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April 28, 2008
Researchers Gather at AAN Meeting
The 60th annual meeting of the American Academy of Neurology (AAN) was held in Chicago April 12-19. Valerie Cwik, MDA medical director and vice president-research, attended the meeting. Here are some highlights
MOTOR NEURON DISEASES
ALS (Amyotrophic Lateral Sclerosis)
Principal investigator Petra Kaufmann at Columbia University Medical Center in New York, who worked with colleagues at 19 U.S. centers, reported that high-dose coenzyme Q10 (coQ10) is not promising enough to warrant further study as a treatment for ALS.
The investigators, with funding from the National Institutes of Health, tested coQ10 at dosages up to 2,700 milligrams per day against an inactive substance (placebo) in 185 people with ALS.
“The difference between the 2,700-milligram coQ10 group and the placebo group was not large enough to suggest that one would find a meaningful difference in a future phase 3 [large-scale] trial,” Kaufmann said. She added, however, that the study didn’t address the question of whether coQ10 might be helpful in combination with other drugs.
Kaufmann said the result was disappointing because they didn’t find a drug that helps people with ALS. However, she noted, it frees ALS patients from believing they have to buy coQ10, and it frees resources to test other drugs rather than conducting an expensive, phase 3 trial of coQ10.
Statins deemed safe in Israeli study
An Israeli research team that analyzed the medical records of 458 people with ALS seen in a Tel Aviv clinic over 10 years found no significant difference in survival between those taking cholesterol-lowering drugs called statins and those not taking these drugs. Statins and low serum cholesterol levels have been suspected of contributing to the development or progression of ALS. The researchers conclude that, while the role of statins as a cause or trigger for ALS needs further exploration, their evidence shows treatment of ALS patients with statins appears to be safe.
- (Note: A study by Vincent Meininger and colleagues in the March 25, 2008, issue of Neurology, suggests high blood fat levels may increase survival time in ALS.)
Shortened survival time found for Vietnam vets
An analysis of 1,085 military veterans with ALS drawn from the ongoing National Registry of Veterans with ALS has found that shortened survival time was associated with: older age at diagnosis, a site of disease onset other than the arms or legs, and past deployment to Vietnam. The investigators say the Vietnam association could be due to a common exposure or shared characteristic among these veterans or to a possible excess of Vietnam veterans compared to others who enrolled in the registry.
Pain more common in ALS than previously assumed
An Italian study of 43 people with ALS found 35 (81 percent) reported pain, with the most common types being cramps and musculoskeletal pain. The investigators say their study indicates pain may be a more common symptom in ALS than generally assumed and that it may reflect underlying neurologic abnormalities related to the disease.
Study found memory impairment, verbal fluency problems
When researchers in Ireland conducted neuropsychological tests in 32 people with ALS, they found 10 (32 percent) had impairments in memory, 27 (84 percent) had difficulties with verbal fluency, and 9 (28 percent) showed delayed recall.
Literature review shows mild thinking problems common
Dutch researchers who examined 14 studies of cognition in ALS have found memory dysfunction and mental slowness appear to be part of the “cognitive profile” of ALS. The studies included a total of 522 ALS patients who didn’t have obvious cognitive impairment (dementia). They found significantly lower than average scores on tests of global cognitive ability, immediate verbal memory, visual memory, executive functioning (decision making, planning and managing), verbal fluency and processing speed. When patients with respiratory impairment were excluded, memory scores were better.
Respiratory failure most common cause of death in French study
A French research group that studied 302 people with ALS found respiratory failure was the most frequent cause of death, accounting for 233 (77 percent) of patient deaths. Thirty people (10 percent) died from nonrespiratory causes, and 40 (13 percent) from causes that could not be precisely determined.
No benefit seen from valproic acid
Researchers in the Netherlands found no evidence of benefit from valproic acid on survival, functional status or levels of a nerve-cell protein called SMN in a trial of 163 people with ALS who were randomly assigned to take the drug or a placebo. The researchers had hypothesized that the drug might raise SMN levels and that higher SMN levels might improve survival or function.
GCSF increased cell production from bone marrow
A study of 26 ALS patients in Italy who were given granulocyte-colony stimulating factor (GCSF) in an attempt to increase production of stem cells from the bone marrow found the drug was effective in doing so and was safe and well tolerated. They say a trial comparing GCSF to a placebo will be needed to see whether the drug has benefit in ALS.
Postmortem brain analysis of stem-cell transplant found inflammation, scarring
A postmortem study of the brain of an ALS patient who underwent brain injections of stemlike cells called olfactory ensheathing cells showed inflammation, scarring, and nondescript cells along the injection track. The researchers, based in Italy, say the results suggest this type of transplantation procedure is likely not safe or effective.
People with ALS have history of higher energy expenditure
Researchers from France added to their previous report in December that people with ALS have a history of significantly greater daily energy expenditure than people without the disease. The December report included findings from 51 people with and 40 people without ALS, and this new report included 115 people with ALS and 115 unaffected people. They found daily energy expenditure was significantly higher in the ALS than in the non-ALS group every decade, starting in the 20s. The researchers hypothesize that a high activity level in people with impaired ability to regulate blood oxygen could set the stage for the type of nervous-system damage seen in ALS.
Soccer players appear to have elevated risk
Soccer players continue to show a higher than expected incidence of ALS, say researchers in Italy who previously found an increased risk of ALS in Italian professional soccer players between 1970 and 2001. They now report an extension of their study, including 7,325 soccer players, 1,973 basketball players and 1,701 bicyclists. None of the basketball players or bicyclists developed ALS, but three soccer players did, in addition to five who previously developed the disease. These researchers say their study shows ALS doesn’t appear to be related to physical activity by itself and that there may be something about soccer and/or the genetic makeup of those who become soccer players that increases the risk of developing the disease. (A recent U.S. study suggested head injury may be a factor.)
Spinal Muscular Atrophy (SMA)
Tetracycline-like compounds show promise
A multicenter U.S. group announced it has found several compounds related to the antibiotic tetracycline that can change the way cells interpret instructions from the SMN2 gene and thereby increase production of full-length SMN protein molecules. SMN protein is needed but deficient in chromosome-5 forms of spinal muscular atrophy (SMA), the most common forms of the disease. One compound, made by Paratek Pharmaceuticals, was particularly effective. The investigators concluded that tetracycline-like compounds show promise for the treatment of SMA.
Proteasome inhibitors may have potential in treating SMA
A team based at the National Institutes of Health reported that compounds known as proteasome inhibitors also have the potential to treat SMA, in this case by prolonging the presence of the small amount of full-length SMN protein made by SMA-affected cells. Proteasomes are cellular disposal systems that degrade proteins after a certain amount of time, and proteasome inhibitors interfere with this activity. The investigators said two new proteasome inhibitors, both thought to be less toxic than one already approved by the Food and Drug Administration for use in conditions other than SMA, effectively increased SMN protein levels.
Functional testing may be more sensitive measure in adult trials
A multicenter team, supported in part by MDA, found that 29 adults who have SMA and three copies of the SMN2 gene had worse scores on the SMA Functional Rating Scale than 17 patients with SMA and four SMN2 gene copies. There was no difference in the two groups on two other tests they performed. The investigators said their findings suggest the functional scale may be a better measure than others to use in clinical trials involving SMA-affected adults.
Mice with SMARD1 benefited from stem cells
A research group based in Milan, Italy, delayed disease progression and increased life span in mice with a disease known as type 1 spinal muscular atrophy with respiratory distress (SMARD1) after transplanting stem cells into their spinal cords. The investigators said they isolated stem cells from the spinal cord of an embryonic mouse and coaxed them to become motor neurons (muscle-controlling nerve cells) in the laboratory before they transplanted them. SMARD1 is caused by mutated IGHMBP2 genes, not mutated SMN genes. The researchers say their data show that this type of stem cell could represent a possible source for cell replacement therapy in patients with SMARD1 and other motor neuron diseases.
MUSCULAR DYSTROPHIES
Duchenne Muscular Dystrophy (DMD)
Becker Muscular Dystrophy (BMD)
Compressed prednisone schedule may reduce some side effects
Two days a week of the corticosteroid prednisone at a high dose appears to be almost as beneficial as a daily moderate dose of the drug in boys with Duchenne muscular dystrophy (DMD), and some side effects may be less severe, investigators reported.
The year-long, multicenter study, supported by MDA and the National Institutes of Health, was conducted by Diana Escolar at Children’s National Medical Center in Washington, with colleagues at many institutions.
The investigators analyzed data from 64 boys with DMD who were 4 to 10 years old, had not previously taken corticosteroids, and were still walking.
The boys were randomly assigned to take prednisone at 0.75 milligrams per kilogram every day, or to take prednisone at 10 milligrams per kilogram per day two days a week. Neither the boys nor the investigators knew who was on which schedule. (Boys on the two-day prednisone schedule received “dummy” pills on the no-prednisone days.)
Effects on strength maintenance were similar in the two groups, but time required to get up from the floor was better in the daily prednisone group.
Growth retardation, a known prednisone side effect, was less severe in the two-day, high-dose prednisone group, but weight gain, another serious side effect, was the same in both groups after a year.
Corticosteroid use increased from 1991 to 2005, but variability continues
An analysis of the medical records of 433 boys with DMD or BMD found the proportion of boys receiving corticosteroids (such as prednisone) in four U.S. states increased from 27 percent in 1991 to 44 percent in 2005.
The study was conducted by the Muscular Dystrophy Surveillance Tracking and Research network (MD STARnet) and funded by the Centers for Disease Control and Prevention (CDC). It examined records of boys with DMD or BMD in Arizona, Colorado, Iowa and Western New York State. The average age for starting corticosteroids was 7.4 years, and the average duration of treatment was 57 months (4.75 years).
The most common reasons for discontinuing steroids were weight gain, behavioral effects and full-time wheelchair use. The most common reasons for changing the dosage were weight gain, behavioral effects and parental request. The examiners found large variability in steroid use among states and among clinics. They plan to repeat the analysis in two years.
Pentoxifylline benefits minimal in DMD
Two studies of the drug pentoxifylline in DMD yielded somewhat disappointing results. It had been hoped that pentoxifylline might slow disease progression by increasing blood flow, reducing scar tissue formation and countering inflammation.
A multicenter study in the United States conducted by Diana Escolar at Children’s National Medical Center in Washington, with many others at different clinics, tested pentoxifylline for a year in 17 boys with DMD who were between 4 and 9 years old and hadn’t taken corticosteroids. Of 17 patients initially enrolled, only nine completed the study. Strength measurements didn’t show a significant change during the study. Five of the eight participants who withdrew did so because of intolerable side effects, such as nausea and vomiting and reduction of white blood cell numbers. The investigators said the lack of deterioration in strength in a year’s time suggests a possible beneficial effect on disease progression and warrants further study with a different formulation of pentoxifylline.
A separate DMD study conducted at centers in the United States, Italy, Canada, Israel, Australia and Argentina, tested the effect of pentoxifylline plus prednisone. Diana Escolar and many others tested this drug combination against prednisone plus a placebo in 64 boys with DMD, 57 of whom completed the study. The average age was 10. Strength measurements at one year were not significantly different between the two groups, but the pentoxifylline-treated patients had more coagulation abnormalities, skin problems and gastrointestinal side effects. The investigators concluded that pentoxifylline was well tolerated in this group but had no effect in slowing DMD disease progression compared to prednisone alone.
Twelve of 19 boys responded to ACE inhibitor treatment of heart problems
A research group that included Jerry Mendell and John Kissel, co-directors of the MDA clinic at Nationwide Children’s Hospital in Columbus, Ohio, found treatment with angiotensin converting enzyme (ACE) inhibitors reversed heart-muscle dysfunction in 12 of 19 boys with DMD or BMD, had no effect on four, and didn’t have a sustained effect in three. They say more data are required before they can make definitive recommendations about ACE inhibitors in these diseases and that cardiac magnetic resonance images (MRIs) might be better than echocardiograms in assessing DMD- and BMD-related heart dysfunction.
Dystrophin mutation analysis predicted age of onset of cardiac problems
A research team found the age of onset of cardiac problems in boys with BMD could be predicted from the location and type of mutation in the dystrophin gene. They say their analysis of 126 BMD patients identifies dystrophin mutations that predispose boys to cardiac muscle deterioration (cardiomyopathy). This analysis should allow clinicians to provide early intervention for at-risk patients. The team included John Kissel and Jerry Mendell, co-directors of the MDA clinic at Nationwide Children’s Hospital in Columbus, Ohio.
Newborn screening program met with enthusiasm
A research group found a high degree of enthusiasm for a program to screen newborn baby boys for DMD. The team implemented the pilot newborn screening program in six hospitals in the central Ohio and Cincinnati areas and tested more than 6,000 newborn boys. More than 99 percent of the 500 program participants surveyed endorsed the program. The researchers said the purpose of newborn screening is to prevent an unplanned second child with DMD; establish a registry for early intervention and for clinical trials; and to determine the incidence of DMD in the general population. The study was supported by the Centers for Disease Control and Prevention (CDC), and included Jerry Mendell, co-director of the MDA clinic at Nationwide Children’s Hospital in Columbus, Ohio.
AAV8 transported gene to heart in mice
In the search for a gene therapy treatment for heart disease associated with DMD, researchers found that a gene transporter called adeno-associated virus 8 (AAV8) successfully delivered a gene to the hearts of DMD-affected mice. The researchers said their data support developing a treatment for heart-muscle dysfunction that uses AAV8 to carry a therapeutic dystrophin gene. The research group included Jerry Mendell, co-director of the MDA clinic at Nationwide Children’s Hospital in Columbus, Ohio
Imatinib helped mmice with DMD
A group based in Cleveland found the anti-inflammatory and anti-fibrotic (anti-scar tissue) drug imatinib substantially benefited DMD-affected (dystrophin-deficient) mice. Mice treated with this drug showed less inflammation of the diaphragm and upper leg muscles, less diaphragm scarring, evidence of less leakage from damaged muscle cells, and better grip strength in their back legs than did untreated mice.
Oculopharyngeal Muscular Dystrophy (OPMD)
OPMD may contribute to sleep-disordered breathing
A group based in Long Beach, Calif., presented findings showing OPMD may contribute to sleep-disordered breathing. The researchers identified four men with OPMD ranging in age from 53 to 69 who had reported snoring and excessive daytime sleepiness. Overnight sleep studies revealed sleep apnea (periodic cessation of breathing during sleep) and periodic limb movements during sleep. The researchers said OPMD might contribute to throat-muscle dysfunction, impairing the maintenance of an open airway.
Myotonic Dystrophy (MMD)
RNA interference strategy applied to MMD1
A research group including Jerry Mendell, co-director of the MDA clinic at Nationwide Children’s Hospital in Columbus, Ohio, presented its findings that a strategy called “RNA interference” has potential in treating type 1 MMD (MMD1). The researchers tested the strategy in cells in laboratory dishes to see whether various compounds could interfere with the abnormal RNA (genetic message) for a protein called DMPK that’s present in this disease.
- They found that four out of six compounds were effective, and plan to conduct further studies. (Abnormally long RNA strands are believed to disrupt cellular processes in MMD1-affected muscle fibers.)
DHEA trial in MMD1 found no benefit
A French research group reported it found no evidence that 12 weeks of treatment with a compound called DHEA improves muscle strength in adults with MMD1. Because of earlier findings that MMD1 patients may have low levels of DHEA in their blood, this group organized a trial involving 75 people with MMD1 who were able to walk. The investigators randomly assigned them to receive either 100 milligrams per day of DHEA, 400 milligrams per day of DHEA or a placebo. There were no differences in muscle strength or any other measurements taken between the placebo group and the combined DHEA-treated groups, or between the placebo group and either of the two DHEA groups separately.
NEUROMUSCULAR JUNCTION DISEASES
Myasthenia gravis (MG)
Removing thymus in children with MG may be beneficial
A group based in Buenos Aires, Argentina, presented results showing that removal of the thymus gland may be beneficial in juvenile myasthenia gravis (MG). They studied the records of 32 patients whose diagnosis was made before the age of 18. Eight (25 percent) experienced complete remission (resolution) of their disease, four (12 percent) achieved remission but still needed to take medication, and 18 (56 percent) had “minimal manifestations” of MG. One patient worsened, and one patient died. The researchers said the observed improvements must be taken with caution because of the natural variation in the course of this disease.
Four small studies found rituximab may help in treatment-resistant MG
A group based in Barcelona, Spain, reported a dramatic improvement in six patients with MG who were given rituximab. The six patients had not improved with other drugs. There were no apparent side effects. The response was better in patients with so-called MuSK-antibody MG than in those with so-called AchR-antibody MG. (These classifications refer to the type of immune-system protein, or “antibody,” that carries out an attack at the nerve-muscle junction in this disease.)
When a group that included Rup Tandan, director of the MDA clinic at the Fletcher Allen Health Care Center in Burlington, Vt., tested rituximab in six female patients, all of whom had not responded well to other treatments, they found a trend towards improvement in muscle strength scores after rituximab treatment and “significant and continuous” improvement in scores on a scale measuring activities of daily living. They say rituximab may be beneficial in MG patients who don’t respond to other treatments.
A group that included Alan Pestronk, MDA clinic director at Washington University in St. Louis, reported successfully treating one woman with MuSK-antibody MG and one with AchR-antibody MG. Neither had responded to other forms of therapy.
A French research team also had success with rituximab in MG. This group followed five patients, four with AchR-antibody MG and one with no detectable antibodies, who had not responded to other treatments. After two years of treatment with rituximab, all patients had stopped corticosteroid medications and reduced their dose of cholinesterase inhibitor medications (two common treatments for MG). The researchers concluded that rituximab is a promising drug for the treatment of MG with an important benefit on clinical status and good tolerability.
METABOLIC MUSCLE DISEASES
Pompe disease (acid maltase deficiency) (AMD)
More rigorous screening might be needed in U.S.
A group based in Portland, Ore., that compared 10 late-onset Pompe patients with late-onset Pompe patients in the Netherlands found the U.S. patients were more severely affected. The American patients, even though they were younger on average than the Dutch group, were more likely to need assisted ventilation and were just as restricted with respect to mobility as the older group in the Netherlands. The researchers suggested increased awareness of late-onset Pompe disease in the Netherlands may promote diagnosis of less severe cases of the disease and that more rigorous screening may be needed to identify more mildly affected patients in the United States.
Myozyme may help with severe late-onset Pompe
A French study of five patients with severe late-onset Pompe disease, all of whom required a wheelchair and a ventilator, found treatment with the replacement enzyme Myozyme improved respiratory and functional measures in some people even in this severely affected group. The patients were treated for a year with Myozyme, a compound developed by Genzyme Corp. to compensate for a deficiency of the acid maltase enzyme, the underlying cause of Pompe disease. Quality of life improved in four of the five study participants.
PERIPHERAL NERVE DISEASES
Charcot-Marie-Tooth Disease (CMT)
CMT1A may worsen with passage from parent to child
An Israeli group reported that type 1A CMT, which results from a mutation on chromosome 17 that causes an excess of the PMP22 protein, appears to worsen as it’s passed from parent to child. In 21 out of 23 parent-child pairs and in 14 out of 16 families studied, there was an earlier age of symptom onset in the children than in their parents, and the average severity in the younger generation was slightly higher than in the parental generation. The researchers said they don’t know what the underlying mechanism of this phenomenon might be. |
