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Transmitting MS To Children: Possible Differences In Men And Women

A new study shows that, in a group of 441 children with a parent with multiple sclerosis, fathers with MS were more likely to pass on the disease to children than mothers with MS. Orhun H. Kantarci, MD, Brian G. Weinshenker, MD (Mayo Clinic, Rochester, MN) and colleagues report their findings in the July 25 issue of Neurology (2006;67:305-310). The study was funded by the National MS Society, the National Institutes of Health and the Mayo Foundation.

Although MS is not directly hereditary, a person who has a first-degree relative (such as a parent or sibling) with MS has a greater risk of developing MS than a person with no MS in the family. Researchers believe that MS occurs in individuals who have genes that make them susceptible to an unknown environmental trigger or triggers. In addition, women are twice as likely as men to develop MS. The reason for this difference is unknown. Dr. Kantarci’s group examined the possibility that if men are more resistant to MS, then those men who actually develop the disease must have more susceptibility genes in order to overcome that resistance. Therefore they might be expected to pass on a larger number or stronger susceptibility genes to their children.

While the average person in the United States has about 1 chance in 750 of developing MS, the risk for a person who has a parent with MS increases to about 1 in 40. Thus, the risk increases significantly for a person whose parent has MS, but still remains relatively low.

According to the National MS Society’s Chief Medical Officer Dr. Aaron Miller, “These findings, if confirmed, are of interest to scientists searching for MS genes, but do not alter genetic counseling advice for families with a parent who has MS.”

The National MS Society is funding several large-scale studies searching for genes that make people susceptible to developing MS. Success in this area would give scientists a roadmap to the cause of MS, as well as to concrete targets for new therapies and possibly even ways to prevent the disease.

National Multiple Sclerosis Society

Special Thanks to our Angel Patricia for finding and sharing this article


NEXT LIVE WEBCAST: Thursday, September 25, 2008

The Stem Cell Debate: Will Your Vote Affect MS Treatment?

With war, the housing crisis and global warming on the front page of every newspaper, where does stem cell and MS treatment research sit on the list of national priorities this election season?

Tune in September 25 as we speak with MS community leaders about stem cell transplants as an MS treatment, the status of stem cell research and whether this potential treatment option might gain more acceptance under a new administration. Our guests explain why the laws around stem cell research make funding difficult and review the presidential candidates’ voting records on the issue. Plus, you’ll find out how you can do to get involved in the debate, no matter which side you’re on.

And, as always, you'll have a chance to ask the experts your questions.

More on Treating MS in our Patient Blog New Cases of PML in MS Patients on Tysabri

Two new cases of PML were reported in MS patients being treated with Tysabri (natalizumab). Trevis explains what happened, how the patients are doing and how he feels about the news.Read the blog

Controlling Symptoms of MS
Trevis wants to hear about the “other” drugs you use to treat your MS. In addition to any disease-modifying treatments, what do you use to keep healthy and control the symptoms of your MS?Read the blog




New PML Cases Reported With Tysabri Monotherapy

August 26, 2008 — Two new cases of progressive multifocal leukoencephalopathy (PML) have been reported in European multiple sclerosis patients receiving natalizumab (Tysabri, Biogen Idec, Inc), the US Food and Drug Administration (FDA) warned yesterday.
Both patients had been receiving natalizumab monotherapy for longer than 1 year, according to an alert issued by MedWatch, the FDA's safety information and adverse event reporting program. In contrast, prior reports of PML had involved use of natalizumab with other immunomodulatory agents.

"While the two patients who developed PML were on monotherapy, the FDA still believes that Tysabri monotherapy may confer a lower risk of PML than when Tysabri is used together with other immunomodulatory medications," the agency emphasized in a news release.
The monoclonal antibody was first approved by the FDA in November 2004 for the treatment of multiple sclerosis and was later withdrawn by the manufacturer in February 2005 after 3 patients developed PML during clinical trials.

After reviewing the study data to confirm the absence of additional PML cases, the reintroduction of natalizumab into the US market was accompanied by a restricted distribution and risk-management program, known as TOUCH. The drug was later approved in January 2008 for the treatment of Crohn's disease.

Under the TOUCH program, each natalizumab-treated patient is closely monitored for the development of PML and other opportunistic infections. According to the FDA, no new PML cases have been reported either among 7500 US patients taking the product for more than 1 year or among an additional 3300 patients who have received treatment for at least 1.5 years.
"Healthcare professionals should continue to monitor patients for sign and symptoms of PML," the agency advised. "Additionally, Tysabri should not be infused if PML is suspected."

Natalizumab monotherapy is indicated to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations in patients with relapsing forms of multiple sclerosis; it also may be used to induce and maintain clinical response and remission in adult patients with moderately to severely active Crohn's disease who have evidence of inflammation. Use of natalizumab is generally reserved for patients who have had inadequate response to, or are unable to tolerate, conventional therapies.

Adverse events related to use of natalizumab should be reported to the FDA's MedWatch reporting program by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at, or by mail to 5600 Fishers Lane, Rockville, MD 20852-9787.

Medscape Today from WebMD

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Teva sues Novartis, Momenta over Copaxone patent

NEW YORK, Aug 28 (Reuters) - Teva Pharmaceutical Industries Ltd sued Swiss drugmaker Novartis AG and Momenta Pharmaceuticals Inc on Thursday, accusing them of infringing patents on its multiple sclerosis drug Copaxone.
The lawsuit, filed in U.S. District Court in Manhattan, claims that any generic version of Copaxone infringes patents that Teva contends are valid and enforceable.

Cambridge, Massachusetts-based Momenta said last month that the generic Copaxone application asserts that Teva's patents are invalid.

Teva is seeking to have the court declare that the defendants have infringed its patents, and that any approval of a Novartis generic not be granted until after Teva's patents expire.

The suit also seeks to prevent Novartis and Momenta from any commercial manufacture or sale of a generic Copaxone.

It asks the court to order Sandoz to withdraw its application seeking to sell the generic and award Teva monetary damages and interest to compensate it for misappropriation of Teva trade secrets as well as any further monetary relief the court deems just and proper.

The Guardian



Elan says Tysabri brain disease link uncertain

LONDON (SHARECAST) - Irish drug giant Elan said the risk of a fatal brain disease in patients treated with its multiple sclerosis drug Tysabri “cannot be precisely estimated.”

The group made the comments as it saw losses narrow for the half year on strong sales of the MS drug.

Shares in Elan more than halved last month after it confirmed two more cases of progressive multifocal leukoencephalopathy (PML) in patients treated with its multiple sclerosis drug Tysabri.

“Patients and their physicians have chosen Tysabri because of its efficacy while being informed of the risk of PML,” it added.

Tysabri, which Elan developed in collaboration with US partner Biogen, recorded in-market sales in the first half of $359.7m, an increase of almost 200% over the $120.5m recorded in the same period of 2007.

At the end of June 2008, approximately 31,800 patients were on therapy worldwide, an increase of 127%.


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Influence of anxiety and reported stressful life events on relapses in multiple sclerosis: a prospective study

Objective: Self-reported stressful life events and infections have been associated with relapses in multiple sclerosis. Also, anxiety has been reported to influence other diseases of unpredictable course. To study relation of self-reported stressful life events, levels of anxiety, and episodes of infection, with relapses of the disease in women with multiple sclerosis.

Results: A total of 291 stressful events, 37 episodes of infection, and 48 relapses, were registered. High level of anxiety were stongly related to the number and the severity of reported stressful events during the preceding period and with the advent of a relapse in the following period (Hamilton score greater than 18 is associated with 4.2 times the rate of relapsing and three or more reported stressful events with 5.7 times the rate of relapsing).

Conclusions: Anxiety and self-reported stressful events may in fact be two measures of the same underlying emotional factor, which plays an important role on the course of the disease, in addition to episodes of infection.

Sage Journals


Safety and immunogenicity of a new formulation of interferon -1a (Rebif® New Formulation) in a Phase IIIb study in patients with relapsing ms

Background: A new formulation of subcutaneous (s.c.) interferon--1a has been developed (Rebif® New Formulation, RNF), produced without fetal bovine serum and without human serum albumin as an excipient, with the aim of improving injection tolerability, and reducing immunogenicity.

Objectives: This article reports 96-week analyses of a Phase IIIb, open-label study of the safety and immunogenicity of RNF compared with historical (EVIDENCE study) and recent (REGARD study) data on the original formulation.

Conclusions: RNF has improved overall immunogenicity and safety profiles compared with the original formulation.

Sage Publications




Quality of life in visual disturbances in multiple sclerosis

In multiple sclerosis (MS) often the visual pathway is impaired. Very early symptom which precedes neurological signs is the retrobulbar optic neuritis. In MS patients near as well as distance, color and peripheral vision can be disturbed. Many patients are not aware of visual impairment which could cause the delay in diagnosis.

The assessment of the visual field in patients with MS enables early diagnosing as well as monitoring of the course of the disease. In monitoring of the course of disease most important is the evaluation of quality of life. The assessment of quality of life in MS is well known, even better than in other neurological diseases. Less known is the question of quality of life diminished because of visual field defects in MS. In review report the value of perimetry in diagnosing MS, visual disturbances in MS and contemporary possibilities of evaluation of quality of life in MS patients including those with defects in visual field has been described. The VFQ-25 questionnaire is a sensitive and useful tool in self-assessing visual function in MS patients.
PMID: 18717046

HighWire Press Stanford University


Clinical Parameters to Predict Response to Interferon in Relapsing Multiple Sclerosis.

Department of Neurology, University Hospital of Dijon, Dijon, France.

Background: To identify clinical parameters of response to beta-interferon (IFN-beta) in relapsing-remitting multiple sclerosis (RRMS) from an East France cohort.

Results: 751 RRMS cases were included. A higher relapse rate in the year preceding IFN-beta onset, an older age at MS onset and having a polysymptomatic onset of MS were significantly associated with a response for the first criterion. With the 3 other criteria, no parameter predicting response was identified.

Conclusion: Only the relapse rate in the year before initiation of IFN-beta treatment appears to be able to predict response to treatment but not the one of 2 years before.
PMID: 18716412

HighWire Press Stanford University


Predictors of life satisfaction among caregivers of individuals with multiple sclerosis.

Wayne State University, Detroit, MI, USA.

Research on life satisfaction among caregivers of persons with multiple sclerosis (MS) is sparse. This study examined the extent to which MS-specific disease and psychosocial characteristics predict caregiver life satisfaction. Participants were 64 caregivers of patients with MS and the patients for whom they care. Multiple regression analysis indicated that caregiver perception of illness uncertainty and patients' unawareness of deficits have unique value in predicting caregiver life satisfaction, even after accounting for general financial status. Gender and level of social support were also important contributing factors to caregiver life satisfaction. The findings suggest that duration and severity of the patients' illness take a greater toll on life satisfaction of caregivers with low versus high social support, particularly among women caregivers.
PMID: 18720271

HighWire Press Stanford University



LIVE WEBCAST TOMORROW: Thursday, August 28, 2008

Symptoms of MS: Recognizing and Treating Optic Neuritis

If you have MS, you’ve likely heard about or even experienced firsthand its close relationship with optic neuritis, a condition that causes a wide range of vision problems. Wondering what you can do about it?

Tune in tomorrow as ophthalmologists who specialize in optic neuritis and other vision problems related to MS explain what causes optic neuritis, how to differentiate its symptoms from other vision trouble and how best to treat it. You’ll find out how long you can expect the visual disability to last, whether or not your vision will fully recover and how to treat pain that often accompanies this condition. Plus, those who aren’t yet diagnosed will find out how likely they are to develop MS if they’ve had optic neuritis.

And, as always, you'll have a chance to ask the experts your questions.

BONUS: Attend the live webcast for your chance to win one of three iPod nanos. Use your nano to download the latest MS podcasts now available at! (Drawing open to U.S. residents only.)

Register Now

For those who have already registered, this e-mail is just a reminder.

Date: Tomorrow, Thursday, August 28, 2008
Time: 5:30 p.m. PDT / 6:30 p.m. MDT / 7:30 p.m. CDT / 8:30 p.m. EDT
Location: On the Internet
How to participate online:
It’s okay if you haven’t registered prior to the webcast – we’d still love for you to attend.

On Thursday, August 28 about 10 minutes prior to show time, go to this Web address from any computer:

Be sure to install Media Player for Mac or Windows and test it before the webcast. Find easy download instructions at

Thank you for tuning in!

We wish you and your family the best of health,
The HealthTalk Multiple Sclerosis Team


Multiple sclerosis

Treatments and drugs

If your attacks are mild or infrequent, your doctor may advise a wait-and-see approach, with counseling and observation.
Medications for relapsing MS
If you have a relapsing form of the disease, your doctor may recommend treatment with disease-modifying medications early in the course of disease. You can't take these medications if you're pregnant or may become pregnant. These medications for multiple sclerosis treatment include:
  • Beta interferons. Interferon beta-1b (Betaseron) and interferon beta-1a (Avonex, Rebif) are genetically engineered copies of proteins that occur naturally in your body. They help fight viral infection and regulate your immune system.
  • Glatiramer (Copaxone). This medication is an alternative to beta interferons if you have relapsing remitting MS. Doctors believe that glatiramer works by blocking your immune system's attack on myelin. You must inject glatiramer subcutaneously once daily. Side effects may include flushing and shortness of breath after injection.
  • Natalizumab (Tysabri). This drug is administered intravenously once a month. It works by blocking the attachment of immune cells to brain blood vessels — a necessary step for immune cells to cross into the brain — thus reducing the immune cells' inflammatory action on brain nerve cells.
  • Other medications. Mitoxantrone (Novantrone) is a chemotherapy drug used for many cancers. This drug is also FDA-approved for treatment of aggressive forms of relapsing remitting MS, as well as certain forms of progressive MS. It's given intravenously, typically every three months.
    Some doctors are also prescribing other chemotherapy drugs, such as cyclophosphamide (Cytoxan), for people with severe, rapidly progressing MS. However, these medications aren't FDA-approved for treatment of MS.
Medications for progressive MS
Some medications may relieve symptoms of progressive MS. They include:
  • Corticosteroids.
  • Muscle relaxants.
  • Medications to reduce fatigue.
  • Other medications.
MS treatments other than medications
In addition to medications, these treatments also may be helpful:
  • Physical and occupational therapy.
  • Counseling.
  • Plasma exchange (plasmapheresis

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Acetyl-L-carnitine: Can it relieve MS fatigue?

I've read that the dietary supplement acetyl-L-carnitine may reduce fatigue in multiple sclerosis. Is this true?

- Rilda / Canada


Some research suggests that acetyl-L-carnitine may improve fatigue associated with multiple sclerosis (MS).

Acetyl-L-carnitine is a form of L-carnitine, an amino acid that is found in nearly all cells of the body. L-carnitine plays a critical role in the production of energy from long chain fatty acids. In addition, it increases the activity of certain nerve cells in the central nervous system.

Fatigue is a common symptom in people with multiple sclerosis. The cause isn't well understood. A study published in 2006 evaluated the benefit of supplementation with L-carnitine in people with MS-related fatigue who had low blood levels of L-carnitine. Study participants were given 3 to 6 grams of oral L-carnitine daily. Researchers reported a decrease in fatigue intensity in 63 percent of participants treated with immunosuppressive drugs, especially in those treated with cyclophosphamide and interferon beta.

Although acetyl-L-carnitine generally has only few or mild side effects, it can interfere with several medications, including anticoagulants, anticonvulsants, cephalosporins, penicillin derivatives, zidovudine and valproic acid. So talk to your doctor before starting acetyl-L-carnitine or any dietary supplement.



TYSABRI BREAKING NEWS..."Biogen, Elan Drug Gets New FDA Warning"

The Food and Drug Administration on Monday said it was expanding its label warning of potentially deadly brain infections for patients taking Biogen Idec(BIIB - Cramer's Take - Stockpickr) and Elan's(ELN - Cramer's Take - Stockpickr) multiple sclerosis treatment Tysabri.
Tysabri was previously removed from the market after being linked to progressive multifocal leukoencephalopathy (PML), but was relaunched with a warning on its label. News of the drug's connection to two confirmed cases of PML since its approval in the European Union and the re-entry into the U.S. market two years ago in July hit shares of companies. Biogen fell 26% and Elan plummeted 45% after the cases were disclosed.

On Monday, the FDA said the label will now include the risk of progressive PML with Tysabri when it's used alone. PML is a known risk of Tysabri, but previous cases in patients with MS were seen in combination with other therapies that affect the immune system. Regulators said they still believe Tysabri monotherapy may have a lower risk of PML than when the drug is used with other immunomodulatory medications.

"We view the label change as relatively minor and believe it reflects the FDA's support for continued Tysabri use," wrote Thomas Weisel Partners' analyst Ian Somaiya in a note Monday. The analyst expects sales could continue to beat estimates, but maintained a market weight rating "given our concern for further downside risk if and when PML cases are confirmed in the U.S."

The two recent cases occurred after 17 and 14 months of treatment, respectively, both in Europe. Biogen said Tuesday that as of Aug. 25, both were clinically stable.

Roughly 39,000 patients have been treated with Tysabri worldwide, with approximately 12,000 patients receiving treatment for a least one year. No new cases have been seen in the U.S., where about 7,500 patients have received the drug for more than a year and roughly 3,300 patients have had it for at least eighteen months.

There are reports of suspected casesof PML in Tysabri patients on the FDA's Adverse Event Reporting System (AERS) database. However, it is not public how many suspected cases of PML currently exist, or the rate at which they turn out to be false alarms.

Biogen said Tuesday that they haven't received any reports of additional confirmed cases of PML in patients treated with Tysabri since the two discussed in late July.

"The physician response has been largely supportive -- they've been pleased to see these cases have been detected early and have been managed," said Biogen Idec spokeswoman Naomi Aoki on Tuesday. Aoki noted that PML with Tysabri use is one of the most communicated drug risks, and thus the emergence of cases was not a surprise.


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Biogen Idec shares gain on Tysabri outlook

Biogen Idec shares rise as Wall Street maintains positive multiple sclerosis drug outlook.

NEW YORK (Associated Press) - Wall Street continues to maintain a positive outlook on Biogen Idec Inc.'s multiple sclerosis drug Tysabri, as another safety label change seems to have appeased the Food and Drug Administration and the company said two patients suffering from potentially fatal side effects are recovering.

The Food and Drug Administration late Monday said it is working with the company to address label changes to the drug, though the Cambridge, Mass.-based company said it has already updated the warning.

The prior label warning addressed the risk for patients taking the drug in combination with other therapies, while the new addition addresses the risk for patients taking only Tysabri to treat the autoimmune disorder.

"In a sign of support for the drug, the FDA stated that Tysabri monotherapy may lead to a lower risk of PML compared to Tysabri used in combination with other immunomodulatory therapies," said Thomas Weisel Partners analyst M. Ian Somaiya, in a note to investors. "We view the label change as relatively minor and believe it reflects the FDA's support for continued Tysabri use."

He reaffirmed a "Market Weight" rating, though, over concern there could be further downside to the stock if new cases are reported in the U.S.

Biogen shares gained 55 cents to reach $54.16 before midday.

American Depository Shares of Elan jumped 60 cents, or 4.2 percent, to $14.85 Tuesday. The stock has traded between $9.55 and $37.45 over the last 52 weeks.

Deutsche Bank-North America analyst Mark Schoenebaum also reaffirmed a "Market Weight" rating on Biogen, keeping a positive outlook for the drug, but acknowledging that more PML cases are likely in the future.

"The lack of new cases and recovery of these two cases may provide a short-term upswing for Biogen's stock," he said, in a note to investors.

He is maintaining an estimate of 56,000 patients on Tysabri by 2013.




Biogen, FDA Work to Alter Tysabri Label

August 26, 2008; Page D2
Biogen Idec Inc. and Elan Corp. are working with the U.S. Food and Drug Administration to amend the label for the multiple-sclerosis drug Tysabri after two patients in Europe got a serious brain disorder while taking it.
The FDA is working with the companies to amend the product labeling to inform patients of the two cases. A company spokeswoman said the updated label will be based on the two cases, which the company had confirmed in late July.
The FDA said it still believes Tysabri, taken alone, may confer a lower risk of the brain disorder progressive multifocal leukoencephalopathy than when it is used in combination with other treatments.
Following the FDA posting the notice on its Web site late Monday, shares of Biogen rose about 2%, closing at $53.48, and Elan gained close to 5%, closing at $14.25. In after-hours trading, Biogen shares rose to $53.51, while those of Elan increased to $14.47.
The Wall Street Journal

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Plasma Exchange Accelerates Natalizumab Clearance

Robert Fox, MD, Cleveland Clinic Foundation, Cleveland, Ohio, reported results of studies that showed that plasma exchange (PLEX) accelerates the clearance of natalizumab, an anti-α4-integrin monoclonal antibody, and restores leukocyte migration into the central nervous system, thereby potentially improving the clinical outcome of patients who have suspected or confirmed cases of progressive multifocal leukoencephalopathy (PML).

The risk of PML, an opportunistic viral infection of the brain, is increased with natalizumab treatment, and, Dr. Fox noted, immune reconstitution is currently the only effective intervention for improving outcomes in patients with PML.

In one study, 12 patients with MS who had received at least 3 monthly infusions with natalizumab 300 mg received three 1.5-volume exchanges, over 5 or 8 days, performed 10 to 14 days following their last natalizumab infusion. Mean serum natalizumab concentrations, monitored throughout the PLEX course, were reduced >95% from baseline immediately following PLEX, Dr. Fox reported, and natalizumab clearance was accelerated by 75 days compared with natural decline.

In a second study, performed in a subset of 6 of 12 patients, peripheral blood mononuclear cells (PBMCs) were assessed for chemokine CCL2-induced migration using an in vitro blood-brain barrier (ivBBB) model during natalizumab treatment and following PLEX. PBMC migration across the ivBBB was shown to increase by 2.2 fold after PLEX. Based on the results of these studies, Dr. Fox noted that PLEX offers potential for immune reconstitution in potential PML cases associated with natalizumab treatment.
Perspectives on CNS Disease Management


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Device restores mobility after nerve damage

Michaelene Needham, 44, of Northbrook has multiple sclerosis and relied on a cane and then a walker for years. Now the mother of three is finding new mobility and energy for her busy life.

Needham, like other people with upper motor neuron injuries including stroke, spinal cord injury and cerebral palsy, can now walk with greater ease using the Walk-Aide System. The WalkAide is an orthotic device made by Innovative Neurotronics that helps people with foot drop, a condition that inhibits a person's ability to raise the front part of the foot.

Approved by the U.S. Food and Drug Administration in 2006, the WalkAide uses advanced sensor technology to analyze the movement of the leg and foot. The system sends electrical signals to the peroneal nerve, which controls movement in the ankle and foot. Gentle electrical impulses activate the muscles to raise the foot at the appropriate time during the step cycle.

The device, which is the size of a pager and fits just below the knee, includes a control unit, a flexible cuff and two electrodes. It must be prescribed by a doctor and, in Illinois, fitted by a licensed orthotist who has completed the WalkAide training program.

"This is the biggest breakthrough in orthotics in 25 years," said Michael Oros, president of Scheck & Siress, the Chicago-based orthotic and prosthetic company that fitted Needham for the WalkAide. Patients with foot drop typically have used a plastic brace that fits inside their shoe and holds the foot at a 90-degree angle. "But with the WalkAide, the patient's own musculature pulls the foot up. It's a powerful feedback mechanism for patients. The WalkAide allows the patient to use their own muscles that in many cases have been dormant for 10 to 12 years."

Needham, who was diagnosed with MS in 1991, started using a cane in 2004 and switched to a walker last September after she fell in her home. "That's when I started deteriorating," she said. "I couldn't walk far. I hung on to the walker and my legs dragged behind me. Because of the dragging, I was fatiguing. I could barely get through the grocery store."

She was fit for the WalkAide in April after her doctor determined she was a candidate. Those eligible for the device must not wear a pacemaker, nor can they have a history of seizures, have a metal implant in or around the lower extremity or be pregnant. In addition, patients need an intact peroneal nerve for the device to work. People with progressive diseases such as MS may use it indefinitely, Oros said.

The WalkAide costs around $5,000 for one foot and is currently not covered by insurance, according to Mary Ann Schultz, spokeswoman for Blue Cross and Blue Shield of Illinois, the state's largest insurer. The device gets a thumbs-up from Dr. Dusan Stefoski, professor of neurology and director of the Multiple Sclerosis Center at Rush University Medical Center. "I am astonished by the WalkAide," he said. "I've been in the field of MS since the late '70s and what I see is quite beautiful from a functional point of view."

The Chicago Tribune



Disability as an outcome in MS clinical trials

From the University of Oxford Department of Clinical Neurology (G.C.E.), John Radcliffe Hospital, Oxford, UK; Sylvia Lawry Centre for Multiple Sclerosis Research (L.H., M.D., C.L.), Munich, Germany; and The Department of Neurology (J.H.N.), the Mayo Clinic College of Medicine, Rochester, MN.

Background: Inferences about long-term effects of therapies in multiple sclerosis (MS) have been based on surrogate markers studied in short-term trials. Preventing progressive disability is the key therapeutic goal but there remains no validated definition for its measurement in a trial context. Meanwhile, MS trials continue to shorten and to depend on unvalidated surrogates. Since there have been no treatment claims for improving unremitting disability, worsening of disability in the placebo/control arm must occur for effectiveness on this outcome to be shown.

Methods: We examined widely-used clinical surrogates of long-term disability progression in individual patients with MS within a unique database from the placebo arms of 31 randomized clinical trials.

Conclusion: Clinical surrogates of unremitting disability used in trials of relapsing-remitting multiple sclerosis cannot be validated. Trials have been too short or degrees of disability change too small to measure the key outcomes. These analyses highlight the difficulty in determining effectiveness of therapy in chronic diseases.

American Academy of Neurology
NEUROLOGY 2008;71:624-631


Cognitive assessment and quantitative magnetic resonance metrics can help to identify benign multiple sclerosis

From the Department of Neurology (M.P.A., E.P., B.G., V.Z., G.S., S.S.), University of Florence; Department of Neurological and Behavioral Sciences (M.L.S., M.B., A.G., A.F., N.D.S.), University of Siena; and Neurology Unit (M.L.B., L.G.), Hospital of Empoli, Italy.

Background: The definition of benign multiple sclerosis (B-MS) is still controversial. This mainly takes into account the subject’s motor ability, with little or no relevance to other important features such as cognition. Moreover, no paraclinical markers are currently available to reliably identify patients who will remain benign in the long term.

Objectives: To assess, by using quantitative magnetic resonance (MR) metrics, differences in tissue damage between B-MS patients after dividing them into two groups on the basis of their cognitive performance.

Conclusions: Cognitive assessment and quantitative magnetic resonance can help to reliably identify benign multiple sclerosis patients.

American Academy of Neurology
NEUROLOGY 2008;71:632-638



Teva Enrolls Patients For A Second Large Global Phase III Trial Of Oral Laquinimod

Teva Pharmaceutical Industries Ltd. (NASDAQ: TEVA) and Active Biotech AB (OMX NORDIC: ACTI) announced that patients are being enrolled for the BRAVO Phase III pivotal trial. BRAVO is a global, 24-month, double-blind study designed to evaluate the efficacy, safety and tolerability of the oral compound laquinimod versus placebo, and to provide risk-benefit data for laquinimod versus a currently available injectable treatment, Avonex®. The BRAVO trial, which was initiated in April this year, aims to enroll approximately 1,200 patients with relapsing-remitting multiple sclerosis (RRMS). A second global Phase III trial of laquinimod including 1,000 patients, ALLEGRO, is also ongoing and recruiting patients globally.

"All currently approved multiple sclerosis (MS) treatments are administered via injection or infusion. The ability to provide a safe and effective oral treatment option would be a significant advancement for the treatment of MS," said Dr. Timothy Vollmer, Medical Director, Rocky Mountain MS Center, Denver, Colorado, and principal investigator of the BRAVO study. "Additionally, the mode of action for laquinimod is unlike any other MS compound, existing or experimental. We are hopeful that this research will expand our abilities to combat the disease through novel targeting."

Data recently published in The Lancet* demonstrated that oral dose of laquinimod significantly reduced the median magnetic resonance imaging (MRI) disease activity by 60 percent, compared to placebo and was well tolerated in RRMS patients. The majority of patients from the study are still receiving treatment with laquinimod in an open-label extension trial.

The safety profiles of oral therapies are of increasing interest to the MS community; We are hopeful that laquinimod will be both efficacious and safe thus providing patients with an optimal risk-benefit profile," said Dr. Per Soelberg Sorensen, Danish Multiple Sclerosis Research Center, Department of Neurology, Copenhagen University Hospital, and principal investigator of the BRAVO study.

About Laquinimod

Laquinimod is a novel once-daily, orally administered immunomodulatory compound that is being developed as a disease-modifying treatment for RRMS. Active Biotech developed laquinimod and licensed it to Teva Pharmaceutical Industries, Ltd. in June 2004. A Phase IIb study in 306 patients was recently published in The Lancet and demonstrated that an oral 0.6 mg dose of laquinimod, administered daily, significantly reduced MRI disease activity by a median of 60 percent versus placebo in RRMS patients. Laquinimod also showed consistent and robust effect on all secondary MRI endpoints.

In addition, the study showed a favorable trend toward reducing annual relapse rates and the number of relapse-free patients compared with placebo. Treatment was well tolerated, with only some transient and dose-dependent increases in liver enzymes reported. Over 460 MS patients have received laquinimod in various Phase I-II clinical trials. In addition to the efficacy that laquinimod has shown in Phase II RRMS clinical trials, laquinimod has demonstrated potent therapeutic efficacy in preclinical models of other autoimmune diseases such as rheumatoid arthritis, insulin-dependent diabetes mellitus, Guillain Barré Syndrome, lupus and Inflammatory Bowel Disease. The broad profile of efficacy in animal models of inflammatory diseases suggests that laquinimod affects a pivotal pathway of inflammation and autoimmunity. Teva expects to initiate the clinical development of laquinimod for Crohn's disease and Lupus Nephritis in the near future.

Medical News Today



Teva enrolls patients for Phase III multiple sclerosis trial

Teva Pharmaceutical Industries and Active Biotech have announced that patients are being enrolled for the Bravo Phase III pivotal trial.

Bravo is a global, 24-month, double-blind study designed to evaluate the efficacy, safety and tolerability of the oral compound laquinimod versus placebo, and to provide risk-benefit data for laquinimod versus a currently available injectable treatment, Avonex.

The Bravo trial, which was initiated in April, 2008, aims to enroll approximately 1,200 patients with relapsing-remitting multiple sclerosis (RRMS). The globally conducted study will include centers in the US, Europe, and Israel. A second global Phase III trial of laquinimod including 1,000 patients, Allegro, is also ongoing and recruiting patients globally.

Timothy Vollmer, principal investigator of the Bravo study, said: "All currently approved multiple sclerosis (MS) treatments are administered via injection or infusion. The ability to provide a safe and effective oral treatment option would be a significant advancement for the treatment of MS.

"Additionally, the mode of action for laquinimod is unlike any other MS compound, existing or experimental. We are hopeful that this research will expand our abilities to combat the disease through novel targeting."

Pharmaceutical Business Review




Pathological Laughter in a Patient With Multiple Sclerosis

From the Department of Neurology at the Geisinger Medical Center in Danville, Pa.

Pseudobulbar affect—such as pathological laughter or crying—is associated with several different neurologic diseases and is most frequently seen in patients with Alzheimer disease. However, many physicians do not recognize it as a symptom associated with multiple sclerosis. The present report describes a case of pathological laughter in a 56-year-old man who was diagnosed as having multiple sclerosis 20 years earlier.

Excerpts from the Case Report:
Laughter is a basic human expression that has been touted as a stress-reducer and complementary therapy for patients. In fact, some preliminary studies and review articles1-3 have linked increased laughter among patients to improved immune system function and outcomes. However, it is important to distinguish everyday laughter, which is an expression of emotion, from pathological laughter, which is a disorder of expression and a sign of a neurologic condition.

Pathological laughter and crying, as well as other emotional displays (eg, smiling), are manifestations of pseudobulbar affect. These symptoms, which can coexist, are associated with conditions such as Alzheimer disease, amyotrophic lateral sclerosis, and stroke.4-6 However, pseudobulbar affect may also occur in patients with multiple sclerosis (MS).7-11

The present report describes a patient with pathological laughter and serves to illustrate a seemingly harmless symptom as a sign of neurologic disease. A brief discussion of the medical literature is also provided.

A search of the terms MS and laughter, pathological laughter and MS, and pseudobulbar affect and MS on the National Library of Medicine's PubMed database yielded few studies. However, one study9 suggested that pathological laughter may occur in up to 10% of patients with MS.9

Just as the characteristics and prevalence of pathological laughter in MS are generally unknown, so are the causes of this disorder. Traditionally, pathological laughter and crying have been suspected to result from damaged pathways in the cerebral cortex that control motor movement.12 In the presence of MS, lesions of the frontal lobe, pons, and cerebellum have been implicated as a possible cause for pseudobulbar affect.7,8 As the debate progresses, it is clear that further neurologic testing will be needed before any consensus is reached.

As in the present report, pathological laughter and crying may improve after the underlying condition is managed.5 However, other pharmacotherapeutic options are available if symptoms persist. One study13 related the rapid resolution of pathological laughter and crying after the administration of selective serotonin reuptake inhibitors. Likewise, antidepressants have been reported to relieve these symptoms.14 Further research into treatment modalities is needed to ensure that patients with pathological laughter, regardless of the underlying neurologic condition, can benefit from improved quality of life.

As described in the present report and previous studies,7-11 pathological laughter can occur in patients with MS. Although much remains to be learned about pseudobulbar affect, the symptoms, which can have a substantial impact on patient quality of life, should not be overlooked by physicians.

Journal of the American Osteopathic Association (JAOA)



MS in Latin America.

Sanatorio Britanico Rosario,5th Floor, Av Wheelwright 1603, Rosario 2000, Argentina

During the last few years, there has been an increasing desire to study and expand current knowledge about the different aspects of Multiple Sclerosis (MS) in Latin America (LATAM). This report analyzes epidemiological data and specific aspects of MS in this region and aims to describe the current situation, based on the very few scientific publications that contain reliable information. Everything seems to indicate that MS in LATAM has some special characteristics that makes it different from what has been described in other areas of the world. Nevertheless, more thorough research has to be carried out in order to obtain conclusive data regarding the behaviour of the disease in LATAM.

PMID: 18713563 [PubMed - in process]
Int MS J. 2008 Mar;15(1):6-11.



Spotlight on fumarates.

Department of Neurology at St Josef-Hospital/Ruhr-University Bochum, Bochum, Germany.

The recent years have witnessed great efforts in establishing new therapeutic options for multiple sclerosis (MS). There is a clear need for more effective, safe and at the same time orally available treatment options. Here we review the potential of fumaric acid esters (FAE) as a new therapeutic option for MS. FAE have been claimed to possess immunomodulatory properties and are already in clinical use as second-line therapy for severe systemic psoriasis. They also displayed beneficial effects in experimental autoimmune encephalomyelitis (EAE), a model mimicking many aspects of MS. In addition, FAE may also act on the blood-brain barrier and exert neuroprotective properties via activation of anti-oxidative pathways. A first magnetic resonance imaging (MRI) based Phase II study in relapsing-remitting MS (RRMS) revealed a dose-dependent, significant reduction of brain lesion activity for BG-12, a dimethyl FAE compound. Currently, two multicentre, Phase III studies for testing clinical efficacy in RRMS are initiated. In view of their profile, FAE compounds may have the potential to add to our therapeutic options in RRMS in the future.

PMID: 18713564 [PubMed - in process]
Int MS J. 2008 Mar;15(1):12-8.



Monoclonal antibody treatments for multiple sclerosis.

Neurovirology Research Laboratory, VA Salt Lake City Health Care System; Department of Neurology, University of Utah Neurovirology Research Laboratory, Salt Lake City, UT 84148, USA.

Monoclonal antibodies (MAbs) may have great potential as therapies for autoimmune diseases. Their development as treatments for multiple sclerosis (MS) is promising.

Partially effective immunomodulatory therapies have been helpful for many MS patients; however, for patients failing these immunomodulatory treatments, MAbs are an important new treatment option.

Currently, MAbs are approved by the US Food and Drug Administration for treatment of many conditions, including autoimmune diseases. Four MAbs that have been investigated as potential treatments for MS are reviewed in this article. Of these MAbs, natalizumab is approved for treatment of MS. The other three MAbs (alemtuzumab, rituximab, and daclizumab) are all promising therapies in development for treatment of MS.

Adverse effects are relatively mild for these MAbs; however, care in administration and management of these agents is emphasized. Overall, these MAb therapies have great promise in the treatment of MS.

PMID: 18713579 [PubMed - in process]
Curr Neurol Neurosci Rep. 2008 Sep;8(5):419-26



Pediatric multiple sclerosis.

University of California, San Francisco, Regional Pediatric Multiple Sclerosis Center, 350 Parnassus Avenue, Suite 908, San Francisco, CA 94117, USA.

Diagnosing multiple sclerosis (MS) in a child is challenging because of the limited diagnostic criteria and their overlap with acute disseminated encephalomyelitis. Pediatric-onset MS patients are more likely to be male, have seizures, and have brainstem and cerebellar symptoms than adults, and are less likely to have spinal cord symptoms than adults. They mostly experience a relapsing-remitting course. Their initial brain MRI shows more frequent involvement of the posterior fossa, less well-defined ovoid lesions, and more confluent lesions that decrease over time in patients with prepubertal onset, making early diagnosis even more difficult. Although disability progression is slower than in adults, pediatric onset MS leads to significant disability at a younger age and may be worse in non-white patients (up to 50% in North America). The rareness of pediatric-onset MS has precluded enrollment in clinical trials. Thus, children are receiving off-label adult therapies without clear evidence of their effectiveness and limited knowledge of their tolerability

PMID: 18713581 [PubMed - in process]
Curr Neurol Neurosci Rep. 2008 Sep;8(5):434-41



Story from the MS News Channel - Letter from Dr. Tim Vollmer regarding Tysabri:

I spoke to Dr. Vollmer about Tysabri yesterday - Stan
I asked him to write me an email outlining what we spoke about...

Here is a copy of the email that I found in my "inbox" this morning....stan

Dear Stan,

As you know, it has been recently reported that two more patients on Tysabri have been diagnosed with PML.

As you remember, PML is a viral infection of the brain that occurs when the immune system is not able to enter the brain to clear the virus.

Since we all carry this virus naturally, anyone on Tysabri may be a risk for this.

The recent cases occurred after only 14 months and 18 months of exposure to Tysabri alone.

This confirms in my mind that it is due to Tysabri and not some interaction with other medications.
There are over 28,000 MS patients on Tysabri at this time with almost half with more than one year of exposure.

Overall the risk of PML with use of Tysabri is not different from what I discussed with you in the past, but it is not better either.

At this time, we do not yet know how the FDA will respond. But in that both of these recent cases were found at a relatively early stage and the drug has been stopped (and in one case plasmapheresis performed) we need to see if the PML is stopped and how much in the way of new neurological symptoms persist in these patients. This will take several months.

Therefore I would recommend the following:

1. If a patient on Tysabri has any new neurological symptoms, Brain MRI should be performed.

2. If the brain MRI has any suspicious lesions, the Tysabri should be stopped and the patient should have the appropriate spinal fluid and blood tests to look for evidence of PML.

3. If the patient has been on Tysabri for around two years, they may want to consider stopping the Tysabri and restarting Copaxone, Rebif, Betaseron or Avonex with close monitoring clinically and by MRI to detect any reactivation of MS. This later point will be controversial and I may change the recommendation in the future.

Please keep in mind that stopping Tysabri within the first year of treatment may result in a rebound effect with increased activity of the MS.
Whatever patients on Tysabri decide to do they should definitely consult their physicians first and work closely with them in managing this drug.

As more information emerges, we will need to rediscuss this issue.

Please let me know if you have questions.

Timothy L. Vollmer, MD

Professor Department of Neurology
University of Colorado Health Sciences Center
Medical Director, Rocky Mountain MS Center


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Stories from the MS News Channel MySpace Page:

The doctor put me on Provigil for FATIGUE. Any suggestions or stories on OCT eye tests?

I went to a new neurologist last week. Not b/c I didn't like my last doctor but b/c this dr. does some work for the MS Society.

He seems very knowledgeable and up on the latest. I was very happy when I came out of his office.

Through my last year and a half of MS, I have been dealing with FATIGUE.

I am thankful that this has been the only consistant symptom. The doctor put me on Provigil for my fatigue

Does any one have any input/stories on Provigil?

Also, on Friday I am going to have an OCT eye test. I can't really find much about it.

Any suggestions, stories, input on OCT eye tests?

Much appreciated :-)




Multiple sclerosis is a complex disease, with genetic and environmental risk factors.

Genetic studies which attempted to find these genes, however, have not met with much success.

I am leading a study, which has recently been funded by the MS Society, into the genetics of multiple sclerosis.

The project will take a new approach to identifying the genes underlying MS risk using novel technology, and analyses an important population - the MS patients from the islands of Orkney and Shetland.

These islands have some of the highest rates of MS in the world and are less complex genetically than urban populations, which is an advantage for finding genes.

The two-year project aims to collect DNA samples from all willing patients and a set of controls, who do not have the disease.

A genome-wide scan will be performed using hundreds of thousands of DNA markers.

The data will then be analysed using homozygosity mapping, a powerful approach which depends on shared ancestry and which has recently successfully located new genes influencing the risk of autism.

Exploring the basic mechanisms underlying susceptibility to MS will increase our knowledge of the disease so that new means of diagnosis and treatment might be identified.

It may eventually be possible to identify new genes that are implicated in the development of the disease, which would potentially act as targets for new drugs.
BBC News Channel


Tysabri Forecast to Achieve Blockbuster Status by 2014

MORRISVILLE, N.C. (Aug. 18, 2008) - AVOS Life Sciences contends that Tysabri will exceed $1 billion in sales by 2014 as previously forecasted in the AVOS Therapeutic Market Outlook (TMO) Multiple Sclerosis Report released on July 1, 2008. In addition, the market dynamics featured in the report remain the same despite the recent cases of progressive multifocal leukoencephalopathy (PML) associated with Tysabri.

On July 31, 2008, Biogen Idec and Elan filed a current report with the Securities and Exchange Commission which was the first public disclosure of the two cases of PML in patients treated with Tysabri monotherapy. The cases were the first report of Tysabri patients suffering from PML since Tysabri was reintroduced to the market in 2006. The speed with which the cases were identified and treated is a testament to the success of the risk-management plans for Tysabri in place in Europe and the U.S.

“The recent cases of PML will not significantly affect the uptake prospects for Tysabri in our model over the course of the entire forecast period,” said Jim Wahl, principle analyst and author of the TMO Multiple Sclerosis report. “We stand by our projection that Tysabri will achieve blockbuster status by 2014.” Based upon information gathered from the AVOS Physician Panel, AVOS determined that neurologists were hopeful for Tysabri but remained apprehensive in prescribing the drug to a wider patient population until more long-term safety data becomes available. In addition to the investigation of input received from the AVOS Physician Panel, the AVOS TMO Multiple Sclerosis Report also probes five major developments affecting the market over the period from 2005-2014:

• Cautious optimism marks Tysabri’s return
• Oral therapies will alter the multiple sclerosis treatment paradigm
• Changes in physician attitudes and prescribing habits
• Market shifts will slow despite new treatment options
• Moderate market growth

AVOS’ analytical tools are structured to assist with real-time decision-making in a dynamic environment.

For more information: from Pharmiweb Solutions - CLICK HERE FOR FULL STORY

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Sexual dysfunction in newly diagnosed multiple sclerosis women.

Department of Urology, University of Thessaly School of Medicine, Larissa, Greece.

OBJECTIVES: The aim of the study was to evaluate female sexuality in a selective population of newly diagnosed multiple sclerosis (MS) women.

RESULTS: All the evaluated patients were ambulant with no major neurological impairment (mean EDSS score 2.5, range 0-3.5). None of the patients were considered clinically depressed, but some of them were sad or worried. According to the sexual history and FSFI scores, sexual dysfunction was diagnosed in 22 (34.9%) out of the 63 patients and in 13 (21.31%) out of the 61 healthy females (P > 0.05).

CONCLUSIONS: In the newly diagnosed MS patients, FSD represent an important issue even though disability and other concomitant disorders affecting sexual function were excluded.

Multiple Sclerosis 2008; 14: 561-563.
PMID: 18710825 [PubMed - in process]


Early relapses after the first dose of natalizumab in active multiple sclerosis patients.

Department of Neuroscience, Neurologic Clinics, Tor Vergata University, Rome, Italy; European Center for Brain Research (CERC)/Fondazione Santa Lucia, Rome, Italy.

Background: Natalizumab is prescribed in Italy in patients who experienced at least two clinical relapses during a 12-month therapy with other approved immunomodulatory agents.

Results: In 7 of 35 patients selected on the basis of these recommendations, we have observed clinical relapses occurring within 24 h after the first dose of natalizumab.

Conclusion: The mechanism by which a first injection of natalizumab may precipitate a clinical relapse in patients with MS is unknown. We speculate that natalizumab can promote the release of inflammatory mediators from lymphocytes present in the central nervous system at the time of the first infusion, thus favoring the clinical manifestation of a pre-existing active lesion.

PMID: 18701574 [PubMed - as supplied by publisher]

Mult Scler. 2008 Aug 13. [Epub ahead of print]



Cognitive impairments in relapsing-remitting multiple sclerosis: a meta-analysis.

Beckman Institute & Department of Psychology, University of Illinois at Urbana-Champaign, Urbana-Champaign, Illinois, USA.

There is debate in the literature regarding the magnitude, nature, and influence of cognitive impairment in individuals with relapsing-remitting multiple sclerosis (RRMS). Therefore, we conducted a meta-analysis that quantified the overall magnitude of cognitive impairment in individuals with RRMS and identified the domains of cognition and clinical/demographic variables that were moderators of the overall effect. We included 57 studies with 3891 participants that yielded a total of 755 effect sizes. Overall, there was a moderate decline in cognitive functioning in individuals with RRMS compared with healthy controls. Larger effects were observed in cognitive domains of motor functioning, mood status and memory and learning. Regarding demographic and clinical variables, age and gender were moderators of cognitive impairment in all cognitive domains, whereas neurological disability and disease duration primarily moderated performance on tasks assessing memory and learning.

PMID: 18701571 [PubMed - as supplied by publisher]

Mult Scler. 2008 Aug 13. [Epub ahead of print]



Is in utero early-exposure to interferon beta a risk factor for pregnancy outcomes in multiple sclerosis?

Dept. of Neurosciences, University of Catania, Via Santa Sofia 78, 95123, Catania, Italy.

OBJECTIVE : There exist controversial and discrepant results on the risk of spontaneous abortions and teratogenesis induced by interferon treatment in people with MS. Aim of this study is to evaluate risks of the administration of INFbeta related not only to the foetus, but also to children development up to 12-months developmental milestones.

CONCLUSIONS: Our results were particularly favourable on pregnancy outcomes, because we observed only a smaller birth weight which was not detrimental for the further development of children. We believe that INFbeta therapy might not be considered to be a reason for interruption of an intact pregnancy once the drug has been discontinued until delivery.

PMID: 18677640 [PubMed - as supplied by publisher]

J Neurol. 2008 Jul 28. [Epub ahead of print]



No Effect of Preterm Birth on the Risk of Multiple Sclerosis: A Population Based Study.

BACKGROUND: Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. A clear parent of origin effect has been shown in several populations, perhaps resulting from factors operating during gestation. Preterm birth (birth at less than 37 weeks gestational age) has been shown to result in long-term health problems including impaired neurological development. Here, in a population-based cohort, we investigate whether preterm birth increases the risk to subsequently develop MS.

CONCLUSIONS: Preterm birth does not appear to contribute to MS aetiology. Other factors involved in foetal and early development need to be explored to elucidate the mechanism of the increased risk conferred by the apparent maternal effect.

PMID: 18673559 [PubMed - as supplied by publisher]

BMC Neurol. 2008 Aug 1;8(1):30. [Epub ahead of print]




How effective are disease-modifying drugs in delaying progression in relapsing onset MS?

Institution: From the Health Outcomes Research Unit (M.G.B.) and Department of Medicine, Neurology (S.K., T.J.M., V.B.) and Department of Medicine (C.S.), Department of Psychiatry (J.D.F.), and Department of Community Health and Epidemiology (M.G.B., T.J.M., I.S.S.), Capital Health District, Nova Scotia; College of Pharmacy (I.S.S.), Dalhousie University, Halifax, Nova Scotia, Canada.

Abstract Objective: Our objective was to estimate the effectiveness of disease-modifying drugs (DMDs) in delaying multiple sclerosis (MS) disability progression in relapsing-onset (R-onset) definite MS patients under "real-world" conditions.

Results: Estimated pretreatment annual EDSS increases were approximately 0.10 of one EDSS point for the RRMS group, 0.31 for the SPMS group, and 0.16 for the R-onset group. Estimates of EDSS increase avoided per treatment year on the first drug were significant for the RRMS group (-0.103, 0.000), the SPMS group (-0.065, 0.011), and the R-onset group (-0.162, 0.000); relative effect size estimates were 112%, 21%, and 105%. Estimated EDSS progression was faster in years after drug switches and treatment stops.

Conclusions: Our estimates of disease-modifying drug (DMD) relative treatment effect size, in the context of "real-world" clinical practice, are similar to DMD treatment efficacy estimates in pivotal trials, though our findings attained statistical significance. DMDs, as a class, are effective in delaying Expanded Disability Status Scale progression in patients with relapsing-onset definite multiple sclerosis (MS) (90%), although effectiveness is much better for relapsing-emitting MS than for secondary progressive MS groups.

Volume 69(15) October 9, 2007


Harvard-Columbia Team Creates Neurons from ALS Patient’s Skin Cells

New Key to Understanding and Treating ALS, and a Step Toward Personalized Regenerative Medicine

NEW YORK (July 31, 2008) – Harvard and Columbia scientists have for the first time used a new technique to transform an ALS (amyotrophic lateral sclerosis, or Lou Gehrig’s disease) patient’s skin cells into motor neurons, a process that may be used in the future to create tailor-made cells to treat the debilitating disease. The research – led by Kevin Eggan, Ph.D. of the Harvard Stem Cell Institute and Chief Scientific Officer of the New York Stem Cell Foundation – will be published July 31 in the online version of the journal Science.

This is the first time that skin cells from a chronically-ill patient have been reprogrammed into a stem cell-like state, and then coaxed into the specific cell types that would be needed to understand and treat the disease. Though cell replacement therapies are probably still years away, the new cells will solve a problem that has hindered ALS research for years: the inability to study a patient’s motor neurons in the laboratory.

ALS is caused by the degeneration and death of motor neurons, the nerve cells which convey nerve impulses from the spinal cord to each of the body’s muscles. The death of motor neurons leads to paralysis of these muscles, including those involved in swallowing and breathing, and ultimately leads to death of the patient. The disease affects about 30,000 people in the United States.“Up until now, it’s been impossible to get access to the neurons affected by ALS and, although everyone was excited by the potential of the new technology, it was uncertain that we would be able to obtain them from patients’ skin cells,” says co-author Chris Henderson, Ph.D., professor of pathology, neurology and neuroscience, co-director of the Center for Motor Neuron Biology and Disease at Columbia, and senior scientific advisor of the Project A.L.S./ Jenifer Estess Laboratory for Stem Cell Research. “Our paper now shows that we can generate hundreds of millions of motor neurons that are genetically identical to a patient’s own neurons. This will be an immense help as we try to uncover the mechanisms behind this disease and screen for drugs that can prolong life.

Scientists had originally hoped to create neurons and other adult cells using “therapeutic cloning,” in which DNA from a patient is inserted into a donated egg to create embryonic stem cells. That technique, however, has still not been successful in humans, and is also hindered by a shortage of donated eggs.
If the iPS technique holds its promise in producing neurons and other cells for research, it will probably replace the “therapeutic cloning” approach, Dr. Henderson says, but there are still lots of questions about the iPS-derived neurons.

“We don’t know yet how similar they are to the motor neurons in ALS patients,” he says. “While the cells exhibit many properties that are typical of motor neurons, we don’t yet know whether they will be prone to degeneration that will allow us to mimic the disease in the culture dish and therefore to screen potential drugs.”

To listen to a media telebriefing held on the new development, please click here.

“Project A.L.S. has always maintained that collaboration between scientists is the answer to understanding and treating this disease,” said Valerie Estess, founder and research director, Project A.L.S. “We are thrilled to have catalyzed the Harvard-Columbia collaboration that led to this discovery.”

“Therapeutic use of the cells is probably a long way off,” Dr. Henderson says. “Right now there are safety issues with iPS cells, including a risk of cancer. We also don’t know how to reintroduce cells into a sick adult in a way that will be beneficial. All these hurdles need to be overcome first before we can think about using the cells to treat disease, but we can start immediately to evaluate them as a tool for drug discovery.”

“We are excited to be able to facilitate and support truly important cross-institutional collaborations such as this significant research effort by Harvard and Columbia,” said Susan L. Solomon, CEO of the New York Stem Cell Foundation.

Above image: Image of motor neuron courtesy Dimos, Rodolfa et al

Columbia University Medical Center



Teva enrolls patients for Phase III multiple sclerosis trial

Teva Pharmaceutical Industries and Active Biotech have announced that patients are being enrolled for the Bravo Phase III pivotal trial.

Bravo is a global, 24-month, double-blind study designed to evaluate the efficacy, safety and tolerability of the oral compound laquinimod versus placebo, and to provide risk-benefit data for laquinimod versus a currently available injectable treatment, Avonex.

The Bravo trial, which was initiated in April, 2008, aims to enroll approximately 1,200 patients with relapsing-remitting multiple sclerosis (RRMS). The globally conducted study will include centers in the US, Europe, and Israel. A second global Phase III trial of laquinimod including 1,000 patients, Allegro, is also ongoing and recruiting patients globally.

Timothy Vollmer, principal investigator of the Bravo study, said: "All currently approved multiple sclerosis (MS) treatments are administered via injection or infusion. The ability to provide a safe and effective oral treatment option would be a significant advancement for the treatment of MS.

"Additionally, the mode of action for laquinimod is unlike any other MS compound, existing or experimental. We are hopeful that this research will expand our abilities to combat the disease through novel targeting."

Pharmaceutical Business Review



Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: a dose-finding trial.

Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, A-8036 Graz, Austria.

OBJECTIVE: Several studies have reported a reduction of relapses after the long-term administration of IV immunoglobulin (IVIG) to patients with relapsing-remitting multiple sclerosis (RRMS), but they were mostly small and differed in terms of predefined outcome variables and treatment regimen. We therefore set out to test two different doses of a new formulation of immunoglobulin termed IGIV-C 10% for suppression of both clinical and MRI disease activity as well as safety.

METHODS: One hundred twenty-seven patients with RRMS participated in this multicenter, randomized, double-blind, placebo-controlled trial. Forty-four and 42 patients received treatment with 0.2 and 0.4 g/kg of IGIV-C 10%, and 41 patients received an equal volume of placebo (0.1% albumin) every 4 weeks for 48 weeks. The primary endpoint was the proportion of relapse-free patients. The main secondary endpoint was lesion activity assessed by 6-weekly MRI.

RESULTS: Baseline variables were similar in IVIG- and placebo-treated groups. After 1 year, the proportion of relapse-free patients did not differ statistically according to treatment (IVIG 0.2 g/kg: 57%; IVIG 0.4 g/kg: 60%; placebo: 68%), and there was no difference regarding the cumulative number of unique newly active MRI lesions (median numbers: IVIG 0.2 g/kg: 8.0; IVIG 0.4 g/kg: 5.0; placebo: 7.2) after 48 weeks. There were no significant between-group differences in the rates of adverse events.

CONCLUSION: Although IV immunoglobulin (IVIG) treatment was well tolerated, this study did not substantiate a beneficial effect of IVIG in doses ranging from 0.2 to 0.4 g/kg. This result seriously questions the utility of IVIG for the treatment of relapsing-remitting multiple sclerosis.

PMID: 18645164 [PubMed - in process]
Neurology. 2008 Jul 22;71(4):265-71.




UM Scientists Pinpoint Key Receptor in Celiac Disease

A study from researchers at the Center for Celiac Research at the University of Maryland School of Medicine answers a fundamental question relating to the cause of celiac disease and, possibly, other autoimmune disorders such as Type I diabetes and multiple sclerosis.

People with celiac disease must not eat foods containing gluten, a protein found in wheat.

For them, gluten triggers an autoimmune response in which the immune system attacks the body, leading to a wide spectrum of serious health problems.

The new study, published in the July 2008 issue of the journal Gastroenterology, identifies the key gluten receptor in the intestine that opens the gateway through which gluten enters the body and triggers a faulty immune response in celiac patients.

"This is a scientific question that had never been answered before," Fasano says. "It is not only significant in the basic science of autoimmune disorders such as celiac disease, but in therapeutic approaches for the future. This opens a new scientific paradigm for the study of immunity.

There are three key components of celiac disease, according to Fasano. One is genes, and researchers have already identified a number of genes that seem common among celiac patients, but none that are consistently found in all patients.

The second component is the environmental trigger that leads to the autoimmune attack. Triggers have remained elusive for all autoimmune diseases except celiac disease, in which gluten is the undisputable trigger.

The third component is a leaky gut, wherein the barrier of the intestine becomes permeable enough to allow in the offending antigen - in this case, gluten, to come through.

The findings may be significant for other autoimmune disorders as well, Fasano says. The same process may occur in patients with Type I diabetes and multiple sclerosis, in which the intestines are the port of entry or the pathway through which the offending antigens in these and other autoimmune disorders get into the body, he explains.

"For the first time, we have evidence of how the foreign antigen gains access to the body, causing the autoimmune response," according to Fasano, who is also a pediatric gastroenterologist at the University of Maryland Medical Center. "Further study is needed, but this could allow us to intervene before the zonulin is either released or activated, preventing the immune response altogether."

University of Maryland, Baltimore


Effects of fluoxetine on disease activity in relapsing multiple sclerosis: a double-blind, placebo-controlled, exploratory study

Department of Neurology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands 2 Department of Radiology, Leiden University Medical Centre, Leiden, The Netherlands 3 NeuroImaging Centre, University of Groningen, Groningen, The Netherlands

Background: Suppressing the antigen-presenting capacity of glial cells could represent a novel way of reducing inflammatory activity in multiple sclerosis (MS).

Aims: To evaluate the effects of fluoxetine on new lesion formation in patients with relapsing MS.

Conclusions: This proof-of-concept study shows that fluoxetine tends to reduce the formation of new enhancing lesions in patients with MS. Further studies with this compound are warranted.

Trial registration: Number: ISRCTN65586975

Journal of Neurology, Neurosurgery, and Psychiatry 2008;79:1027-1031
JNNP Online



Survival and cause of death in multiple sclerosis: a prospective population-based study

Helen Durham Neuro-inflammatory Centre, Department of Neurology, University Hospital of Wales, Heath Park, Cardiff, UK 2 Department of Neurology, Ninewells Hospital, Dundee, UK 3 Department of Clinical Neurosciences, University of Cambridge Clinical School, Addenbrooke’s Hospital, Cambridge, UK 4 Department of Social Medicine, Canynge Hall, University of Bristol, Bristol, UK

Background: Detailed studies of mortality in multiple sclerosis (MS) are limited. Studying death certificates in a prospective cohort of patients known to have MS is of value in establishing mortality data and can also provide important information on the accuracy and use of death certificates for epidemiological studies.

Conclusions: These results confirm a continuing trend of premature death in patients with MS. Relying on data derived from death certificates will underestimate disease prevalence. Differences were identified between those dying from MS-related causes and those dying from other causes.

JNNP Online
Published Online First: 26 February 2008. doi:10.1136/jnnp.2007.127332Journal of Neurology, Neurosurgery, and Psychiatry 2008;79:1016-1021Copyright © 2008 by the BMJ Publishing Group Ltd.



Lilly helps fund MS drug trial

EDMONTON (CP) — BioMS Medical Corp., a leading developer in the treatment of multiple sclerosis, says drug giant Eli Lilly and Co. has agreed to give it $10 million towards one of its trials after an independent drug safety board gave it the go-ahead.

The Edmonton-based company said Wednesday that the Drug Safety Monitoring Board has done its testing of the so-called Maestro-O1 trial "and has recommended that the trial continue to completion."

The trial is for patients with secondary progressive MS.

"Based on the decision, Eli Lilly and Co. has agreed to provide the $10 million milestone payment to BioMS as part of the terms of the licensing and collaboration agreement," BioMS said Wednesday.

MS is thought to affect as many as 2.5 million people, including about 75,000 in Canada.

The Chronicle Herald


Multiple sclerosis relapses: a multivariable analysis of residual disability determinants.

Department of Neuroscience, University of Turin, Italy.

Background - Recovery from multiple sclerosis (MS) relapses is variable. The factors influencing persistence of residual disability (RD) after a relapse are still to be thoroughly elucidated.

Aims of study - To assess RD after MS relapses and to define the factors associated with persistence of RD. Methods - Data were retrospectively collected for all relapses in a population of relapsing-remitting MS patients during 3 years. Relapse severity and RD after 1 year were calculated on Expanded Disability Status Scale basis. A multivariable analysis for factors influencing RD and relapse severity was performed (variables: age, gender, disease duration, oligoclonal bands, relapse severity, monosymptomatic/polysymptomatic relapse, immunomodulating treatment, incomplete recovery at 1 month).

Conclusions - Incomplete recovery at 1 month is a predictor of long-term persistence of RD. Higher relapse severity is associated with higher risk of RD. Risk of severe relapses is lower in patients treated with immunomodulating drugs.

PMID: 18684216
HighWire Press Stanford University

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