opiate receptors are made up in part of a common sequence of amino acids: Tyr-Gly-Gly-Phe-Met or Leu. An interesting speculation is that glatiramer acetate, which is a random polymer, may contain occasional sequences of its constituent amino acids (Glu, Ala, Lys, Tyr) that are similar to those of the circulating endogenous opiate peptides, and will allow loose binding to the opiate receptors. So, it is conceivable that a small amount of certain random permutations of this polymer bind to the "opiate receptors" in a manner similar to naltrexone. This theory is pure speculation on my part, but it can be easily tested. Administration of glatiramer acetate should result in an increase of beta-endorphins, same as naltrexone.

Regarding compatibility of LDN and natalizumab, I don't foresee any theoretical objections, but natalizumab is still a new drug and much remains to be learned.

Can you summarize the case for initiating clinical trials of LDN as a treatment for MS?

Sure. Some of these have been discussed before:

Patients frustrated with conventional drug therapy are increasingly turning in droves to LDN. Frequently, this decision is made against the wishes of their neurologist. It is the responsibility of neurologists to prove or disprove the utility of LDN in a clinical trial. They must do it for their own patients. A proper trial may show that LDN does not work; this will prevent patients from using an ineffective therapy. Alternatively, a trial may show that LDN is effective, in which case irreparable harm may result from not taking it in the first place.
The fact that such a large number of patients are taking LDN suggests to me that there can be no smoke without fire. This is also reflected in the numerous reports in the public media (see www.LDNers.org and www.remedyfind.com). Many snake-oil remedies for MS have been touted in the past, but none has gained such wide spread acceptance.
Two physicians, one in the US (Dr. Bihari) and one in the U.K. (Dr. Lawrence) have independently observed that LDN works in their patient population. In fact, Dr. Lawrence has MS himself and takes LDN for it. Since the drug is already FDA approved and the clinical experience of Drs. Bihari and Lawrence supports it, a clinical trial is the next logical step.
If the respected Cochrane Database Reviews (www.cochrane.org) are to be taken at face value, patients are currently being prescribed ineffective or only modestly effective therapies for MS. When the alternatives are ineffective, what is the downside of doing a trial of LDN?
A scientific hypothesis, and a method for testing it, have now been proposed for LDN (see Medical Hypotheses, 2004, in press).

What would you want to see studied in these trials?

Any trial should consider the following components:

The scientific validity of the hypothesis should be confirmed. That is, the levels of ROS and glutamate should decrease in the CSF upon treatment with LDN. Beta-endorphins may increase in response to LDN.
Three main claims are made in favor of LDN: it prevents relapses, it prevents progression, and it provides symptomatic relief. Interestingly, the standard drugs apparently reduce relapses, but do not prevent long-term progression. These claims for LDN should be studied by monitoring the number of relapses, EDSS disability and MRI's.
To deal with the ethical dilemma of providing an untested therapy (LDN), and withholding an established drug therapy (ABCRs), one could potentially start off by designing a trial where glatiramer acetate + placebo is compared against glatiramer acetate + LDN.
LDN should be tested in RRMS as well as either SPMS or PPMS patients. The RRMS patients will be a sensitive indicator of the ability to reduce the number of relapses, whilst the SPMS/PPMS patients will be better for monitoring progression.
Relief of bladder symptoms and general well being due to raised endorphins should be documented.

There have been many calls from the patient community for clinical trials. What is the current status of these efforts?

Some of these are listed at www.LDNers.org and www.lowdosenaltrexone.org. I would, however, prefer that those doing the trials inform the public about them.

Given that naltrexone is already an FDA approved drug, these trials would presumably be able to leverage existing safety data, especially since we're talking about using a far lower dose. Does that mean that animal trials to study LDN with the EAE model of MS are not necessary?

The next step should be a human trial. The EAE mouse model, flawed as it is, may be useful at a later stage to determine the detailed biological effects of LDN.

Can you describe any further research that you are doing (or plan to do) with respect to furthering scientific knowledge on naltrexone and its use in MS or other conditions?

I have contacted multiple doctors in the UK, Italy, Germany, Australia and the US regarding a clinical trial. Some of this has borne fruit in the form of pending trials. I am planning to further contact various experts, both in this country and abroad, about investigating the merits of LDN. The hope is that some enlightened physicians will be motivated enough to check out LDN.

Dr. Agrawal, thank you for spending this time educating Boston Cure Project's readers about the possible use of LDN to treat MS.

References/Recommended Reading:

Therapy with glatiramer acetate for multiple sclerosis (Cochrane Review). Munari L, Lovati R, Boiko A. The Cochrane Library, Issue 4, 2004. Chichester, UK: John Wiley & Sons, Ltd.
http://www.cochrane.org/cochrane/revabstr/AB004678 .htm
Interferon in relapsing-remitting multiple sclerosis (Cochrane Review). Rice G PA, Incorvaia B, Munari L, Ebers G, Polman C, D'Amico R, Filippini G. The Cochrane Library, Issue 4, 2004. Chichester, UK: John Wiley & Sons, Ltd.
http://www.cochrane.org/cochrane/revabstr/AB002002 .htm
Multiple sclerosis is not an autoimmune disease Chaudhuri A, Behan PO Arch Neurol. 2004 Oct;61(10):1610-2.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd= Retrieve&db=pubmed&dopt=Abstract&list_uids=1547752 0
Pathogenesis of multiple sclerosis revisited. Behan PO, Chaudhuri A, Roep BO. J R Coll Phys Edinb 2002;32: 244-65.
http://www.rcpe.ac.uk/press/F_Pathogenesis_of_MS.p df
Shared scheme for assessing drugs for multiple sclerosis: why are eyes tightly shut to considering causes other than autoimmunity? Chaudhuri A, Behan PO. BMJ. 2003 May 31;326(7400):1213.
http://bmj.bmjjournals.com/cgi/content/full/326/74 00/1213
Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Barnett MH, Prineas JW. Ann Neurol. 2004 Apr;55(4):458-68.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd= Retrieve&db=pubmed&dopt=Abstract&list_uids=1504888 4
The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. Gilgun-Sherki Y, Melamed E, Offen D. J Neurol. 2004 Mar;251(3):261-8.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd= Retrieve&db=pubmed&dopt=Abstract&list_uids=1501500 4
Resistance of human adult oligodendrocytes to AMPA/kainate receptor-mediated glutamate injury. Wosik K, Ruffini F, Almazan G, Olivier A, Nalbantoglu J, Antel JP. Brain. 2004 Dec;127(Pt 12):2636-48. Epub 2004 Dec.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd= Retrieve&db=pubmed&dopt=Abstract&list_uids=1550962 4
Beta endorphin concentrations in PBMC of patients with different clinical phenotypes of multiple sclerosis. Gironi M, Furlan R, Rovaris M, Comi G, Filippi M, Panerai AE, Sacerdote P. J Neurol Neurosurg Psychiatry. 2003 Apr;74(4):495-7.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd= Retrieve&db=pubmed&dopt=Abstract&list_uids=1264007 1
Beta-endorphin concentrations in peripheral blood mononuclear cells of patients with multiple sclerosis: effects of treatment with interferon beta. Gironi M, Martinelli V, Brambilla E, Furlan R, Panerai AE, Comi G, Sacerdote P. Arch Neurol. 2000 Aug;57(8):1178-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd= Retrieve&db=pubmed&dopt=Abstract&list_uids=1092779 8
Ultra-low dose naltrexone potentiates the anticonvulsant effect of low dose morphine on clonic seizures. Honar H, Riazi K, Homayoun H, Sadeghipour H, Rashidi N, Ebrahimkhani MR, Mirazi N, Dehpour AR. Neuroscience. 2004;129(3):733-42.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd= Retrieve&db=pubmed&dopt=Abstract&list_uids=1554189 4
Culture of Mycobacterium avium subspecies paratuberculosis from the blood of patients with Crohn's disease Naser SA, Ghobrial G, Romero C, Valentine JF. Lancet. 2004 Sep 18;364(9439):1039-44.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd= Retrieve&db=pubmed&dopt=Abstract&list_uids=1538096 2

Medscape interview with Dr. Mark Freedman

art — Wed, 01 Dec 2004 09:51:21 -0500

Medscape (a free registration required site) has posted an interview with MS specialist Mark Freedman of the University of Ottawa in Ontario, Canada. In this interview, he discusses the Treatment Optimization Recommendations model (a system for determining when/whether to alter treatment in a person with MS), the use of MRI in clinical care, and high-dose, high-frequency IFN, among other topics.

Interview with Pediatric MS Specialist Brenda Banwell

art — Mon, 29 Nov 2004 11:40:03 -0500

The Path to a Cure
Interview with pediatric MS specialist Brenda Banwell

Boston Cure Project, November 2004
www.bostoncure.org

Hollie: Can you tell us about how you came to work in the field of pediatric MS?

Brenda: A few years ago, when I was doing my fellowship at the Mayo Clinic and preparing to come back to Sick Kids, I received a phone call from someone at the Toronto chapter of the MS Society of Canada. This person told me that five families had registered with them who had children with MS and who felt a little bit lost. I was asked whether I would look after them. All five children were under the care of neurologists, but were not receiving care in a focused MS clinic. Two of the children had been seen in an adult MS clinic, but had found this very intimidating. An 8-year old doesn't belong in an adult hospital or an adult waiting room, particularly in an adult MS clinic where some of the people there may be quite far along in their disease. I said I'd be happy to help these families.

Once I was back at Sick Kids I discussed the situation with my nursing staff, Jennifer Boyd and Lynn McMillan. We realized that we were being asked to care for children for whom there were really no existing services - there were no clinics focused on childhood MS at that point and very little ongoing research focused on childhood MS. There certainly were some groups around the world who had done some nice work in the area, but there wasn't a big childhood MS presence and to the best of my knowledge, childhood MS had never been presented at the major meetings or conferences as a course or seminar. We decided that if we were going to start a pediatric MS clinic, we had to start it properly, with a multidisciplinary approach in which people could work together to understand the complexity of the disease. We arranged to have occupational physiotherapy, psychiatry, and neuroophthalmology, and eventually a clinical coordinator (funded by the MS Society). We started the clinic in October 1999 and it has grown and grown, following not only children with confirmed MS but also children with a first attack of demyelination who are at risk for MS. All told we look after over 200 children now, of whom 50 have confirmed MS.

What types of clinical research and related programs have you launched there?

One of our biggest concerns is the effect of MS in childhood on learning, cognition, and academic performance. We've done one research project in that area and we're in the process of designing a grant to look at this in more depth across the ages, from our youngest to our oldest children. My nurses are also just now completing a quality-of-life project looking at how children cope with the diagnosis of this disease, how they feel, what their questions and needs are, and how we should address them, because there's not a lot on that either. In terms of clinical education, we work with the National MS Society in the US and the Canadian MS Society who have been putting together a series of programs and informational materials for children and families with MS. That initiative started just two years ago in collaboration with Lauren Krupp in the US and other people around the world.

We're also working on educating our colleagues because there are still plenty of professionals out there who don't think that MS can happen in children. For instance, a lot of doctors seeing a child who has optic neuritis at age 7 and hemisensory loss at age 9 just wouldn't think about MS in this scenario. This delays diagnosis for the affected child, who continues to complain about things like fatigue and slowing down academically in school, but nobody recognizes that it's part of a disease process. So we've spoken on this topic at several meetings. There is now a pediatric MS program at the American Academy of Neurology that Lauren Krupp, Anita Belman, and I chair. I also chair a symposium on childhood MS at the Consortium of MS Centers, and we're starting to work towards something similar at the European MS conference. We've worked really hard at trying to disseminate information about childhood MS in multiple places because there are many more children who have this disease than are recognized.

Along those lines, do you think that growing awareness of MS in children is responsible for what seems like an increasing number of pediatric MS cases being identified? Or could it actually be that more kids are getting MS now than before?

Well, that's a hard question, because if something was poorly diagnosed and underrecognized before, then it's hard to know whether or not we just missed it. My sense is that it was there all along and we missed it, because if you query adults with MS about when they think their disease started, about 25% will tell you that they knew something was wrong at least in adolescence, if not before. This is not the best methodology of course, because it's retrospective, it relies on memory, and it's biased entirely by the fact that the people asked know they have the disease now. But even if that number is an overestimate, it still suggests that the number we currently use, which is that 3-5% of all MS patients start in childhood, is a gross underestimate. Probably somewhere in the middle is the true percentage of MS patients for whom the disease, at least clinically, started in childhood. And now it seems we're starting to identify 10 to 15% of MS patients before adulthood, because of MRI, increased awareness, and education. But this still doesn't tell us whether the total value has truly increased.

What would these kids who have MS but were "missed" have been diagnosed with, if not MS?

One of the most popular terms has been "post-viral something," even when no virus can be identified. A lot of people believe that if someone had a viral infection within 3 months of their demyelinating event, that's significant. Well, if you take a group of Canadian children in January and ask how many of them have had at least sniffles or some sort of a cough, you're going to get 85-90% positivity, because that's what we have in the winter. Nonetheless, viral infection may be a trigger of demyelination, and viral exposures in childhood may be part of the environmental component of MS etiology.

A lot of physicians also use the term ADEM, or acute disseminated encephalomyelitis, to describe any form of demyelination in children. If a child comes in with optic neuritis in one eye and their MRI shows 10 to 15 lesions, but they have no symptoms from those lesions, many pediatricians, and pediatric neurologists for that matter, would say that the child has ADEM. Whereas if that were a 25-year old young woman, we would say she has optic neuritis and is at a high risk of MS. Of those children who have classic ADEM which presents as fever, headache, confusion, seizures and multiple other neurological problems, 30% will go on to develop MS. I'm sure the percentage of children with optic neuritis and 15 MRI lesions would be much greater. I'm part of a working group through the NMSS that will develop a working definition of ADEM to help pediatric healthcare providers in using this term. Also, in our prospective 5-year study of every child in Canada with their first attack of demyelination, we will obviously be looking to see whether an ADEM type of presentation is more likely to lead to MS compared with other presentations.

In addition to misdiagnosis, the lack of desire to make a life-long diagnosis in a child is a reason why children might not be thought about as having MS. Nobody wants to wrongly tell a child that they have MS, and find out later that their immune system settles down and nothing further happens.

The other very real possibility is that certain symptoms may be underreported by young children. A 6-year old may not articulate, "My arm is numb," as well as a 46-year old would. The other one that we probably miss a fair bit is unilateral optic neuritis. When you think about it, even adults often don't notice that one eye is blurry because they very quickly compensate for it.

Does pediatric MS differ in any significant way from adult MS, aside from the earlier age of onset?

One difference seems to be the impact on learning, particularly for the children that present under age 10. They are having inflammation and disease activity occurring prior to completing their core educational building blocks, so those children seem to be the ones who develop more problems with their academics later on. We don't have enough data yet to say this with confidence, but in comparison to an adult MS population, the types of deficits seem to be a bit different. And that's not too surprising. Someone whose ability to learn basic things such as mathematics or advanced sentence structure is disrupted might have quite different issues compared with an adult who had already acquired all that. Also, the frequency of a multiple symptom onset may be a little bit higher in children than in adults. Kids might have a more dramatic first attack than you might see in adults.

Do you treat it any differently? I understand none of the MS-specific drugs have been tested specifically in children yet, do you use them anyway?

We do.

How do you know how to use them in children?

We're obviously very careful with them, so we start at lower doses proportional to the size of the child, and increase gradually toward the full dose if the child can tolerate it and it's appropriate. We monitor liver function and blood count for the children on interferon very carefully, and that has been just fine. Certainly we see our children more frequently and are more vigilant about side effect profile analysis than you might need to be in an adult population where those side effects are better understood. But truthfully the kids tolerate the medications very well.

I know it's hard to tell because you're not doing a controlled study, but do they seem to respond to the drugs?

They do. You're quite right, the accurate answer to that is it requires several hundred kids and a control population to be certain,. But clinically, the children do seem to have a reduction in their relapses, their MRIs seem to stabilize, and the families and the clinicians here and in other centers that I've spoken with also believe that these patients are doing very well on these drugs. So we all feel confident that we're doing the right thing in treating children with these drugs. Overall, I'd have to say the drugs seem to be working quite nicely, with the obvious limitation that that's not based on a scientific study.

Let's turn now to your five-year study of children with initial demyelinating attacks. What are you hoping to learn about the causes or triggers of MS through this study, and what other topics are you exploring?

My personal biggest interest in MS, which I think this population can address better than any adult population, is the question of what triggers MS. A very young MS population is uniquely able to indicate if there's an environmental trigger, whether it's a positive trigger (something that you acquire), or a negative trigger (something that you should have had but didn't receive). In a 30-year old with MS, there are 30 years worth of environmental triggers, events, exposures, etc. to try to sort through. On the other hand, a 5-year old is much closer to the biological onset of the disease.

We've been focusing on viral exposures, not that we think a particular virus causes MS, but perhaps the sequence or series of viruses you're exposed to in early childhood modifies your immune system in such a manner that it could respond against yourself.

My collaborator Amit Bar-Or works with me on all of my projects, and his focus is on the immune system of MS patients. We feel that if you look at the initial immune target of the MS disease process before the disease has been present for very long, we may be able to identify the initial inciting antigen. That would be very exciting in terms of therapeutics. It may also help in terms of recognition and diagnosis of MS, because if we can tell which antigen is being targeted in someone's first attack, we might theoretically be able to predict who's going to be more likely to develop chronic disease versus who's going to recover.

The other main area of our work is using MRI to diagnose and understand MS in children. In terms of diagnosis, we have already established that the current adult criteria do not apply particularly well to MS in children. One component of the McDonald criteria requires nine T2 lesions, which comes out of the fact that adults often have had other things such as small strokes or hypertension that can cause white matter lesions. Requiring nine lesions helps avoid mistakenly lumping someone with hypertension into the MS population. However, we don't have a whole lot of hypertensive children, so perhaps this criteria should be changed for children. The things that you have to rule out in children are different from the things you rule out in adults, and the MRI appearance of controls not surprisingly is also different, so our criteria are going to be a little different. Working on this is very important, because if healthcare practitioners had an MRI scoring tool that gave them confidence in distinguishing childhood MS from other conditions, it would be of great value to our patients. That is why we are currently developing MRI criteria for children.

In another application of MRI, with Doug Arnold, we're using advanced techniques to look at the non-involved white matter in 3-, 4- or 5-year olds at their first demyelinating attack, to help answer the fundamental question of whether white matter is abnormal in persons with MS from the very start. This question has been addressed in adults before, and we do see abnormalities in the normal-appearing white matter at the time of their first attack in MS, but nobody can say whether those have been there for life or developed later as part of the disease process. However, if the white matter is very abnormal in someone who is 5 or younger at the time of the first attack, we have to question whether it was abnormal from birth. We're also looking at things such as white matter atrophy and white matter maturation. One question we're asking is whether the progressive loss of white matter in children who have had their first attack can confirm or predict that they will go on to develop MS. One would imagine it probably does, but no one's ever studied that. No one has also ever looked at what happens if you disrupt primary maturation of the white matter. Myelination of our brains isn't complete until almost 20 years of age, so if you start demyelinating when you haven't even fully myelinated, what happens? In other words, do children with MS have more deficits down the road in terms of cognition because the primary white matter formation was disrupted in the first place?

In addition to our MRI collaboration, we are working with Dessa Sadovnick and George Ebers on some of their genetic questions. We want to know whether one of the reasons why some people develop MS very early in life is because they have a greater number of genetic risk factors for MS. So we are involved in a pretty broad range of studies.

I'd say so! Perhaps one of the benefits of being in this relatively unexplored territory is that there are so many things you can investigate if you have the right people involved.

You're quite right - there are so many areas that are wide open for review. But it's not that we are scattered, I don't want to give that impression. The Canada-wide study is a very cohesive, coordinated study. We've created databases that are all linked. Although we are doing multiple analyses, we have crafted the data analysis component of our study to allow that to all be pulled in and linked together. Our overall goal is to find out whether we predict MS in the cohort of children who've had their first attack. If we can, what are the predictors? We've kept our minds completely open. It may be a set of clinical symptoms, it may be a particular MRI appearance or recovery pattern, it may be the initial target of the immune system, it might be a genetic link, or it might be a combination of several things. If you believe in MS being a multi-hit disorder where you have to have several things stacked together in the wrong direction to lead to an MS outcome, then perhaps by looking at this cohort of children we can pull them out. So although we have multiple areas of research, we have linked them together in an organized, structured way so that we can interpret them in light of each other.

Presumably you're going to have a lot of data when all the results are in. How are you planning to analyze it?

Well, we have a whole team of statisticians which helps. We're also using some database interfacing which the Center for Computational Biology here at Sick Kids has facilitated.

When do you expect to have something to report from this study?

Well, we just launched in September, so realistically, I think that we will be reporting the most exciting data at least two years from now. We may have some preliminary MRI data to look at within a year, because we do MRIs at baseline, 3 months, 6 months, and 12 months. But the main product of this grant, the result of the predictive model of MS outcome, is five years away because we can't finalize it until we have all of our data.

Another piece of the project that we'll be able to report every year will come through a surveillance program that the Canadian Pediatric Society operates for diseases of interest to child and youth health. Every five years they choose around seven or eight diseases to monitor and have recently included demyelination of the central nervous system. Through this program every pediatric healthcare provider in the country, even if they're not at one of our 22 research sites, will receive a notice every month asking them to report if they've seen any children with demyelination. Anyone who does report will then get a more detailed reporting form which is anonymous and therefore doesn't require informed consent from the family. So over the five years of this program we will have annual incidence data, an annual review of what the presentations were, and where they were located across Canada.

Is Canada the first country to do something like this?

Yes!

Let's look back a little bit at your previous research. At the Boston Cure Project we're primarily concerned with finding out what causes MS, and so we were very interested in the paper you published in JAMA in April that had some noteworthy results concerning the Epstein-Barr virus (EBV). Could you recap these findings for us?

This study related to our question of whether or not particular exposures in the environment, such as viruses, trigger or foster an abnormal immune response that leads to MS. We looked at the Epstein-Barr virus first because it's a very powerful virus in the human immune system. It's also ubiquitous, so in Canada 97-98% of the population ultimately are exposed to it. When we initially proposed to investigate it, a lot of people wondered how EBV can possibly relate to a disease like MS when everybody is infected. Our response is that it may not be a question of whether you get it but when. We hypothesized that if you're exposed to EBV during a particular window of risk, such as a certain age range, it may modify how your immune system responds to future events. What we found is that Canadian children with MS were much more likely to have been exposed to EBV than their age-matched non-MS counterparts. Now if our observation is relevant only in Canada, then you have to ponder what that means. However, if it's relevant across the world despite different geographies and different environments, then our finding has a lot more power. So we've since expanded our investigation to a six-country study of childhood MS, which is taking place in Canada, the US, Argentina, Finland, Italy, and Russia. We presented our preliminary international data at ECTRIMS, and so far it shows the same results we had in the Canadian data, with 80-85% of children with MS being positive for remote EBV infection, versus somewhere between 25 and 40% of controls.

By the way, one of the world experts on EBV is Dr. Ascherio at the Harvard School of Public Health, and he and his group of epidemiologists have been studying EBV in adult MS for a long time.

How might one interpret these results?

Well, they might mean that EBV triggers or is involved in the early events of MS, or they may just mean that children with MS are more prone to EBV. One step we're taking to help answer this question is including a very detailed panel of about twenty viruses in our prospective Canada study, so when children come in with their first attack, we can see whether they've had EBV or other infections. If EBV is there at the first attack, that supports the idea that it's a trigger; if it comes between the first attack and second, it may be a propagating agent.

The next step involves designing some assays to look at how T and B immune cells behave. In other words, although we all get EBV, perhaps our immune systems handle it differently. If you have been infected with EBV, the virus will live in your B cells. It remains dormant, but it's always there. One question is whether there is a difference in the proportion of infected B cells in people who have MS versus people who don't. Another question is, do people who have EBV infectivity have a different immune response? Normally, our T cells monitor the number of EBV-infected B cells in our bodies, and if there are too many, the T cells come along and dampen them down. One thing to ask is if you have MS and you receive your EBV infection when you're young, what happens to your T cells? Obviously they've proliferated to protect you from EBV, but in doing that did something about the EBV viral protein trigger those T cells to enter the brain and react? We know that there is at least one region of EBV nuclear protein antigen that has a similar genetic sequence to myelin basic protein (MBP), so could this allow T cells to react against MBP because they previously had to react against EBV? And does this happen at a key vulnerable age when something is happening in myelin maturation or otherwise to allow this abnormal reaction? That's a pretty broad question and there will not be a simple answer, but we're designing some assays to see whether children who have MS react differently to certain antigens compared with children who don't, and then we'll try to see whether that plays a role in how the immune system reacts to actual myelin preparations. There's a great deal of work to take what is currently an observation and move it towards a theory and then towards something more concrete, and we are very much at the beginning. But we have some ideas and we're moving forward.

We know that Epstein-Barr persists in our cells and can be reactivated. Do you think this reactivation could also be involved in triggering relapses on an ongoing basis?

That's been postulated as a factor in adult MS. We don't know yet whether that could be important in kids because we're just starting to look at that. It's entirely possible that relapses are not due to the activity of the virus, but rather the reactivation of the immune system. In anyone who's ever had EBV, periodically during the year, EBV reactivates and is released from the body which is why it's so infectious. As that process happens, every time it happens, your immune system has to respond. So your T cells have to increase in number and they have to dampen down this proliferating virus again. If your T cells are more active, one could postulate that that might lead to an increased chance of there being an MS attack. So it may not be that the virus itself is in the brain, but just that it triggers your immune system to activate again, which leads to an increased number of circulating immune cells, some of which go into the brain and cause yet another attack. That's very theoretical, but it might be true.

Is anyone working on EBV vaccines to prevent infection, or treatments to keep it from reactivating, if we should find that EBV is involved in triggering MS and/or relapses?

Yes, and no. The problem with vaccines for EBV is that you would really have to understand our biology better to be sure that's the right thing to do. When you give a vaccine, like the measles-mumps-rubella vaccine, it's usually designed to instigate immunity against the virus by creating a circulating set of immune cells that were stimulated against the vaccine. In other words, you get the immune response without having a real infection. In MS, it may be not the infection that's the problem but the ongoing immune response, in which case a vaccine may not be the way to go. My other comment which is more philosophical is that any virus that has survived to the degree that EBV has, and can exist in almost every person, suggests that somehow it may confer an as-yet unrecognized advantage to humans. Rarely in nature does a virus or other infectious organism survive and become ubiquitous in the environment unless the host either gains an advantage from it or is unable to kill it. So before you would want to modify something like that, you would really want to understand what it does. We know for example that EBV in equatorial Africa leads to Burkitt's lymphoma. You might question then why it hasn't been weeded out in humans there. One of the reasons is believed to be that it has some protective effect against malaria. So we need to understand EBV better before we would want to wipe it out, and we also need to understand whether trying to wipe it out might just instigate the disease in everybody. If you gave the vaccine to everybody at the same age, and that age happened to be a bad time for their immune system, we could theoretically make the MS problem worse.

Remember that the data we have on EBV is just a highly statistically significant observation. Our responsibility now is to take that observation now and study very carefully its association with the disease to be sure we understand what it means. That's not a simple process, and we're certainly not suggesting that the virus itself causes the disease. We're looking at a very complex interaction between the immune system, the environment, your own genetic predisposition and a little bit of chance. I don't think any one thing is going to be the final answer, but who knows? Cervical cancer is now largely known to be an infectious disease - and nobody predicted that 20 years ago.

Thank you so much for your time today! Before we wrap up, is there anything else you'd like our audience to know?

The one thing I always emphasize is that none of what we do would be possible if the MS societies hadn't been so supportive of our work. In our case, the Canadian MS Society and the MS Scientific Research Foundation have been particularly supportive. They had the confidence to invest in a group of MS patients that people previously didn't even think about. I know that all the families I care for are enormously grateful that these societies have placed an interest in helping children and understanding their disease. One other thing I'd say is that the biggest thing we can do in childhood MS is to work together. We are already part of a national and North American collaboration on this topic, and now we also see an emerging interest in international collaboration which is terrific.

Note: To find out more about the 5-year study on "Demyelination of the Central Nervous System in Canadian Children," funded by the Multiple Sclerosis Scientific Research Foundation, please go to: http://pedsdemyelination.ccb.sickkids.ca/.