Multiple Sclerosis

Clinical MRI studies are typically performed with 1.5-tesla (T) magnets, though the use of 3-T systems is becoming more common. The use of ultrahigh-field-strength MRI—using 7-T magnets—remains largely the domain of major research facilities such as New York University.

Dr. Yulin Ge, a radiologist at New York University, New York, and his colleagues have been using 7-T MRI to further their understanding of the pathophysiology of multiple sclerosis.

There are two main advantages to high-field MRI over imaging with conventional field-strength magnets. The higher signal intensity-to-noise ratio (SNR) that can be achieved with a stronger magnet strength allows for greater resolution, which in turn can improve the detection of lesions. Lesion counts may be 45% greater using a 4T system with better appreciation of tissue heterogeneity within lesions as compared with a 1.5-T system.

Separately, higher field strength also boosts susceptibility effects. Magnetic susceptibility is the degree of magnetization of a material in response to an applied magnetic field. Oxyhemoglobin in arterial blood has no substantial magnetic properties, but deoxyhemoglobin, which is present in the draining veins after the oxygen has been unloaded in the tissues, is strongly paramagnetic. It can thus serve as an intrinsic paramagnetic contrast agent, the effect of which is increased with greater field strength. This in turn improves the examination of microscopic venous structures, brain iron, and microbleeds. “So venous structures can be shown very well on high-field MRI,” Dr. Ge said in an interview.

The researchers have been able to directly see small vascular abnormalities—mainly small venous structures—at a very early stage of MS. “These findings have never been shown on conventional MR,” he said. High-field MRI detects these changes before the blood-brain barrier breakdown that can be seen on conventional MRI.

The MS lesions appear to be centered on a small venule. “We can see the abnormal signals on and around the venous wall,” Dr. Ge said. “And the lesion developed along the veins—along the venous course in the initial stage of development can be clearly seen on 7T MRI.” These findings may be direct in vivo evidence of the vascular pathogenesis of lesions, he added. While it takes only 6 minutes to perform such susceptibility-sensitive imaging, slices are 2 mm thick with pixel resolution of 0.2x0.2 mm

These vascular abnormalities are “not seen in one or two lesions but in many lesions,” he said (as shown in image A). The number of lesions with vascular abnormalities that can be detected “gives you a very important indication of disease activity beyond the resolution of conventional MRI.”

Gadolinium-enhancing lesions currently are considered the first detectable MR abnormalities in MS patients. However, the fact that vascular abnormalities detected using ultrahigh-field MRI can be seen even earlier “has important implications for treatment,” said Dr. Ge.

High-field-strength MRI might allow physicians to track the early disease activity and the effectiveness of treatments. This is particularly important now that disease-modifying therapies are available.

The immunomodulatory drugs—interferon β-1a IM (Avonex), interferon β-1b SC (Betaseron) glatiramer acetate SC (Copaxone), or interferon β-1a SC (Rebif) are approved for and are currently used in the United States as first-line therapies for MS to prevent relapses or disease progression.

Newer compounds approved by the Food and Drug Administration for use in MS include mitoxantrone (Novantrone) and natalizumab (Tysabri). Last year, natalizumab was reintroduced for the treatment of relapsing forms of MS with a black box warning about the risk of progressive multifocal leukoencephalopathy associated with treatment. The drug had previously been voluntarily suspended from the market following the development of PML in three patients treated with the drug (two for MS and one for Crohn's disease).

Ultra-high-field MRI shows an intimate relationship between lesions and centered small veins (arrows), suggesting a primarily vascular pathogenesis of MS lesions. Photos courtesy Dr. Yulin Ge

Clinical MRI studies are typically performed with 1.5-tesla (T) magnets, though the use of 3-T systems is becoming more common. The use of ultrahigh-field-strength MRI—using 7-T magnets—remains largely the domain of major research facilities such as New York University.

Dr. Yulin Ge, a radiologist at New York University, New York, and his colleagues have been using 7-T MRI to further their understanding of the pathophysiology of multiple sclerosis.

There are two main advantages to high-field MRI over imaging with conventional field-strength magnets. The higher signal intensity-to-noise ratio (SNR) that can be achieved with a stronger magnet strength allows for greater resolution, which in turn can improve the detection of lesions. Lesion counts may be 45% greater using a 4T system with better appreciation of tissue heterogeneity within lesions as compared with a 1.5-T system.

Separately, higher field strength also boosts susceptibility effects. Magnetic susceptibility is the degree of magnetization of a material in response to an applied magnetic field. Oxyhemoglobin in arterial blood has no substantial magnetic properties, but deoxyhemoglobin, which is present in the draining veins after the oxygen has been unloaded in the tissues, is strongly paramagnetic. It can thus serve as an intrinsic paramagnetic contrast agent, the effect of which is increased with greater field strength. This in turn improves the examination of microscopic venous structures, brain iron, and microbleeds. “So venous structures can be shown very well on high-field MRI,” Dr. Ge said in an interview.

The researchers have been able to directly see small vascular abnormalities—mainly small venous structures—at a very early stage of MS. “These findings have never been shown on conventional MR,” he said. High-field MRI detects these changes before the blood-brain barrier breakdown that can be seen on conventional MRI.

The MS lesions appear to be centered on a small venule. “We can see the abnormal signals on and around the venous wall,” Dr. Ge said. “And the lesion developed along the veins—along the venous course in the initial stage of development can be clearly seen on 7T MRI.” These findings may be direct in vivo evidence of the vascular pathogenesis of lesions, he added. While it takes only 6 minutes to perform such susceptibility-sensitive imaging, slices are 2 mm thick with pixel resolution of 0.2x0.2 mm

These vascular abnormalities are “not seen in one or two lesions but in many lesions,” he said (as shown in image A). The number of lesions with vascular abnormalities that can be detected “gives you a very important indication of disease activity beyond the resolution of conventional MRI.”

Gadolinium-enhancing lesions currently are considered the first detectable MR abnormalities in MS patients. However, the fact that vascular abnormalities detected using ultrahigh-field MRI can be seen even earlier “has important implications for treatment,” said Dr. Ge.

High-field-strength MRI might allow physicians to track the early disease activity and the effectiveness of treatments. This is particularly important now that disease-modifying therapies are available.

The immunomodulatory drugs—interferon β-1a IM (Avonex), interferon β-1b SC (Betaseron) glatiramer acetate SC (Copaxone), or interferon β-1a SC (Rebif) are approved for and are currently used in the United States as first-line therapies for MS to prevent relapses or disease progression.

Newer compounds approved by the Food and Drug Administration for use in MS include mitoxantrone (Novantrone) and natalizumab (Tysabri). Last year, natalizumab was reintroduced for the treatment of relapsing forms of MS with a black box warning about the risk of progressive multifocal leukoencephalopathy associated with treatment. The drug had previously been voluntarily suspended from the market following the development of PML in three patients treated with the drug (two for MS and one for Crohn's disease).

Ultra-high-field MRI shows an intimate relationship between lesions and centered small veins (arrows), suggesting a primarily vascular pathogenesis of MS lesions. Photos courtesy Dr. Yulin Ge

Clinical MRI studies are typically performed with 1.5-tesla (T) magnets, though the use of 3-T systems is becoming more common. The use of ultrahigh-field-strength MRI—using 7-T magnets—remains largely the domain of major research facilities such as New York University.

Dr. Yulin Ge, a radiologist at New York University, New York, and his colleagues have been using 7-T MRI to further their understanding of the pathophysiology of multiple sclerosis.

There are two main advantages to high-field MRI over imaging with conventional field-strength magnets. The higher signal intensity-to-noise ratio (SNR) that can be achieved with a stronger magnet strength allows for greater resolution, which in turn can improve the detection of lesions. Lesion counts may be 45% greater using a 4T system with better appreciation of tissue heterogeneity within lesions as compared with a 1.5-T system.

Separately, higher field strength also boosts susceptibility effects. Magnetic susceptibility is the degree of magnetization of a material in response to an applied magnetic field. Oxyhemoglobin in arterial blood has no substantial magnetic properties, but deoxyhemoglobin, which is present in the draining veins after the oxygen has been unloaded in the tissues, is strongly paramagnetic. It can thus serve as an intrinsic paramagnetic contrast agent, the effect of which is increased with greater field strength. This in turn improves the examination of microscopic venous structures, brain iron, and microbleeds. “So venous structures can be shown very well on high-field MRI,” Dr. Ge said in an interview.

The researchers have been able to directly see small vascular abnormalities—mainly small venous structures—at a very early stage of MS. “These findings have never been shown on conventional MR,” he said. High-field MRI detects these changes before the blood-brain barrier breakdown that can be seen on conventional MRI.

The MS lesions appear to be centered on a small venule. “We can see the abnormal signals on and around the venous wall,” Dr. Ge said. “And the lesion developed along the veins—along the venous course in the initial stage of development can be clearly seen on 7T MRI.” These findings may be direct in vivo evidence of the vascular pathogenesis of lesions, he added. While it takes only 6 minutes to perform such susceptibility-sensitive imaging, slices are 2 mm thick with pixel resolution of 0.2x0.2 mm

These vascular abnormalities are “not seen in one or two lesions but in many lesions,” he said (as shown in image A). The number of lesions with vascular abnormalities that can be detected “gives you a very important indication of disease activity beyond the resolution of conventional MRI.”

Gadolinium-enhancing lesions currently are considered the first detectable MR abnormalities in MS patients. However, the fact that vascular abnormalities detected using ultrahigh-field MRI can be seen even earlier “has important implications for treatment,” said Dr. Ge.

High-field-strength MRI might allow physicians to track the early disease activity and the effectiveness of treatments. This is particularly important now that disease-modifying therapies are available.

The immunomodulatory drugs—interferon β-1a IM (Avonex), interferon β-1b SC (Betaseron) glatiramer acetate SC (Copaxone), or interferon β-1a SC (Rebif) are approved for and are currently used in the United States as first-line therapies for MS to prevent relapses or disease progression.

Newer compounds approved by the Food and Drug Administration for use in MS include mitoxantrone (Novantrone) and natalizumab (Tysabri). Last year, natalizumab was reintroduced for the treatment of relapsing forms of MS with a black box warning about the risk of progressive multifocal leukoencephalopathy associated with treatment. The drug had previously been voluntarily suspended from the market following the development of PML in three patients treated with the drug (two for MS and one for Crohn's disease).

Ultra-high-field MRI shows an intimate relationship between lesions and centered small veins (arrows), suggesting a primarily vascular pathogenesis of MS lesions. Photos courtesy Dr. Yulin Ge

SAN DIEGO — More than one-third of multiple sclerosis patients missed at least one injection of a first-line disease-modifying therapy over a 4-week period, results from a large multicenter study showed.

The most frequently reported reasons were forgetting to take the injection, not feeling like taking it, and being tired of the shot, Katherine A. Treadaway reported in a poster session at the annual meeting of the American Academy of Neurology.

The study marks the first time that adherence to all four first-line disease-modifying therapies (DMTs) approved for the management of multiple sclerosis—Avonex, Betaseron, Copaxone, and Rebif—were assessed in a multicenter patient population.

Patients who were most compliant with their medication schedule had a higher quality of life, lower rates of depression, and higher levels of hope. Neurologists “need to ask their patients if they're taking their medications and whether the medications are causing problems,” Ms. Treadaway, a licensed clinical social worker at the Multiple Sclerosis Program and Clinical Center, of the University of Texas Southwestern Medical Center at Dallas, said in an interview. “Depression might also be something neurologists can ask about, because we want people to stay on the medications.”

Ms. Treadaway and her associates at 17 sites nationwide recruited patients to participate in a Web-based survey to determine what factors influence adherence to DMT injection schedules. The survey included the Multiple Sclerosis Quality of Life-54 (MSQOL-54), the Beck Depression Inventory (BDI) Fast Screen, the Herth Hope Index, and questions about medication compliance. Study participants were surveyed at baseline, 4 weeks, and 8 weeks.

Adherence was defined as not missing an injection of a DMT in the last 4 weeks. Nonadherence was defined as missing at least one DMT injection in the last 4 weeks.

Of the 798 survey respondents, 77% were female and their median disease duration was 5 years.

Overall, more than one-third of patients were nonadherent, which remained consistent across all three time periods. Adherence rates were 61% at baseline, 63% at 4 weeks, and 64% at 8 weeks.

The top five reasons for nonadherence as reported by patients were forgetting to administer the injection (58%), not feeling like taking the injection (22%), being tired of taking the injection (16%), fatigue (12%), and inconvenience of the dosing schedule (8%). Study patients were allowed to report more than one reason for noncompliance.

Ms. Treadaway also reported that compared with adherent patients, nonadherent patients had significantly worse perceived quality of life based on the MSQOL-54, lower levels of hope based on the Herth Hope Index (39.5 vs. 38.2), and significantly higher depression scores based on the BDI Fast Screen (scores ranged from 2.5 to 3.4 on a scale of 1–21).

“I think education is a big key to keeping people on their [DMT] medications,” she commented. “If they're satisfied and they feel like it's working, they're going to be more adherent.”

Limitations of the study include its observational design and its reliance on patient self-reports, she noted.

The study was supported by an unrestricted grant from Biogen Idec Inc., which manufactures Avonex. Ms. Treadaway disclosed that she has received speaker honoraria from Biogen Idec and from Teva Neuroscience Inc., which manufactures Copaxone.

SAN DIEGO — More than one-third of multiple sclerosis patients missed at least one injection of a first-line disease-modifying therapy over a 4-week period, results from a large multicenter study showed.

The most frequently reported reasons were forgetting to take the injection, not feeling like taking it, and being tired of the shot, Katherine A. Treadaway reported in a poster session at the annual meeting of the American Academy of Neurology.

The study marks the first time that adherence to all four first-line disease-modifying therapies (DMTs) approved for the management of multiple sclerosis—Avonex, Betaseron, Copaxone, and Rebif—were assessed in a multicenter patient population.

Patients who were most compliant with their medication schedule had a higher quality of life, lower rates of depression, and higher levels of hope. Neurologists “need to ask their patients if they're taking their medications and whether the medications are causing problems,” Ms. Treadaway, a licensed clinical social worker at the Multiple Sclerosis Program and Clinical Center, of the University of Texas Southwestern Medical Center at Dallas, said in an interview. “Depression might also be something neurologists can ask about, because we want people to stay on the medications.”

Ms. Treadaway and her associates at 17 sites nationwide recruited patients to participate in a Web-based survey to determine what factors influence adherence to DMT injection schedules. The survey included the Multiple Sclerosis Quality of Life-54 (MSQOL-54), the Beck Depression Inventory (BDI) Fast Screen, the Herth Hope Index, and questions about medication compliance. Study participants were surveyed at baseline, 4 weeks, and 8 weeks.

Adherence was defined as not missing an injection of a DMT in the last 4 weeks. Nonadherence was defined as missing at least one DMT injection in the last 4 weeks.

Of the 798 survey respondents, 77% were female and their median disease duration was 5 years.

Overall, more than one-third of patients were nonadherent, which remained consistent across all three time periods. Adherence rates were 61% at baseline, 63% at 4 weeks, and 64% at 8 weeks.

The top five reasons for nonadherence as reported by patients were forgetting to administer the injection (58%), not feeling like taking the injection (22%), being tired of taking the injection (16%), fatigue (12%), and inconvenience of the dosing schedule (8%). Study patients were allowed to report more than one reason for noncompliance.

Ms. Treadaway also reported that compared with adherent patients, nonadherent patients had significantly worse perceived quality of life based on the MSQOL-54, lower levels of hope based on the Herth Hope Index (39.5 vs. 38.2), and significantly higher depression scores based on the BDI Fast Screen (scores ranged from 2.5 to 3.4 on a scale of 1–21).

“I think education is a big key to keeping people on their [DMT] medications,” she commented. “If they're satisfied and they feel like it's working, they're going to be more adherent.”

Limitations of the study include its observational design and its reliance on patient self-reports, she noted.

The study was supported by an unrestricted grant from Biogen Idec Inc., which manufactures Avonex. Ms. Treadaway disclosed that she has received speaker honoraria from Biogen Idec and from Teva Neuroscience Inc., which manufactures Copaxone.

SAN DIEGO — More than one-third of multiple sclerosis patients missed at least one injection of a first-line disease-modifying therapy over a 4-week period, results from a large multicenter study showed.

The most frequently reported reasons were forgetting to take the injection, not feeling like taking it, and being tired of the shot, Katherine A. Treadaway reported in a poster session at the annual meeting of the American Academy of Neurology.

The study marks the first time that adherence to all four first-line disease-modifying therapies (DMTs) approved for the management of multiple sclerosis—Avonex, Betaseron, Copaxone, and Rebif—were assessed in a multicenter patient population.

Patients who were most compliant with their medication schedule had a higher quality of life, lower rates of depression, and higher levels of hope. Neurologists “need to ask their patients if they're taking their medications and whether the medications are causing problems,” Ms. Treadaway, a licensed clinical social worker at the Multiple Sclerosis Program and Clinical Center, of the University of Texas Southwestern Medical Center at Dallas, said in an interview. “Depression might also be something neurologists can ask about, because we want people to stay on the medications.”

Ms. Treadaway and her associates at 17 sites nationwide recruited patients to participate in a Web-based survey to determine what factors influence adherence to DMT injection schedules. The survey included the Multiple Sclerosis Quality of Life-54 (MSQOL-54), the Beck Depression Inventory (BDI) Fast Screen, the Herth Hope Index, and questions about medication compliance. Study participants were surveyed at baseline, 4 weeks, and 8 weeks.

Adherence was defined as not missing an injection of a DMT in the last 4 weeks. Nonadherence was defined as missing at least one DMT injection in the last 4 weeks.

Of the 798 survey respondents, 77% were female and their median disease duration was 5 years.

Overall, more than one-third of patients were nonadherent, which remained consistent across all three time periods. Adherence rates were 61% at baseline, 63% at 4 weeks, and 64% at 8 weeks.

The top five reasons for nonadherence as reported by patients were forgetting to administer the injection (58%), not feeling like taking the injection (22%), being tired of taking the injection (16%), fatigue (12%), and inconvenience of the dosing schedule (8%). Study patients were allowed to report more than one reason for noncompliance.

Ms. Treadaway also reported that compared with adherent patients, nonadherent patients had significantly worse perceived quality of life based on the MSQOL-54, lower levels of hope based on the Herth Hope Index (39.5 vs. 38.2), and significantly higher depression scores based on the BDI Fast Screen (scores ranged from 2.5 to 3.4 on a scale of 1–21).

“I think education is a big key to keeping people on their [DMT] medications,” she commented. “If they're satisfied and they feel like it's working, they're going to be more adherent.”

Limitations of the study include its observational design and its reliance on patient self-reports, she noted.

The study was supported by an unrestricted grant from Biogen Idec Inc., which manufactures Avonex. Ms. Treadaway disclosed that she has received speaker honoraria from Biogen Idec and from Teva Neuroscience Inc., which manufactures Copaxone.

LOS ANGELES — There is limited risk of developing progressive multifocal leukoencephalopathy with the use of natalizumab, according to the results of a safety evaluation presented at the annual Digestive Disease Week.

Researchers from the Mayo Clinic in Rochester, Minn., and Cedars-Sinai Medical Center in Los Angeles evaluated patients who had taken the drug while participating in clinical trials of its use in treating Crohn's disease, multiple sclerosis, and rheumatoid arthritis.

Trials involving natalizumab (marketed as Tysabri) were halted in 2005 after there were two reports of patients who developed progressive multifocal leukoencephalopathy (PML) while taking combination therapy with natalizumab and interferon-β. A third report described a patient who was taking natalizumab alone and had previously taken the drug in combination with azathioprine.

Earlier this year, the FDA lifted is clinical hold on trials of the drug for multiple sclerosis. The agency has yet to announce a decision about wider marketing of the drug.

For the safety evaluation, the researchers screened participants in the two suspended studies and a completed 2004 study of multiple sclerosis. The majority of patients from the original studies participated in the safety evaluation.

No additional cases were found to have the JC virus, which has been associated with PML, according to the researchers. They found that the absolute risk of developing PML after taking natalizumab was about 0.1%.

Since only three patients developed PML, it was difficult for researchers to identify any risk factors for the rare disorder, said lead study author Dr. William Sandborn of the Mayo Clinic. Dr. Sandborn is a consultant for Elan, which jointly markets the drug with Biogen Idec. The companies funded the safety evaluation.

However, Dr. Sandborn noted that the patients who developed PML had taken natalizumab in combination with either interferon-β or azathioprine, and physicians were likely to use the drug as monotherapy until the risk factors were better understood.

It is unclear whether a screening strategy would be effective for PML, according to the researchers.

LOS ANGELES — There is limited risk of developing progressive multifocal leukoencephalopathy with the use of natalizumab, according to the results of a safety evaluation presented at the annual Digestive Disease Week.

Researchers from the Mayo Clinic in Rochester, Minn., and Cedars-Sinai Medical Center in Los Angeles evaluated patients who had taken the drug while participating in clinical trials of its use in treating Crohn's disease, multiple sclerosis, and rheumatoid arthritis.

Trials involving natalizumab (marketed as Tysabri) were halted in 2005 after there were two reports of patients who developed progressive multifocal leukoencephalopathy (PML) while taking combination therapy with natalizumab and interferon-β. A third report described a patient who was taking natalizumab alone and had previously taken the drug in combination with azathioprine.

Earlier this year, the FDA lifted is clinical hold on trials of the drug for multiple sclerosis. The agency has yet to announce a decision about wider marketing of the drug.

For the safety evaluation, the researchers screened participants in the two suspended studies and a completed 2004 study of multiple sclerosis. The majority of patients from the original studies participated in the safety evaluation.

No additional cases were found to have the JC virus, which has been associated with PML, according to the researchers. They found that the absolute risk of developing PML after taking natalizumab was about 0.1%.

Since only three patients developed PML, it was difficult for researchers to identify any risk factors for the rare disorder, said lead study author Dr. William Sandborn of the Mayo Clinic. Dr. Sandborn is a consultant for Elan, which jointly markets the drug with Biogen Idec. The companies funded the safety evaluation.

However, Dr. Sandborn noted that the patients who developed PML had taken natalizumab in combination with either interferon-β or azathioprine, and physicians were likely to use the drug as monotherapy until the risk factors were better understood.

It is unclear whether a screening strategy would be effective for PML, according to the researchers.

LOS ANGELES — There is limited risk of developing progressive multifocal leukoencephalopathy with the use of natalizumab, according to the results of a safety evaluation presented at the annual Digestive Disease Week.

Researchers from the Mayo Clinic in Rochester, Minn., and Cedars-Sinai Medical Center in Los Angeles evaluated patients who had taken the drug while participating in clinical trials of its use in treating Crohn's disease, multiple sclerosis, and rheumatoid arthritis.

Trials involving natalizumab (marketed as Tysabri) were halted in 2005 after there were two reports of patients who developed progressive multifocal leukoencephalopathy (PML) while taking combination therapy with natalizumab and interferon-β. A third report described a patient who was taking natalizumab alone and had previously taken the drug in combination with azathioprine.

Earlier this year, the FDA lifted is clinical hold on trials of the drug for multiple sclerosis. The agency has yet to announce a decision about wider marketing of the drug.

For the safety evaluation, the researchers screened participants in the two suspended studies and a completed 2004 study of multiple sclerosis. The majority of patients from the original studies participated in the safety evaluation.

No additional cases were found to have the JC virus, which has been associated with PML, according to the researchers. They found that the absolute risk of developing PML after taking natalizumab was about 0.1%.

Since only three patients developed PML, it was difficult for researchers to identify any risk factors for the rare disorder, said lead study author Dr. William Sandborn of the Mayo Clinic. Dr. Sandborn is a consultant for Elan, which jointly markets the drug with Biogen Idec. The companies funded the safety evaluation.

However, Dr. Sandborn noted that the patients who developed PML had taken natalizumab in combination with either interferon-β or azathioprine, and physicians were likely to use the drug as monotherapy until the risk factors were better understood.

It is unclear whether a screening strategy would be effective for PML, according to the researchers.

Magnetization transfer imaging (MTI) assays macromolecular protons through their intimate connection and interaction with surrounding tissue water.

“Anywhere it's applied, MTI is very sensitive to macromolecular makeup of the tissue,” said Seth Smith, Ph.D., a postdoctoral fellow at the F.M. Kirby Imaging Center at Johns Hopkins University in Baltimore. In the case of patients with multiple sclerosis (MS), this means myelin. “MTI is a much more sensitive myelin marker than any other conventional imaging technique,” he said.

Conventional MRI targets only water, making it hard to assess the macromolecular subunits of CNS tissue, like myelin. With MTI, an initial off-resonance radiofrequency pulse is applied to the spinal column. This pulse selectively saturates the magnetization of protons attached to such macromolecules as myelin. Some of this magnetization is transferred to free protons in tissue, which reduces the intensity of the observed water signal. Since MT's effect depends on the density of macromolecules in the tissue, “it's a backdoor method for getting at the macromolecular structure,” said Dr. Smith.

The researchers then calculate a slightly modified magnetization transfer ratio, based on the difference in the signal intensity with and without an MT prepulse, to quantify differences between patients with MS and healthy controls.

In the past, it was difficult to ascertain whether or not spinal cord lesions were a significant factor in MS. Conventional MR imaging did not reveal the amount of tissue damage that was actually present in the spinal cord, though inflammation can be seen. MTI reveals much more MS pathology. It is now hypothesized that a lot of the clinical deficit in MS arises from spinal cord damage. “When we use MT imaging, what we find is that every cord [from patients with MS] is damaged in some way,” said Dr. Smith.

The presence of MS spinal lesions on MTI correlates better with the patient's symptoms at presentation than does the presence of brain lesions detected by MRI. A patient with MS brain lesions may be walking at presentation. However, “if I look at the spinal cord and see a bunch of lesions, I can guarantee that the patient is not walking well,” said Dr. Smith.

The researchers have imaged patients of varying ages and at a spectrum of stages in MS: relapsing-remitting, secondary progressive, etc. Since it is difficult to get a patient before he or she has had an attack, information from such studies about the early stages of the disease may prove useful, said Dr. Smith. The researchers also are imaging MS patients periodically (3, 6, 12, and 24 months) to see if they can detect changes in the disease over time.

The researchers are seeking links between MS-induced changes on spinal MTI and brain MTI and the neurologic presentation of patients with MS. The correlation between spinal MTI and the neurologic presentation has been striking.

“We and others find in the brain there is little correlation with clinical presentation. However, the second we look at the spine, everything starts to correlate,” said Dr. Smith. The spine is the main pipeline for nerves in the body, so “if you get a small lesion in something the size of a quarter, the effects could be massive.”

MRI is used to confirm the clinical findings in patients suspected of MS. “We're hoping to make MTI more of a diagnostic tool,” Dr. Smith said. A strong enough correlation between MTI spinal imaging findings and the neurologic presentation could lead to the primary use of MRI to diagnose MS and predict outcome.

MTI also has implications for therapy. Right now, patients with MS often are treated with axonal protection agents, but the effects may take a long time to be seen. “What we hope to see is, can we within a shorter amount of time see that there is any sort of change in the tissue due to therapeutic intervention,” said Dr. Smith.

MTI scans can be done with most higher field MRI scanners using a surface/spine coil and each scan takes only 7 minutes using a 3T magnet. This implies that the technique could easily be integrated into an imaging center or hospital radiology department.

Dr. Smith's collaborators include Dr. Peter Calabresi; Peter van Zijl, Ph.D.; Craig Jones, Ph.D.; Eliza Gordon-Lipkin; and Kathleen Zackowski, Ph.D.

Healthy spine by T2 and T1 3T MRI and MTCSF (top): While T2 and T1 MRI show slight cord atrophy in an MS patient, MTCSF shows hyperintensities in the lateral (green arrow) and dorsal (yellow arrow) column (bottom). Images courtesy Dr. Seth Smith

Magnetization transfer imaging (MTI) assays macromolecular protons through their intimate connection and interaction with surrounding tissue water.

“Anywhere it's applied, MTI is very sensitive to macromolecular makeup of the tissue,” said Seth Smith, Ph.D., a postdoctoral fellow at the F.M. Kirby Imaging Center at Johns Hopkins University in Baltimore. In the case of patients with multiple sclerosis (MS), this means myelin. “MTI is a much more sensitive myelin marker than any other conventional imaging technique,” he said.

Conventional MRI targets only water, making it hard to assess the macromolecular subunits of CNS tissue, like myelin. With MTI, an initial off-resonance radiofrequency pulse is applied to the spinal column. This pulse selectively saturates the magnetization of protons attached to such macromolecules as myelin. Some of this magnetization is transferred to free protons in tissue, which reduces the intensity of the observed water signal. Since MT's effect depends on the density of macromolecules in the tissue, “it's a backdoor method for getting at the macromolecular structure,” said Dr. Smith.

The researchers then calculate a slightly modified magnetization transfer ratio, based on the difference in the signal intensity with and without an MT prepulse, to quantify differences between patients with MS and healthy controls.

In the past, it was difficult to ascertain whether or not spinal cord lesions were a significant factor in MS. Conventional MR imaging did not reveal the amount of tissue damage that was actually present in the spinal cord, though inflammation can be seen. MTI reveals much more MS pathology. It is now hypothesized that a lot of the clinical deficit in MS arises from spinal cord damage. “When we use MT imaging, what we find is that every cord [from patients with MS] is damaged in some way,” said Dr. Smith.

The presence of MS spinal lesions on MTI correlates better with the patient's symptoms at presentation than does the presence of brain lesions detected by MRI. A patient with MS brain lesions may be walking at presentation. However, “if I look at the spinal cord and see a bunch of lesions, I can guarantee that the patient is not walking well,” said Dr. Smith.

The researchers have imaged patients of varying ages and at a spectrum of stages in MS: relapsing-remitting, secondary progressive, etc. Since it is difficult to get a patient before he or she has had an attack, information from such studies about the early stages of the disease may prove useful, said Dr. Smith. The researchers also are imaging MS patients periodically (3, 6, 12, and 24 months) to see if they can detect changes in the disease over time.

The researchers are seeking links between MS-induced changes on spinal MTI and brain MTI and the neurologic presentation of patients with MS. The correlation between spinal MTI and the neurologic presentation has been striking.

“We and others find in the brain there is little correlation with clinical presentation. However, the second we look at the spine, everything starts to correlate,” said Dr. Smith. The spine is the main pipeline for nerves in the body, so “if you get a small lesion in something the size of a quarter, the effects could be massive.”

MRI is used to confirm the clinical findings in patients suspected of MS. “We're hoping to make MTI more of a diagnostic tool,” Dr. Smith said. A strong enough correlation between MTI spinal imaging findings and the neurologic presentation could lead to the primary use of MRI to diagnose MS and predict outcome.

MTI also has implications for therapy. Right now, patients with MS often are treated with axonal protection agents, but the effects may take a long time to be seen. “What we hope to see is, can we within a shorter amount of time see that there is any sort of change in the tissue due to therapeutic intervention,” said Dr. Smith.

MTI scans can be done with most higher field MRI scanners using a surface/spine coil and each scan takes only 7 minutes using a 3T magnet. This implies that the technique could easily be integrated into an imaging center or hospital radiology department.

Dr. Smith's collaborators include Dr. Peter Calabresi; Peter van Zijl, Ph.D.; Craig Jones, Ph.D.; Eliza Gordon-Lipkin; and Kathleen Zackowski, Ph.D.

Healthy spine by T2 and T1 3T MRI and MTCSF (top): While T2 and T1 MRI show slight cord atrophy in an MS patient, MTCSF shows hyperintensities in the lateral (green arrow) and dorsal (yellow arrow) column (bottom). Images courtesy Dr. Seth Smith

Magnetization transfer imaging (MTI) assays macromolecular protons through their intimate connection and interaction with surrounding tissue water.

“Anywhere it's applied, MTI is very sensitive to macromolecular makeup of the tissue,” said Seth Smith, Ph.D., a postdoctoral fellow at the F.M. Kirby Imaging Center at Johns Hopkins University in Baltimore. In the case of patients with multiple sclerosis (MS), this means myelin. “MTI is a much more sensitive myelin marker than any other conventional imaging technique,” he said.

Conventional MRI targets only water, making it hard to assess the macromolecular subunits of CNS tissue, like myelin. With MTI, an initial off-resonance radiofrequency pulse is applied to the spinal column. This pulse selectively saturates the magnetization of protons attached to such macromolecules as myelin. Some of this magnetization is transferred to free protons in tissue, which reduces the intensity of the observed water signal. Since MT's effect depends on the density of macromolecules in the tissue, “it's a backdoor method for getting at the macromolecular structure,” said Dr. Smith.

The researchers then calculate a slightly modified magnetization transfer ratio, based on the difference in the signal intensity with and without an MT prepulse, to quantify differences between patients with MS and healthy controls.

In the past, it was difficult to ascertain whether or not spinal cord lesions were a significant factor in MS. Conventional MR imaging did not reveal the amount of tissue damage that was actually present in the spinal cord, though inflammation can be seen. MTI reveals much more MS pathology. It is now hypothesized that a lot of the clinical deficit in MS arises from spinal cord damage. “When we use MT imaging, what we find is that every cord [from patients with MS] is damaged in some way,” said Dr. Smith.

The presence of MS spinal lesions on MTI correlates better with the patient's symptoms at presentation than does the presence of brain lesions detected by MRI. A patient with MS brain lesions may be walking at presentation. However, “if I look at the spinal cord and see a bunch of lesions, I can guarantee that the patient is not walking well,” said Dr. Smith.

The researchers have imaged patients of varying ages and at a spectrum of stages in MS: relapsing-remitting, secondary progressive, etc. Since it is difficult to get a patient before he or she has had an attack, information from such studies about the early stages of the disease may prove useful, said Dr. Smith. The researchers also are imaging MS patients periodically (3, 6, 12, and 24 months) to see if they can detect changes in the disease over time.

The researchers are seeking links between MS-induced changes on spinal MTI and brain MTI and the neurologic presentation of patients with MS. The correlation between spinal MTI and the neurologic presentation has been striking.

“We and others find in the brain there is little correlation with clinical presentation. However, the second we look at the spine, everything starts to correlate,” said Dr. Smith. The spine is the main pipeline for nerves in the body, so “if you get a small lesion in something the size of a quarter, the effects could be massive.”

MRI is used to confirm the clinical findings in patients suspected of MS. “We're hoping to make MTI more of a diagnostic tool,” Dr. Smith said. A strong enough correlation between MTI spinal imaging findings and the neurologic presentation could lead to the primary use of MRI to diagnose MS and predict outcome.

MTI also has implications for therapy. Right now, patients with MS often are treated with axonal protection agents, but the effects may take a long time to be seen. “What we hope to see is, can we within a shorter amount of time see that there is any sort of change in the tissue due to therapeutic intervention,” said Dr. Smith.

MTI scans can be done with most higher field MRI scanners using a surface/spine coil and each scan takes only 7 minutes using a 3T magnet. This implies that the technique could easily be integrated into an imaging center or hospital radiology department.

Dr. Smith's collaborators include Dr. Peter Calabresi; Peter van Zijl, Ph.D.; Craig Jones, Ph.D.; Eliza Gordon-Lipkin; and Kathleen Zackowski, Ph.D.

Healthy spine by T2 and T1 3T MRI and MTCSF (top): While T2 and T1 MRI show slight cord atrophy in an MS patient, MTCSF shows hyperintensities in the lateral (green arrow) and dorsal (yellow arrow) column (bottom). Images courtesy Dr. Seth Smith

SAN DIEGO — A very large genetic linkage study has pinpointed the major histocompatibility complex on the short arm of chromosome 6 as the key genetic player in multiple sclerosis.

The study is not the first to implicate the major histocompatibility complex (MHC), a cluster of genes critical to the recognition of the body's own cells as “self.”

However, this study is the largest and most definitive to date, and its findings call into question data from smaller studies that suggested critical roles for other genetic regions.

Jonathan Haines, Ph.D., of Vanderbilt University, Nashville, Tenn., presented the findings on behalf of the International Multiple Sclerosis Genetics Consortium.

The team typed 4,506 single nucleotide polymorphism markers in 730 families who had more than one family member with multiple sclerosis.

Subjects were from Australia, Scandinavia, the United Kingdom, and the United States. Genes from 945 pairs of relatives were studied for genetic linkages.

“Highly significant linkage is observed in the region of the MJC ([linkage analysis] logarithm of the odds score 11.7), and suggestive linkage is found on chromosomes 17 and 5,” Dr. Haines stated in a poster presented at the annual meeting of the American Neurological Association.

An ordered subset analysis identified a further locus on chromosome 19.

The mean information extraction from the marker panel is 80%, with a range of 42%–91%, Dr. Haines reported.

Observed Mendelian inconsistencies suggest that within the data set, the genotyping error rate was just 0.002%.

“Our results confirm the strong role of the major histocompatibility complex genes in MS, and provide a definitive statement that no other region of the genome harbors a gene with a similar overall influence on MS genetics,” Dr. Haines said in a statement released at the meeting.

“Other genes may still play an important role in MS but finding them will require using new genomic techniques,” he added.

Dr. Haines said the findings have “profound implications for the future directions of multiple sclerosis genetics research and suggest that previous efforts in this area are almost all substantially underpowered.”

Future association studies should include at least 500–1,000 cases of multiple sclerosis to be considered reliable, he said.

SAN DIEGO — A very large genetic linkage study has pinpointed the major histocompatibility complex on the short arm of chromosome 6 as the key genetic player in multiple sclerosis.

The study is not the first to implicate the major histocompatibility complex (MHC), a cluster of genes critical to the recognition of the body's own cells as “self.”

However, this study is the largest and most definitive to date, and its findings call into question data from smaller studies that suggested critical roles for other genetic regions.

Jonathan Haines, Ph.D., of Vanderbilt University, Nashville, Tenn., presented the findings on behalf of the International Multiple Sclerosis Genetics Consortium.

The team typed 4,506 single nucleotide polymorphism markers in 730 families who had more than one family member with multiple sclerosis.

Subjects were from Australia, Scandinavia, the United Kingdom, and the United States. Genes from 945 pairs of relatives were studied for genetic linkages.

“Highly significant linkage is observed in the region of the MJC ([linkage analysis] logarithm of the odds score 11.7), and suggestive linkage is found on chromosomes 17 and 5,” Dr. Haines stated in a poster presented at the annual meeting of the American Neurological Association.

An ordered subset analysis identified a further locus on chromosome 19.

The mean information extraction from the marker panel is 80%, with a range of 42%–91%, Dr. Haines reported.

Observed Mendelian inconsistencies suggest that within the data set, the genotyping error rate was just 0.002%.

“Our results confirm the strong role of the major histocompatibility complex genes in MS, and provide a definitive statement that no other region of the genome harbors a gene with a similar overall influence on MS genetics,” Dr. Haines said in a statement released at the meeting.

“Other genes may still play an important role in MS but finding them will require using new genomic techniques,” he added.

Dr. Haines said the findings have “profound implications for the future directions of multiple sclerosis genetics research and suggest that previous efforts in this area are almost all substantially underpowered.”

Future association studies should include at least 500–1,000 cases of multiple sclerosis to be considered reliable, he said.

SAN DIEGO — A very large genetic linkage study has pinpointed the major histocompatibility complex on the short arm of chromosome 6 as the key genetic player in multiple sclerosis.

The study is not the first to implicate the major histocompatibility complex (MHC), a cluster of genes critical to the recognition of the body's own cells as “self.”

However, this study is the largest and most definitive to date, and its findings call into question data from smaller studies that suggested critical roles for other genetic regions.

Jonathan Haines, Ph.D., of Vanderbilt University, Nashville, Tenn., presented the findings on behalf of the International Multiple Sclerosis Genetics Consortium.

The team typed 4,506 single nucleotide polymorphism markers in 730 families who had more than one family member with multiple sclerosis.

Subjects were from Australia, Scandinavia, the United Kingdom, and the United States. Genes from 945 pairs of relatives were studied for genetic linkages.

“Highly significant linkage is observed in the region of the MJC ([linkage analysis] logarithm of the odds score 11.7), and suggestive linkage is found on chromosomes 17 and 5,” Dr. Haines stated in a poster presented at the annual meeting of the American Neurological Association.

An ordered subset analysis identified a further locus on chromosome 19.

The mean information extraction from the marker panel is 80%, with a range of 42%–91%, Dr. Haines reported.

Observed Mendelian inconsistencies suggest that within the data set, the genotyping error rate was just 0.002%.

“Our results confirm the strong role of the major histocompatibility complex genes in MS, and provide a definitive statement that no other region of the genome harbors a gene with a similar overall influence on MS genetics,” Dr. Haines said in a statement released at the meeting.

“Other genes may still play an important role in MS but finding them will require using new genomic techniques,” he added.

Dr. Haines said the findings have “profound implications for the future directions of multiple sclerosis genetics research and suggest that previous efforts in this area are almost all substantially underpowered.”

Future association studies should include at least 500–1,000 cases of multiple sclerosis to be considered reliable, he said.

SAN DIEGO — Pulsed, intrathecal methotrexate was safe and well-tolerated in patients with primary progressive or secondary progressive multiple sclerosis, and appears to have stabilized their disease in a small, open-label, phase I tolerability and safety study that followed patients only 2 years, Saud A. Sadiq, M.D., reported at the annual meeting of the American Neurological Association.

Dr. Sadiq, director of the Multiple Sclerosis Research and Treatment Center at St. Luke's Roosevelt Hospital Center in New York, said that a larger, longer study would be needed to confirm the usefulness of intrathecal methotrexate in this notoriously difficult-to-treat population.

Nonetheless, his poster detailing the treatment in 126 patients drew considerable interest at the meeting, where clinicians expressed hope that the therapy might represent an alternative for these two groups of patients who currently have very few treatment options.

To be eligible for the study, patients had to have undergone treatment with at least three FDA-approved, disease-modifying drugs for multiple sclerosis (MS) for at least 1 year. Despite this therapy, eligible patients still had active disease with continued relapses, worsening Expanded Disability Status Scale (EDSS) scores, or increased disease burden seen on MRI.

Exclusion criteria included known allergy to methotrexate, pregnancy, active infection, or a significant associated medical condition such as heart disease. Patients ranged in age from 30 to 74 years. Females outnumbered males, 87 to 39. There were 91 patients with secondary progressive MS and 35 patients with primary progressive MS. Their baseline EDSS scores ranged from 3.0 to 9.0.

Preservative-free methotrexate was administered at a dose of 12 mg every 2 months, either via lumbar puncture with a 24− or 25-gauge needle (91 patients), or through the access port of a surgically implanted Medtronic pump that patients had received for spasticity control (35 patients). Each injection was followed by injection of 3 cc of the patient's previously drawn cerebrospinal fluid (CSF) to ensure that the drug entered the CSF and there was no dead-space loss.

Brain MRI studies were performed in 50 randomly selected patients both before and after at least four treatment cycles. After methotrexate treatment, disease stabilized in 32 of 39 patients with secondary progressive MS and 9 of 11 patients with primary progressive MS.

In the total cohort, improved or stabilized EDSS scores were noted in 85 of 91 patients with secondary progressive MS and 32 of 35 patients with primary progressive MS. Quality of life scores improved (57 patients) or remained unchanged (23 patients) in patients with secondary progressive MS, while just 11 reported a decreased quality of life at the end of the 2-year study.

Among patients with primary progressive MS, 14 patients improved, 15 patients remained the same, and 6 patients had decreased quality of life scores.

Laboratory studies using mouse stem cells and CSF from a study patient and an MS patient not receiving methotrexate showed that the drug appeared to have no effect on oligodendroglial or neuronal cell development, but that it inhibited astroglial proliferation, key to sclerosis formation.

Dr. Sadiq said the findings suggest a possible mechanism of action.

Patients generally tolerated the drug well. No drug-related deaths occurred (a 74-year-old patient died of a myocardial infarction). There were no cases of meningitis or serious infection, CNS tumors, or lymphomas.

Patients reported transient fatigue after 34 of a total of 489 treatments. Mild leucopenia was seen in two patients. Postspinal headache was reported after nine treatments, and vomiting was reported after one. One patient had shingles.

A total of 21 patients discontinued treatment, most citing a lack of effect after two or three treatments. No patient dropped out of the trial due to adverse effects.

“In patients that we selected for this study … disease course is inexorably progressive, with definite decline in function every few months. Stability in this population is very exciting,” said Dr. Sadiq following the meeting.

“Obviously, the longer this can go on, the better. To date, no patients who appeared to have an initial favorable response appear to have subsequently declined.”

To be sure, “other studies verifying efficacy for a longer term are needed,” he said.

A randomized, controlled study is planned that will compare intrathecal methotrexate with intravenous pulsed Cytoxan, according to Dr. Sadiq, who serves on the neurology faculty at the Albert Einstein College of Medicine, New York.

No pharmaceutical company support was used to fund Dr. Sadiq's study.

SAN DIEGO — Pulsed, intrathecal methotrexate was safe and well-tolerated in patients with primary progressive or secondary progressive multiple sclerosis, and appears to have stabilized their disease in a small, open-label, phase I tolerability and safety study that followed patients only 2 years, Saud A. Sadiq, M.D., reported at the annual meeting of the American Neurological Association.

Dr. Sadiq, director of the Multiple Sclerosis Research and Treatment Center at St. Luke's Roosevelt Hospital Center in New York, said that a larger, longer study would be needed to confirm the usefulness of intrathecal methotrexate in this notoriously difficult-to-treat population.

Nonetheless, his poster detailing the treatment in 126 patients drew considerable interest at the meeting, where clinicians expressed hope that the therapy might represent an alternative for these two groups of patients who currently have very few treatment options.

To be eligible for the study, patients had to have undergone treatment with at least three FDA-approved, disease-modifying drugs for multiple sclerosis (MS) for at least 1 year. Despite this therapy, eligible patients still had active disease with continued relapses, worsening Expanded Disability Status Scale (EDSS) scores, or increased disease burden seen on MRI.

Exclusion criteria included known allergy to methotrexate, pregnancy, active infection, or a significant associated medical condition such as heart disease. Patients ranged in age from 30 to 74 years. Females outnumbered males, 87 to 39. There were 91 patients with secondary progressive MS and 35 patients with primary progressive MS. Their baseline EDSS scores ranged from 3.0 to 9.0.

Preservative-free methotrexate was administered at a dose of 12 mg every 2 months, either via lumbar puncture with a 24− or 25-gauge needle (91 patients), or through the access port of a surgically implanted Medtronic pump that patients had received for spasticity control (35 patients). Each injection was followed by injection of 3 cc of the patient's previously drawn cerebrospinal fluid (CSF) to ensure that the drug entered the CSF and there was no dead-space loss.

Brain MRI studies were performed in 50 randomly selected patients both before and after at least four treatment cycles. After methotrexate treatment, disease stabilized in 32 of 39 patients with secondary progressive MS and 9 of 11 patients with primary progressive MS.

In the total cohort, improved or stabilized EDSS scores were noted in 85 of 91 patients with secondary progressive MS and 32 of 35 patients with primary progressive MS. Quality of life scores improved (57 patients) or remained unchanged (23 patients) in patients with secondary progressive MS, while just 11 reported a decreased quality of life at the end of the 2-year study.

Among patients with primary progressive MS, 14 patients improved, 15 patients remained the same, and 6 patients had decreased quality of life scores.

Laboratory studies using mouse stem cells and CSF from a study patient and an MS patient not receiving methotrexate showed that the drug appeared to have no effect on oligodendroglial or neuronal cell development, but that it inhibited astroglial proliferation, key to sclerosis formation.

Dr. Sadiq said the findings suggest a possible mechanism of action.

Patients generally tolerated the drug well. No drug-related deaths occurred (a 74-year-old patient died of a myocardial infarction). There were no cases of meningitis or serious infection, CNS tumors, or lymphomas.

Patients reported transient fatigue after 34 of a total of 489 treatments. Mild leucopenia was seen in two patients. Postspinal headache was reported after nine treatments, and vomiting was reported after one. One patient had shingles.

A total of 21 patients discontinued treatment, most citing a lack of effect after two or three treatments. No patient dropped out of the trial due to adverse effects.

“In patients that we selected for this study … disease course is inexorably progressive, with definite decline in function every few months. Stability in this population is very exciting,” said Dr. Sadiq following the meeting.

“Obviously, the longer this can go on, the better. To date, no patients who appeared to have an initial favorable response appear to have subsequently declined.”

To be sure, “other studies verifying efficacy for a longer term are needed,” he said.

A randomized, controlled study is planned that will compare intrathecal methotrexate with intravenous pulsed Cytoxan, according to Dr. Sadiq, who serves on the neurology faculty at the Albert Einstein College of Medicine, New York.

No pharmaceutical company support was used to fund Dr. Sadiq's study.

SAN DIEGO — Pulsed, intrathecal methotrexate was safe and well-tolerated in patients with primary progressive or secondary progressive multiple sclerosis, and appears to have stabilized their disease in a small, open-label, phase I tolerability and safety study that followed patients only 2 years, Saud A. Sadiq, M.D., reported at the annual meeting of the American Neurological Association.

Dr. Sadiq, director of the Multiple Sclerosis Research and Treatment Center at St. Luke's Roosevelt Hospital Center in New York, said that a larger, longer study would be needed to confirm the usefulness of intrathecal methotrexate in this notoriously difficult-to-treat population.

Nonetheless, his poster detailing the treatment in 126 patients drew considerable interest at the meeting, where clinicians expressed hope that the therapy might represent an alternative for these two groups of patients who currently have very few treatment options.

To be eligible for the study, patients had to have undergone treatment with at least three FDA-approved, disease-modifying drugs for multiple sclerosis (MS) for at least 1 year. Despite this therapy, eligible patients still had active disease with continued relapses, worsening Expanded Disability Status Scale (EDSS) scores, or increased disease burden seen on MRI.

Exclusion criteria included known allergy to methotrexate, pregnancy, active infection, or a significant associated medical condition such as heart disease. Patients ranged in age from 30 to 74 years. Females outnumbered males, 87 to 39. There were 91 patients with secondary progressive MS and 35 patients with primary progressive MS. Their baseline EDSS scores ranged from 3.0 to 9.0.

Preservative-free methotrexate was administered at a dose of 12 mg every 2 months, either via lumbar puncture with a 24− or 25-gauge needle (91 patients), or through the access port of a surgically implanted Medtronic pump that patients had received for spasticity control (35 patients). Each injection was followed by injection of 3 cc of the patient's previously drawn cerebrospinal fluid (CSF) to ensure that the drug entered the CSF and there was no dead-space loss.

Brain MRI studies were performed in 50 randomly selected patients both before and after at least four treatment cycles. After methotrexate treatment, disease stabilized in 32 of 39 patients with secondary progressive MS and 9 of 11 patients with primary progressive MS.

In the total cohort, improved or stabilized EDSS scores were noted in 85 of 91 patients with secondary progressive MS and 32 of 35 patients with primary progressive MS. Quality of life scores improved (57 patients) or remained unchanged (23 patients) in patients with secondary progressive MS, while just 11 reported a decreased quality of life at the end of the 2-year study.

Among patients with primary progressive MS, 14 patients improved, 15 patients remained the same, and 6 patients had decreased quality of life scores.

Laboratory studies using mouse stem cells and CSF from a study patient and an MS patient not receiving methotrexate showed that the drug appeared to have no effect on oligodendroglial or neuronal cell development, but that it inhibited astroglial proliferation, key to sclerosis formation.

Dr. Sadiq said the findings suggest a possible mechanism of action.

Patients generally tolerated the drug well. No drug-related deaths occurred (a 74-year-old patient died of a myocardial infarction). There were no cases of meningitis or serious infection, CNS tumors, or lymphomas.

Patients reported transient fatigue after 34 of a total of 489 treatments. Mild leucopenia was seen in two patients. Postspinal headache was reported after nine treatments, and vomiting was reported after one. One patient had shingles.

A total of 21 patients discontinued treatment, most citing a lack of effect after two or three treatments. No patient dropped out of the trial due to adverse effects.

“In patients that we selected for this study … disease course is inexorably progressive, with definite decline in function every few months. Stability in this population is very exciting,” said Dr. Sadiq following the meeting.

“Obviously, the longer this can go on, the better. To date, no patients who appeared to have an initial favorable response appear to have subsequently declined.”

To be sure, “other studies verifying efficacy for a longer term are needed,” he said.

A randomized, controlled study is planned that will compare intrathecal methotrexate with intravenous pulsed Cytoxan, according to Dr. Sadiq, who serves on the neurology faculty at the Albert Einstein College of Medicine, New York.

No pharmaceutical company support was used to fund Dr. Sadiq's study.

CLEVELAND — Treatment with a tumor necrosis factor-α inhibitor may trigger a demyelinating polyneuropathy with Guillain-Barré-like symptoms, according to MaryAnn Mays, M.D., of the Cleveland Clinic Foundation.

The case in point, presented in a poster at a symposium on the treatment of autoimmune and inflammatory disorders sponsored by the clinic, was that of a 56-year-old man with seropositive rheumatoid arthritis who became severely disabled after infliximab infusions were added to his methotrexate therapy.

Dr. Mays, a neurologist, said in an interview that following his first anti-TNF treatment in 2002, the patient's rheumatoid arthritis symptoms lessened dramatically, but following an infusion in late 2003, he had dizziness and hearing loss for a week. The symptoms recurred and lasted longer following a third infusion 2 months later.

The next infliximab infusion in April 2004 produced worsening neurologic symptoms, including blurred vision, headaches, dysarthria, hearing loss, ataxia, dysphagia requiring percutaneous endoscopic gastrostomy for nutrition, and progressive weakness, according to Dr. Mays.

“Initial evaluation included cerebrospinal fluid WBC of 123, protein 79, and electromyograph consistent with demyelinating polyneuropathy. But the overall pattern was not typical of Guillain-Barré syndrome [GBS],” Dr. Mays said. “He had high white count and normal protein. Auditory evoked potentials showed a right central conduction disturbance. His detrusor urinae muscle were unresponsive, which is typical of GBS. His right Babinski sign was atypical of GBS.”

Feyrouz Al-Ashkar, M.D., the lead investigator and a rheumatologist, noted in an interview that by the time the patient was brought to the clinic, he “could not walk, use his hands, lift his head, or feed himself, although he could still breathe on his own.”

“He received intravenous immunoglobulin [IVIg] and steroids before we saw him. When he got here, he again received intravenous steroids and another course of intravenous immunoglobulin, and slowly but surely, he recovered completely,” Dr. Al-Ashkar said.

Dr. Mays noted that the patient's response to IVIg supports the diagnosis of a demyelinating polyneuropathy other than GBS.”

Dr. Al-Ashkar said that the onset of neurologic deficits or demyelinating diseases in patients on infliximab is a red flag to stop TNF blockade. “In such cases, our experience would suggest that there is potential for worsening of neurologic deficits with each infliximab treatment, and that continuing treatments after onset of neurologic symptoms would be relatively contraindicated,” according to the poster.

CLEVELAND — Treatment with a tumor necrosis factor-α inhibitor may trigger a demyelinating polyneuropathy with Guillain-Barré-like symptoms, according to MaryAnn Mays, M.D., of the Cleveland Clinic Foundation.

The case in point, presented in a poster at a symposium on the treatment of autoimmune and inflammatory disorders sponsored by the clinic, was that of a 56-year-old man with seropositive rheumatoid arthritis who became severely disabled after infliximab infusions were added to his methotrexate therapy.

Dr. Mays, a neurologist, said in an interview that following his first anti-TNF treatment in 2002, the patient's rheumatoid arthritis symptoms lessened dramatically, but following an infusion in late 2003, he had dizziness and hearing loss for a week. The symptoms recurred and lasted longer following a third infusion 2 months later.

The next infliximab infusion in April 2004 produced worsening neurologic symptoms, including blurred vision, headaches, dysarthria, hearing loss, ataxia, dysphagia requiring percutaneous endoscopic gastrostomy for nutrition, and progressive weakness, according to Dr. Mays.

“Initial evaluation included cerebrospinal fluid WBC of 123, protein 79, and electromyograph consistent with demyelinating polyneuropathy. But the overall pattern was not typical of Guillain-Barré syndrome [GBS],” Dr. Mays said. “He had high white count and normal protein. Auditory evoked potentials showed a right central conduction disturbance. His detrusor urinae muscle were unresponsive, which is typical of GBS. His right Babinski sign was atypical of GBS.”

Feyrouz Al-Ashkar, M.D., the lead investigator and a rheumatologist, noted in an interview that by the time the patient was brought to the clinic, he “could not walk, use his hands, lift his head, or feed himself, although he could still breathe on his own.”

“He received intravenous immunoglobulin [IVIg] and steroids before we saw him. When he got here, he again received intravenous steroids and another course of intravenous immunoglobulin, and slowly but surely, he recovered completely,” Dr. Al-Ashkar said.

Dr. Mays noted that the patient's response to IVIg supports the diagnosis of a demyelinating polyneuropathy other than GBS.”

Dr. Al-Ashkar said that the onset of neurologic deficits or demyelinating diseases in patients on infliximab is a red flag to stop TNF blockade. “In such cases, our experience would suggest that there is potential for worsening of neurologic deficits with each infliximab treatment, and that continuing treatments after onset of neurologic symptoms would be relatively contraindicated,” according to the poster.

CLEVELAND — Treatment with a tumor necrosis factor-α inhibitor may trigger a demyelinating polyneuropathy with Guillain-Barré-like symptoms, according to MaryAnn Mays, M.D., of the Cleveland Clinic Foundation.

The case in point, presented in a poster at a symposium on the treatment of autoimmune and inflammatory disorders sponsored by the clinic, was that of a 56-year-old man with seropositive rheumatoid arthritis who became severely disabled after infliximab infusions were added to his methotrexate therapy.

Dr. Mays, a neurologist, said in an interview that following his first anti-TNF treatment in 2002, the patient's rheumatoid arthritis symptoms lessened dramatically, but following an infusion in late 2003, he had dizziness and hearing loss for a week. The symptoms recurred and lasted longer following a third infusion 2 months later.

The next infliximab infusion in April 2004 produced worsening neurologic symptoms, including blurred vision, headaches, dysarthria, hearing loss, ataxia, dysphagia requiring percutaneous endoscopic gastrostomy for nutrition, and progressive weakness, according to Dr. Mays.

“Initial evaluation included cerebrospinal fluid WBC of 123, protein 79, and electromyograph consistent with demyelinating polyneuropathy. But the overall pattern was not typical of Guillain-Barré syndrome [GBS],” Dr. Mays said. “He had high white count and normal protein. Auditory evoked potentials showed a right central conduction disturbance. His detrusor urinae muscle were unresponsive, which is typical of GBS. His right Babinski sign was atypical of GBS.”

Feyrouz Al-Ashkar, M.D., the lead investigator and a rheumatologist, noted in an interview that by the time the patient was brought to the clinic, he “could not walk, use his hands, lift his head, or feed himself, although he could still breathe on his own.”

“He received intravenous immunoglobulin [IVIg] and steroids before we saw him. When he got here, he again received intravenous steroids and another course of intravenous immunoglobulin, and slowly but surely, he recovered completely,” Dr. Al-Ashkar said.

Dr. Mays noted that the patient's response to IVIg supports the diagnosis of a demyelinating polyneuropathy other than GBS.”

Dr. Al-Ashkar said that the onset of neurologic deficits or demyelinating diseases in patients on infliximab is a red flag to stop TNF blockade. “In such cases, our experience would suggest that there is potential for worsening of neurologic deficits with each infliximab treatment, and that continuing treatments after onset of neurologic symptoms would be relatively contraindicated,” according to the poster.

CLEVELAND — Tumor necrosis factor-α blockade should not be instituted in patients with known multiple sclerosis and should be used with caution in patients with family histories or other risk factors for MS, according to Jeffrey A. Cohen, M.D., a neurologist at the Cleveland Clinic, Ohio.

Physicians should also be alert to uncommon CNS manifestations in patients receiving tumor necrosis factor (TNF) blockade for their inflammatory diseases, he said at a meeting on the treatment of autoimmune and inflammatory disorders.

TNF inhibitors currently approved by the Food and Drug Administration include the monoclonal antibodies infliximab (Remicade) and adalimumab (Humira) and the fusion protein etanercept (Enbrel).

TNF blockade both prevents and abrogates demyelinating disease in vitro and in animal studies. In humans, TNF blockade actually increased MS activity, said Dr. Cohen, citing data from two studies of infliximab and the discontinued lenercept. “In addition, treatment of other diseases for which TNF inhibitors are highly effective, including rheumatoid arthritis, Crohn's disease, and psoriasis, on rare occasions leads to CNS inflammatory demyelinating syndromes,” Dr. Cohen said at a summit sponsored by the Cleveland Clinic.

Failure of anti-TNF therapy in MS may be due to pleiotropic aspects of TNF actions, he noted. “In the CNS, TNF mediates cellular apoptosis and tissue damage, has important immunoregulatory functions, and is involved in tissue repair and regeneration. This experience reminds us that in the development of novel therapeutics, one must be cautious in extrapolating from animal models to human disease and from the results in one human disease to another,” he said. CNS demyelination can occur anytime after an anti-TNF agent is started. Demyelination appears to be a class effect of all TNF antagonists.

Dr. Cohen recommends avoiding TNF blockade for patients with or at risk for MS. Withhold TNF inhibitor infusions from patients who have had a previous clinically isolated CNS syndrome and have cranial MRIs that look suggestive of MS but do not yet have clinical manifestations, advised Dr. Cohen.

Dr. Cohen, a neurologist, advised against looking for MS in every patient prior to starting a TNF inhibitor for treatment of inflammatory bowel disease, rheumatoid arthritis, or psoriasis. “In particular, I would not obtain an MRI unless there was some clinical suggestion of potential (for MS).” However, uveitis is a different story: “Uveitis is a manifestation that can occur in MS, so I would look very carefully for any indication of MS involvement” before beginning TNF blockade.

CLEVELAND — Tumor necrosis factor-α blockade should not be instituted in patients with known multiple sclerosis and should be used with caution in patients with family histories or other risk factors for MS, according to Jeffrey A. Cohen, M.D., a neurologist at the Cleveland Clinic, Ohio.

Physicians should also be alert to uncommon CNS manifestations in patients receiving tumor necrosis factor (TNF) blockade for their inflammatory diseases, he said at a meeting on the treatment of autoimmune and inflammatory disorders.

TNF inhibitors currently approved by the Food and Drug Administration include the monoclonal antibodies infliximab (Remicade) and adalimumab (Humira) and the fusion protein etanercept (Enbrel).

TNF blockade both prevents and abrogates demyelinating disease in vitro and in animal studies. In humans, TNF blockade actually increased MS activity, said Dr. Cohen, citing data from two studies of infliximab and the discontinued lenercept. “In addition, treatment of other diseases for which TNF inhibitors are highly effective, including rheumatoid arthritis, Crohn's disease, and psoriasis, on rare occasions leads to CNS inflammatory demyelinating syndromes,” Dr. Cohen said at a summit sponsored by the Cleveland Clinic.

Failure of anti-TNF therapy in MS may be due to pleiotropic aspects of TNF actions, he noted. “In the CNS, TNF mediates cellular apoptosis and tissue damage, has important immunoregulatory functions, and is involved in tissue repair and regeneration. This experience reminds us that in the development of novel therapeutics, one must be cautious in extrapolating from animal models to human disease and from the results in one human disease to another,” he said. CNS demyelination can occur anytime after an anti-TNF agent is started. Demyelination appears to be a class effect of all TNF antagonists.

Dr. Cohen recommends avoiding TNF blockade for patients with or at risk for MS. Withhold TNF inhibitor infusions from patients who have had a previous clinically isolated CNS syndrome and have cranial MRIs that look suggestive of MS but do not yet have clinical manifestations, advised Dr. Cohen.

Dr. Cohen, a neurologist, advised against looking for MS in every patient prior to starting a TNF inhibitor for treatment of inflammatory bowel disease, rheumatoid arthritis, or psoriasis. “In particular, I would not obtain an MRI unless there was some clinical suggestion of potential (for MS).” However, uveitis is a different story: “Uveitis is a manifestation that can occur in MS, so I would look very carefully for any indication of MS involvement” before beginning TNF blockade.

CLEVELAND — Tumor necrosis factor-α blockade should not be instituted in patients with known multiple sclerosis and should be used with caution in patients with family histories or other risk factors for MS, according to Jeffrey A. Cohen, M.D., a neurologist at the Cleveland Clinic, Ohio.

Physicians should also be alert to uncommon CNS manifestations in patients receiving tumor necrosis factor (TNF) blockade for their inflammatory diseases, he said at a meeting on the treatment of autoimmune and inflammatory disorders.

TNF inhibitors currently approved by the Food and Drug Administration include the monoclonal antibodies infliximab (Remicade) and adalimumab (Humira) and the fusion protein etanercept (Enbrel).

TNF blockade both prevents and abrogates demyelinating disease in vitro and in animal studies. In humans, TNF blockade actually increased MS activity, said Dr. Cohen, citing data from two studies of infliximab and the discontinued lenercept. “In addition, treatment of other diseases for which TNF inhibitors are highly effective, including rheumatoid arthritis, Crohn's disease, and psoriasis, on rare occasions leads to CNS inflammatory demyelinating syndromes,” Dr. Cohen said at a summit sponsored by the Cleveland Clinic.

Failure of anti-TNF therapy in MS may be due to pleiotropic aspects of TNF actions, he noted. “In the CNS, TNF mediates cellular apoptosis and tissue damage, has important immunoregulatory functions, and is involved in tissue repair and regeneration. This experience reminds us that in the development of novel therapeutics, one must be cautious in extrapolating from animal models to human disease and from the results in one human disease to another,” he said. CNS demyelination can occur anytime after an anti-TNF agent is started. Demyelination appears to be a class effect of all TNF antagonists.

Dr. Cohen recommends avoiding TNF blockade for patients with or at risk for MS. Withhold TNF inhibitor infusions from patients who have had a previous clinically isolated CNS syndrome and have cranial MRIs that look suggestive of MS but do not yet have clinical manifestations, advised Dr. Cohen.

Dr. Cohen, a neurologist, advised against looking for MS in every patient prior to starting a TNF inhibitor for treatment of inflammatory bowel disease, rheumatoid arthritis, or psoriasis. “In particular, I would not obtain an MRI unless there was some clinical suggestion of potential (for MS).” However, uveitis is a different story: “Uveitis is a manifestation that can occur in MS, so I would look very carefully for any indication of MS involvement” before beginning TNF blockade.

MIAMI BEACH — Four different interferon-β products and dosing schedules appear equally effective as initial therapy for relapsing/remitting multiple sclerosis, Volker Limmroth, M.D., reported in a poster session at the annual meeting of the American Academy of Neurology.

However, all IFN-β products were significantly less effective when used as follow-up therapy, said Dr. Limmroth, of the University of Essen (Germany), and his colleagues.

“These results suggest that patients do not gain further benefit when switching from one IFN-β product to another,” according to Dr. Limmroth.

Dr. Limmroth presented the results of the global Quality Assessment in Multiple Sclerosis Therapy (QUASIMS) study which examined long-term outcomes in more than 7,000 patients from 11 countries who took different IFN-β products and dosing regimens. The study broke results down among those who took IFN-β as initial therapy and those who took it as follow-up therapy.

The patients' mean age was 36 years; about 70% were female. Their mean disease duration was about 5 years. Their mean treatment duration was about 40 months and mean Expanded Disability Status Scale (EDSS) was 2.4–2.9.

The therapies examined were intramuscular IFN-β-1a, 30 mcg once weekly; subcutaneous IFN-β-1b, 8 mIU every other day; subcutaneous IFN-β-1a, 22 mcg three times weekly; and subcutaneous IFN-β-1a, 44 mcg three times weekly. Patients had to have been on at least 2 years' uninterrupted therapy (either initial or follow-up). Overall, there were no significant differences on EDSS between the therapies at 1 or 2 years' follow-up. Some differences emerged, however, when the drugs were stratified as either initial or follow-up therapy.

All drugs were more effective as initial therapy than as follow-up therapy. Intramuscular IFN-β-1a resulted in the highest percentage of progression-free patients at 2 years (66%). For the other therapies, the percentage of progression-free patients was 62.2% for subcutaneous IFN-β-1a 44 mcg; 61% for subcutaneous IFN-β-1a 22 mcg; and 52.7% for IFN-β-1b.

Intramuscular IFN-β-1a also resulted in the highest percentage of relapse-free patients over 2 years (50.2%). The percentages for the other therapies were 42% for IFN-β-1b; 37% for subcutaneous IFN-β-1a 22 mcg; and 33.8% for subcutaneous IFN-β-1a 44 mcg.

There were no significant differences in the drugs' effectiveness when they were used as follow-up therapy.

The percentage of progression-free patients ranged from 51.7% for IFN-β-1b to 62% for subcutaneous IFN-β-1a 44 mcg. The percentage of relapse-free patients over 2 years ranged from 33.8% for subcutaneous IFN-β-1a 44 mcg to 42% for IFN-β-1b.

During the study, 18% (1,309 patients) changed therapy. The most frequent reason was perceived lack of efficacy. Switch rates were intramuscular IFN-β-1a, 45%; IFN-β-1b, 31%; subcutaneous IFN-β-1a 22 mcg, 38%; subcutaneous IFN-β-1a 44 mcg, 40%.

Dr. Limmroth is a paid investigator for Biogen Idec Inc. which sponsored the study.

MIAMI BEACH — Four different interferon-β products and dosing schedules appear equally effective as initial therapy for relapsing/remitting multiple sclerosis, Volker Limmroth, M.D., reported in a poster session at the annual meeting of the American Academy of Neurology.

However, all IFN-β products were significantly less effective when used as follow-up therapy, said Dr. Limmroth, of the University of Essen (Germany), and his colleagues.

“These results suggest that patients do not gain further benefit when switching from one IFN-β product to another,” according to Dr. Limmroth.

Dr. Limmroth presented the results of the global Quality Assessment in Multiple Sclerosis Therapy (QUASIMS) study which examined long-term outcomes in more than 7,000 patients from 11 countries who took different IFN-β products and dosing regimens. The study broke results down among those who took IFN-β as initial therapy and those who took it as follow-up therapy.

The patients' mean age was 36 years; about 70% were female. Their mean disease duration was about 5 years. Their mean treatment duration was about 40 months and mean Expanded Disability Status Scale (EDSS) was 2.4–2.9.

The therapies examined were intramuscular IFN-β-1a, 30 mcg once weekly; subcutaneous IFN-β-1b, 8 mIU every other day; subcutaneous IFN-β-1a, 22 mcg three times weekly; and subcutaneous IFN-β-1a, 44 mcg three times weekly. Patients had to have been on at least 2 years' uninterrupted therapy (either initial or follow-up). Overall, there were no significant differences on EDSS between the therapies at 1 or 2 years' follow-up. Some differences emerged, however, when the drugs were stratified as either initial or follow-up therapy.

All drugs were more effective as initial therapy than as follow-up therapy. Intramuscular IFN-β-1a resulted in the highest percentage of progression-free patients at 2 years (66%). For the other therapies, the percentage of progression-free patients was 62.2% for subcutaneous IFN-β-1a 44 mcg; 61% for subcutaneous IFN-β-1a 22 mcg; and 52.7% for IFN-β-1b.

Intramuscular IFN-β-1a also resulted in the highest percentage of relapse-free patients over 2 years (50.2%). The percentages for the other therapies were 42% for IFN-β-1b; 37% for subcutaneous IFN-β-1a 22 mcg; and 33.8% for subcutaneous IFN-β-1a 44 mcg.

There were no significant differences in the drugs' effectiveness when they were used as follow-up therapy.

The percentage of progression-free patients ranged from 51.7% for IFN-β-1b to 62% for subcutaneous IFN-β-1a 44 mcg. The percentage of relapse-free patients over 2 years ranged from 33.8% for subcutaneous IFN-β-1a 44 mcg to 42% for IFN-β-1b.

During the study, 18% (1,309 patients) changed therapy. The most frequent reason was perceived lack of efficacy. Switch rates were intramuscular IFN-β-1a, 45%; IFN-β-1b, 31%; subcutaneous IFN-β-1a 22 mcg, 38%; subcutaneous IFN-β-1a 44 mcg, 40%.

Dr. Limmroth is a paid investigator for Biogen Idec Inc. which sponsored the study.

MIAMI BEACH — Four different interferon-β products and dosing schedules appear equally effective as initial therapy for relapsing/remitting multiple sclerosis, Volker Limmroth, M.D., reported in a poster session at the annual meeting of the American Academy of Neurology.

However, all IFN-β products were significantly less effective when used as follow-up therapy, said Dr. Limmroth, of the University of Essen (Germany), and his colleagues.

“These results suggest that patients do not gain further benefit when switching from one IFN-β product to another,” according to Dr. Limmroth.

Dr. Limmroth presented the results of the global Quality Assessment in Multiple Sclerosis Therapy (QUASIMS) study which examined long-term outcomes in more than 7,000 patients from 11 countries who took different IFN-β products and dosing regimens. The study broke results down among those who took IFN-β as initial therapy and those who took it as follow-up therapy.

The patients' mean age was 36 years; about 70% were female. Their mean disease duration was about 5 years. Their mean treatment duration was about 40 months and mean Expanded Disability Status Scale (EDSS) was 2.4–2.9.

The therapies examined were intramuscular IFN-β-1a, 30 mcg once weekly; subcutaneous IFN-β-1b, 8 mIU every other day; subcutaneous IFN-β-1a, 22 mcg three times weekly; and subcutaneous IFN-β-1a, 44 mcg three times weekly. Patients had to have been on at least 2 years' uninterrupted therapy (either initial or follow-up). Overall, there were no significant differences on EDSS between the therapies at 1 or 2 years' follow-up. Some differences emerged, however, when the drugs were stratified as either initial or follow-up therapy.

All drugs were more effective as initial therapy than as follow-up therapy. Intramuscular IFN-β-1a resulted in the highest percentage of progression-free patients at 2 years (66%). For the other therapies, the percentage of progression-free patients was 62.2% for subcutaneous IFN-β-1a 44 mcg; 61% for subcutaneous IFN-β-1a 22 mcg; and 52.7% for IFN-β-1b.

Intramuscular IFN-β-1a also resulted in the highest percentage of relapse-free patients over 2 years (50.2%). The percentages for the other therapies were 42% for IFN-β-1b; 37% for subcutaneous IFN-β-1a 22 mcg; and 33.8% for subcutaneous IFN-β-1a 44 mcg.

There were no significant differences in the drugs' effectiveness when they were used as follow-up therapy.

The percentage of progression-free patients ranged from 51.7% for IFN-β-1b to 62% for subcutaneous IFN-β-1a 44 mcg. The percentage of relapse-free patients over 2 years ranged from 33.8% for subcutaneous IFN-β-1a 44 mcg to 42% for IFN-β-1b.

During the study, 18% (1,309 patients) changed therapy. The most frequent reason was perceived lack of efficacy. Switch rates were intramuscular IFN-β-1a, 45%; IFN-β-1b, 31%; subcutaneous IFN-β-1a 22 mcg, 38%; subcutaneous IFN-β-1a 44 mcg, 40%.

Dr. Limmroth is a paid investigator for Biogen Idec Inc. which sponsored the study.

Soon-to-be published reports describing three patients who developed a progressive, demyelinating brain disorder during treatment with natalizumab have some experts wondering whether the drug—now under voluntary suspension from the market—might safely be given to multiple sclerosis patients if they are carefully monitored.

“Compared with what I knew before, I'm more optimistic,” said John Richert, M.D., who heads research and clinical programs for the National Multiple Sclerosis Society. “We still need to hear more …, but I think there's a reasonable likelihood that the drug will be brought back.”

He and others point mainly to two observations detailed in the reports—that progressive multifocal leukoencephalopathy (PML), caused by activation of the human polyomavirus JC virus, may be preceded by JC virus viremia, and that the disorder is not necessarily life-threatening—in explaining their new but guarded optimism. It might be possible to discontinue the drug in patients in time to prevent PML from developing into a life-threatening illness.

The reports, to be published in the July 28 issue of the New England Journal of Medicine, detail the clinical course of three patients who participated in clinical trials of the monoclonal antibody natalizumab (Tysabri) for MS, Crohn's disease, and rheumatoid arthritis.

Two of the patients had MS and developed PML after having taken natalizumab for over 2 years in combination with interferon β-1a. Their cases were the impetus for the drug makers' suspension earlier this year of all dosing and marketing of the drug (see CLINICAL NEUROLOGY NEWS, April 2005, p. 5).

The third patient had Crohn's disease and took the drug—which received accelerated approval from the FDA in late 2004 for the treatment of immune-mediated disorders, including MS—for a much shorter duration. He was found to have had PML after the MS cases prompted investigators to reevaluate a presumed malignant astrocytoma.

The New England Journal of Medicine, which had published some of the original studies on the efficacy of the drug, lifted its embargo early and posted the reports—as well as two editorials and correspondence from one manufacturer—on the its Web site last month after the Boston Globe reported that the FDA was investigating a possible case of PML in a fourth patient who received natalizumab. (A press report of a fifth case of suspected PML being reported to the FDA was published since then. At press time, the FDA said only that there were “no additional confirmed cases.”)

In the case of the Crohn's disease patient, who had previously received other immunomodulatory agents with no reactivation of JC virus infection, retrospective analysis of serum samples showed that JC virus became detectable after only three injections of natalizumab monotherapy and 2 months before the appearance of symptomatic PML, which led to the patient's death.

Within those 2 months, the serum viral load increased by a factor of 12, Gert Van Assche, M.D., and associates at the University of Leuven (Belgium) Hospitals (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMoa051586. Available from www.nejm.org

Before recovering partially, one patient's condition worsened after the cessation of natalizumab therapy—despite treatment with corticosteroids, cidofovir, and intravenous immune globulin—but eventually improved (not completely, but significantly) 2 months after initiation of systemic therapy with cytarabine, which penetrates the CNS poorly.

It is possible, however, “that the extensive breakdown of his blood-brain barrier improved penetration of cytarabine into the CNS,” wrote Annette Langer-Gould, M.D., of Stanford (Calif.) University, and her colleagues (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMoa051847. Available from www.nejm.org

Such findings, Dr. Richert said, give him hope that it may be possible to fashion preventive strategies against development of PML in patients wanting to take natalizumab or similar drugs in the future. And in an editorial, Joseph R. Berger, M.D., of the University of Kentucky, Lexington, and Igor J. Koralnik, M.D., of Harvard Medical School, Boston, expressed similar optimism.

“The prospective measurement of the JC viral load in plasma and the preemptive reduction of doses or interruption of treatment if JC virus DNA appears in the blood might actually prevent the development of PML in this setting,” they wrote (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMe058122. Available from www.nejm.org

Dr. Langer-Gould and her colleagues also note in their report that “more frequent MRI monitoring of patients who receive natalizumab may be warranted.”

Kenneth L. Tyler, M.D., an author on the second MS case report, cautioned that “it's exceedingly dangerous to prognosticate on the future with such a small subset (of patients.” Still, he told this newspaper, he is left with the questions, “is viremia a useful warning sign? And if you discontinue the medicine, will [development of PML] subside?”

The case of the Crohn's patient, Dr. Tyler noted, is significant because it indicates “that neither concurrent use of Avonex [interferon β-1a] or underlying neurologic disease like MS is necessary” for the development of PML in patients taking Tysabri.

All agree that while the new reports clarify the association between treatment with natalizumab and the occurrence of PML, questions about the magnitude of risk need to be answered before the drug can be brought back to the market.

“There's a big interest in bringing [Tysabri] back, but the viability of the drug will depend on our ability to predict risk of PML and know how great a risk PML is for MS patients,” said Michael Kaufman, M.D., director of the MS Center at Carolinas Health Care in Charlotte, N.C., and an investigator in one of the Tysabri trials.

“Two cases out of hundreds with MS … could be the tip of the iceberg, or it could be the only two who were susceptible to it,” he said.

Despite her patient's partial recovery, Dr. Langer-Gould told this newspaper she fears that if the drug were prescribed for longer periods of time, “it would be highly likely we would see many more cases of PML resulting in death or significant life-long disability as well as other toxicities.”

According to a short “correspondence” written by leaders at the Cambridge, Mass.-based Biogen Idec Inc., a panel established by the company is currently reviewing all suspicious and ambiguous findings to evaluate them for PML (NEJM [Epub ahead of print], June 9, 2005. Article DOI:10.1056/NEJMc055235. Available from www.nejm.com

A spokesman for Biogen Idec and Elan Corp. told CLINICAL NEUROLOGY NEWS that once they have a better understanding of the risks of PML—perhaps later this summer—the companies will share their findings with the FDA and European regulatory agencies, and “together, the compan[ies] and agencies will make a decision about how to proceed with the drug.”

In the NEJM reports, Dr. Langer-Gould, Dr. Berger, and Dr. Koralnik each report having received consulting and/or lecture fees from Biogen Idec.

Soon-to-be published reports describing three patients who developed a progressive, demyelinating brain disorder during treatment with natalizumab have some experts wondering whether the drug—now under voluntary suspension from the market—might safely be given to multiple sclerosis patients if they are carefully monitored.

“Compared with what I knew before, I'm more optimistic,” said John Richert, M.D., who heads research and clinical programs for the National Multiple Sclerosis Society. “We still need to hear more …, but I think there's a reasonable likelihood that the drug will be brought back.”

He and others point mainly to two observations detailed in the reports—that progressive multifocal leukoencephalopathy (PML), caused by activation of the human polyomavirus JC virus, may be preceded by JC virus viremia, and that the disorder is not necessarily life-threatening—in explaining their new but guarded optimism. It might be possible to discontinue the drug in patients in time to prevent PML from developing into a life-threatening illness.

The reports, to be published in the July 28 issue of the New England Journal of Medicine, detail the clinical course of three patients who participated in clinical trials of the monoclonal antibody natalizumab (Tysabri) for MS, Crohn's disease, and rheumatoid arthritis.

Two of the patients had MS and developed PML after having taken natalizumab for over 2 years in combination with interferon β-1a. Their cases were the impetus for the drug makers' suspension earlier this year of all dosing and marketing of the drug (see CLINICAL NEUROLOGY NEWS, April 2005, p. 5).

The third patient had Crohn's disease and took the drug—which received accelerated approval from the FDA in late 2004 for the treatment of immune-mediated disorders, including MS—for a much shorter duration. He was found to have had PML after the MS cases prompted investigators to reevaluate a presumed malignant astrocytoma.

The New England Journal of Medicine, which had published some of the original studies on the efficacy of the drug, lifted its embargo early and posted the reports—as well as two editorials and correspondence from one manufacturer—on the its Web site last month after the Boston Globe reported that the FDA was investigating a possible case of PML in a fourth patient who received natalizumab. (A press report of a fifth case of suspected PML being reported to the FDA was published since then. At press time, the FDA said only that there were “no additional confirmed cases.”)

In the case of the Crohn's disease patient, who had previously received other immunomodulatory agents with no reactivation of JC virus infection, retrospective analysis of serum samples showed that JC virus became detectable after only three injections of natalizumab monotherapy and 2 months before the appearance of symptomatic PML, which led to the patient's death.

Within those 2 months, the serum viral load increased by a factor of 12, Gert Van Assche, M.D., and associates at the University of Leuven (Belgium) Hospitals (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMoa051586. Available from www.nejm.org

Before recovering partially, one patient's condition worsened after the cessation of natalizumab therapy—despite treatment with corticosteroids, cidofovir, and intravenous immune globulin—but eventually improved (not completely, but significantly) 2 months after initiation of systemic therapy with cytarabine, which penetrates the CNS poorly.

It is possible, however, “that the extensive breakdown of his blood-brain barrier improved penetration of cytarabine into the CNS,” wrote Annette Langer-Gould, M.D., of Stanford (Calif.) University, and her colleagues (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMoa051847. Available from www.nejm.org

Such findings, Dr. Richert said, give him hope that it may be possible to fashion preventive strategies against development of PML in patients wanting to take natalizumab or similar drugs in the future. And in an editorial, Joseph R. Berger, M.D., of the University of Kentucky, Lexington, and Igor J. Koralnik, M.D., of Harvard Medical School, Boston, expressed similar optimism.

“The prospective measurement of the JC viral load in plasma and the preemptive reduction of doses or interruption of treatment if JC virus DNA appears in the blood might actually prevent the development of PML in this setting,” they wrote (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMe058122. Available from www.nejm.org

Dr. Langer-Gould and her colleagues also note in their report that “more frequent MRI monitoring of patients who receive natalizumab may be warranted.”

Kenneth L. Tyler, M.D., an author on the second MS case report, cautioned that “it's exceedingly dangerous to prognosticate on the future with such a small subset (of patients.” Still, he told this newspaper, he is left with the questions, “is viremia a useful warning sign? And if you discontinue the medicine, will [development of PML] subside?”

The case of the Crohn's patient, Dr. Tyler noted, is significant because it indicates “that neither concurrent use of Avonex [interferon β-1a] or underlying neurologic disease like MS is necessary” for the development of PML in patients taking Tysabri.

All agree that while the new reports clarify the association between treatment with natalizumab and the occurrence of PML, questions about the magnitude of risk need to be answered before the drug can be brought back to the market.

“There's a big interest in bringing [Tysabri] back, but the viability of the drug will depend on our ability to predict risk of PML and know how great a risk PML is for MS patients,” said Michael Kaufman, M.D., director of the MS Center at Carolinas Health Care in Charlotte, N.C., and an investigator in one of the Tysabri trials.

“Two cases out of hundreds with MS … could be the tip of the iceberg, or it could be the only two who were susceptible to it,” he said.

Despite her patient's partial recovery, Dr. Langer-Gould told this newspaper she fears that if the drug were prescribed for longer periods of time, “it would be highly likely we would see many more cases of PML resulting in death or significant life-long disability as well as other toxicities.”

According to a short “correspondence” written by leaders at the Cambridge, Mass.-based Biogen Idec Inc., a panel established by the company is currently reviewing all suspicious and ambiguous findings to evaluate them for PML (NEJM [Epub ahead of print], June 9, 2005. Article DOI:10.1056/NEJMc055235. Available from www.nejm.com

A spokesman for Biogen Idec and Elan Corp. told CLINICAL NEUROLOGY NEWS that once they have a better understanding of the risks of PML—perhaps later this summer—the companies will share their findings with the FDA and European regulatory agencies, and “together, the compan[ies] and agencies will make a decision about how to proceed with the drug.”

In the NEJM reports, Dr. Langer-Gould, Dr. Berger, and Dr. Koralnik each report having received consulting and/or lecture fees from Biogen Idec.

Soon-to-be published reports describing three patients who developed a progressive, demyelinating brain disorder during treatment with natalizumab have some experts wondering whether the drug—now under voluntary suspension from the market—might safely be given to multiple sclerosis patients if they are carefully monitored.

“Compared with what I knew before, I'm more optimistic,” said John Richert, M.D., who heads research and clinical programs for the National Multiple Sclerosis Society. “We still need to hear more …, but I think there's a reasonable likelihood that the drug will be brought back.”

He and others point mainly to two observations detailed in the reports—that progressive multifocal leukoencephalopathy (PML), caused by activation of the human polyomavirus JC virus, may be preceded by JC virus viremia, and that the disorder is not necessarily life-threatening—in explaining their new but guarded optimism. It might be possible to discontinue the drug in patients in time to prevent PML from developing into a life-threatening illness.

The reports, to be published in the July 28 issue of the New England Journal of Medicine, detail the clinical course of three patients who participated in clinical trials of the monoclonal antibody natalizumab (Tysabri) for MS, Crohn's disease, and rheumatoid arthritis.

Two of the patients had MS and developed PML after having taken natalizumab for over 2 years in combination with interferon β-1a. Their cases were the impetus for the drug makers' suspension earlier this year of all dosing and marketing of the drug (see CLINICAL NEUROLOGY NEWS, April 2005, p. 5).

The third patient had Crohn's disease and took the drug—which received accelerated approval from the FDA in late 2004 for the treatment of immune-mediated disorders, including MS—for a much shorter duration. He was found to have had PML after the MS cases prompted investigators to reevaluate a presumed malignant astrocytoma.

The New England Journal of Medicine, which had published some of the original studies on the efficacy of the drug, lifted its embargo early and posted the reports—as well as two editorials and correspondence from one manufacturer—on the its Web site last month after the Boston Globe reported that the FDA was investigating a possible case of PML in a fourth patient who received natalizumab. (A press report of a fifth case of suspected PML being reported to the FDA was published since then. At press time, the FDA said only that there were “no additional confirmed cases.”)

In the case of the Crohn's disease patient, who had previously received other immunomodulatory agents with no reactivation of JC virus infection, retrospective analysis of serum samples showed that JC virus became detectable after only three injections of natalizumab monotherapy and 2 months before the appearance of symptomatic PML, which led to the patient's death.

Within those 2 months, the serum viral load increased by a factor of 12, Gert Van Assche, M.D., and associates at the University of Leuven (Belgium) Hospitals (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMoa051586. Available from www.nejm.org

Before recovering partially, one patient's condition worsened after the cessation of natalizumab therapy—despite treatment with corticosteroids, cidofovir, and intravenous immune globulin—but eventually improved (not completely, but significantly) 2 months after initiation of systemic therapy with cytarabine, which penetrates the CNS poorly.

It is possible, however, “that the extensive breakdown of his blood-brain barrier improved penetration of cytarabine into the CNS,” wrote Annette Langer-Gould, M.D., of Stanford (Calif.) University, and her colleagues (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMoa051847. Available from www.nejm.org

Such findings, Dr. Richert said, give him hope that it may be possible to fashion preventive strategies against development of PML in patients wanting to take natalizumab or similar drugs in the future. And in an editorial, Joseph R. Berger, M.D., of the University of Kentucky, Lexington, and Igor J. Koralnik, M.D., of Harvard Medical School, Boston, expressed similar optimism.

“The prospective measurement of the JC viral load in plasma and the preemptive reduction of doses or interruption of treatment if JC virus DNA appears in the blood might actually prevent the development of PML in this setting,” they wrote (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMe058122. Available from www.nejm.org

Dr. Langer-Gould and her colleagues also note in their report that “more frequent MRI monitoring of patients who receive natalizumab may be warranted.”

Kenneth L. Tyler, M.D., an author on the second MS case report, cautioned that “it's exceedingly dangerous to prognosticate on the future with such a small subset (of patients.” Still, he told this newspaper, he is left with the questions, “is viremia a useful warning sign? And if you discontinue the medicine, will [development of PML] subside?”

The case of the Crohn's patient, Dr. Tyler noted, is significant because it indicates “that neither concurrent use of Avonex [interferon β-1a] or underlying neurologic disease like MS is necessary” for the development of PML in patients taking Tysabri.

All agree that while the new reports clarify the association between treatment with natalizumab and the occurrence of PML, questions about the magnitude of risk need to be answered before the drug can be brought back to the market.

“There's a big interest in bringing [Tysabri] back, but the viability of the drug will depend on our ability to predict risk of PML and know how great a risk PML is for MS patients,” said Michael Kaufman, M.D., director of the MS Center at Carolinas Health Care in Charlotte, N.C., and an investigator in one of the Tysabri trials.

“Two cases out of hundreds with MS … could be the tip of the iceberg, or it could be the only two who were susceptible to it,” he said.

Despite her patient's partial recovery, Dr. Langer-Gould told this newspaper she fears that if the drug were prescribed for longer periods of time, “it would be highly likely we would see many more cases of PML resulting in death or significant life-long disability as well as other toxicities.”

According to a short “correspondence” written by leaders at the Cambridge, Mass.-based Biogen Idec Inc., a panel established by the company is currently reviewing all suspicious and ambiguous findings to evaluate them for PML (NEJM [Epub ahead of print], June 9, 2005. Article DOI:10.1056/NEJMc055235. Available from www.nejm.com

A spokesman for Biogen Idec and Elan Corp. told CLINICAL NEUROLOGY NEWS that once they have a better understanding of the risks of PML—perhaps later this summer—the companies will share their findings with the FDA and European regulatory agencies, and “together, the compan[ies] and agencies will make a decision about how to proceed with the drug.”

In the NEJM reports, Dr. Langer-Gould, Dr. Berger, and Dr. Koralnik each report having received consulting and/or lecture fees from Biogen Idec.