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New and Noteworthy Information—September 2013
A recent case–control study provides further evidence against the Zamboni hypothesis that chronic cerebrospinal venous insufficiency is involved with multiple sclerosis (MS), researchers reported August 14 in PLOS One. The researchers randomly selected 100 patients with MS between ages 18 and 65 and 100 controls with no known history of MS or other neurologic condition. All participants underwent ultrasound imaging of the veins of the neck and the deep cerebral veins, as well as MRI of the neck veins and brain. The investigators found no evidence of reflux, stenosis, or blockage in the internal jugular veins or vertebral veins in any study participant and no evidence of reflux or cessation of flow in the deep cerebral veins in any subject.
Breastfeeding may reduce a woman’s risk of Alzheimer’s disease, according to research published online ahead of print July 23 in the Journal of Alzheimer’s Disease. Investigators collected reproductive history data from and conducted Alzheimer’s disease diagnostic interviews with a cohort of elderly British women. Analysis using Cox proportional-hazard models indicated that longer breastfeeding duration corresponded to reduced risk of Alzheimer’s disease. Women who breastfed had lower risk of Alzheimer’s disease than women who did not breastfeed. Breastfeeding practices are an important modifier of cumulative endogenous hormone exposure for mothers, according to the researchers. Future studies should consider how reproductive history leads to variation in endogenous hormone exposure and how this variation may influence the relationship between hormones and Alzheimer’s disease, the investigators concluded.
Among older adults, anemia may be associated with an increased risk of dementia, according to a study published August 6 in Neurology. Researchers studied 2,552 older adults (mean age, 76) participating in the Health, Aging, and Body Composition study and who were free of dementia at baseline. Of the total population, 392 participants had anemia at baseline. Over 11 years of follow-up, 455 participants developed dementia. An unadjusted analysis indicated that subjects with baseline anemia had an increased risk of dementia (23% vs 17%) compared with subjects without anemia. The association remained significant after adjusting for demographics, APOE ε4, baseline Modified Mini-Mental State score, comorbidities, and renal function. Additional adjustment for other anemia measures, erythropoietin, and C-reactive protein did not affect the results significantly.
The FDA has approved Trokendi XR, a once-daily extended release formulation of topiramate for the treatment of epilepsy. The agency granted a waiver for certain pediatric study requirements and a deferral for the submission of postmarketing pediatric pharmacokinetic assessments. Trokendi XR is indicated for initial monotherapy in patients ages 10 and older with partial onset or primary generalized tonic–clonic seizures. The drug also is approved as adjunctive therapy in patients ages 6 and older with partial onset or primary generalized tonic–clonic seizures, and as adjunctive therapy in patients ages 6 and older with seizures associated with Lennox–Gastaut syndrome. The product will be available in 25-, 50-, 100- and 200-mg extended-release capsules. Supernus Pharmaceuticals (Rockville, Maryland) expects to launch the product in September 2013.
The FDA has approved scored tablet and oral suspension formulations of ONFI (clobazam) CIV. ONFI is an oral antiepileptic drug of the benzodiazepine class (ie, a 1,5 benzodiazepine). The agency originally approved ONFI in 2011 as a prescription medication to treat seizures associated with Lennox–Gastaut syndrome in adults and children age 2 or older. The new oval-shaped ONFI scored tablets (10 mg and 20 mg) will replace the round, nonscored tablets and are similar in size. The new tablets contain the same ingredients as the round tablet, and the score allows patients or their caregivers to split the tablets in half. ONFI oral suspension (2.5 mg/mL) has a berry flavor. ONFI, manufactured by Lundbeck (Deerfield, Illinois), will no longer be available in a 5-mg tablet.
An incomplete circle of Willis may be more common in patients with migraine with aura than in the general population, according to research published July 26 in PLOS One. Investigators enrolled 56 migraineurs with aura, 61 migraineurs without aura, and 53 controls in an observational study. The researchers performed magnetic resonance angiography to examine subjects’ circle of Willis anatomy and measured cerebral blood flow with arterial spin–labeled perfusion MRI. An incomplete circle of Willis was significantly more common in migraineurs with aura, compared with controls (73% vs 51%). A similar trend was observed among migraineurs without aura (67% vs 51%). Compared with subjects with a complete circle of Willis, subjects with an incomplete circle had greater asymmetry in hemispheric cerebral blood flow.
Some patients with chronic pain diagnosed as fibromyalgia may have unrecognized small-fiber polyneuropathy (SFPN), according to research published online ahead of print June 7 in Pain. Investigators analyzed symptoms associated with SFPN, neurologic examinations, and pathologic and physiologic markers in 27 patients with fibromyalgia and 30 matched normal controls. Study instruments included the Michigan Neuropathy Screening Instrument (MNSI), the Utah Early Neuropathy Scale (UENS), distal-leg neurodiagnostic skin biopsies, and autonomic-function testing (AFT). Approximately 41% of skin biopsies from subjects with fibromyalgia supported a diagnosis of SFPN, compared with 3% of biopsies from control subjects. MNSI and UENS scores were higher in patients with fibromyalgia than in control subjects. Abnormal AFTs were prevalent among patients with fibromyalgia, suggesting that fibromyalgia-associated SFPN is primarily somatic, said the researchers.
High glucose levels may be a risk factor for dementia, even among persons without diabetes, according to a study published August 8 in the New England Journal of Medicine. Researchers examined 35,264 clinical measurements of glucose levels and 10,208 measurements of glycated hemoglobin levels from 2,067 participants (1,228 women) without dementia. Participants’ mean age at baseline was 76. Of the total population, 232 participants had diabetes. During a median follow-up of 6.8 years, 524 participants developed dementia (74 with diabetes). Among participants without diabetes, higher average glucose levels within the preceding five years were related to an increased risk of dementia. A glucose level of 115 mg/dL, compared with 100 mg/dL, was associated with an adjusted hazard ratio for dementia of 1.18.
A majority of Alzheimer’s disease investigators favor disclosing amyloid imaging results to participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), according to a survey published online ahead of print August 21 in Neurology. Shortly before the FDA approved the amyloid-binding radiotracer florbetapir, all ADNI investigators and personnel were asked to complete an anonymous online survey that contained fixed-choice and free-text questions. Although ADNI participants often requested amyloid imaging results, the majority of ADNI investigators (approximately 90%) did not return amyloid imaging results to the participants. Most investigators reported that if the FDA approved florbetapir, they would support the return of amyloid imaging results to participants with mild cognitive impairment and normal cognition, however. ADNI investigators emphasized the need for guidance on how to provide these results to participants.
A sudden decrease of testosterone may induce nigrostriatal pathologies in mice through a decrease in glial-derived neurotrophic factor (GDNF) mediated by inducible nitric-oxide synthase (iNOS), investigators reported in the July 19 Journal of Biological Chemistry. Levels of iNOS, glial markers, and α-synuclein were higher in the nigra of castrated male mice than in normal male mice. After castration, the level of GDNF markedly decreased in the nigra of male mice, however. Subcutaneous implantation of 5 α-dihydrotestosterone pellets reversed nigrostriatal pathologies in castrated male mice, suggesting that the male sex hormone plays a role in castration-induced nigrostriatal pathology. Castrated young male mice may be used as a simple, toxin-free, and nontransgenic animal model to study Parkinson’s disease-related nigrostriatal pathologies, thus facilitating the screening of drugs against Parkinson’s disease, said the researchers.
IV thrombolysis within 90 minutes may be associated with excellent outcomes in patients with moderate and mild stroke, according to research published online ahead of print August 22 in Stroke. Investigators prospectively collected data for consecutive ischemic stroke patients who received IV thrombolysis at 10 European stroke centers. Logistic regression analysis suggested that shorter onset-to-treatment time was significantly associated with excellent outcome. Patients with onset-to-treatment time of 90 minutes or less had lower frequency of intracranial hemorrhage. After adjusting for age, sex, admission glucose level, and year of treatment, the researchers found that onset-to-treatment time of 90 minutes or less was associated with excellent outcome in patients with NIH Stroke Scale (NIHSS) score from 7 to 12, but not in patients with baseline NIHSS score greater than 12 and baseline NIHSS 0 to 6.
A neo-substrate approach involving the adenosine triphosphate (ATP) analog kinetin triphosphate (KTP) can increase the activity of Parkinson’s disease–related mutant PINK1G309D and PINK1WT, according to research published on August 15 in Cell. Investigators found that the normal and mutated versions of PINK1 bind to KTP. The application of KTP precursor kinetin to cells resulted in biologically significant increases in PINK1 activity, which were manifest as higher levels of Parkin recruitment to depolarized mitochondria, reduced mitochondrial motility in axons, and lower levels of apoptosis. Kinetin could treat patients with a known PINK1 mutation and also slow disease progression in patients without a family history of the disease, said the researchers. The search for neo-substrates for kinases could provide a novel way of regulating kinase activity, they concluded.
The effect of copper on brain amyloid-β homeostasis depends on whether it is accumulated in the capillaries or in the parenchyma, researchers reported online ahead of print August 19 in Proceedings of the National Academy of Sciences. In aging mice, the accumulation of copper in brain capillaries was associated with its reduction in low-density lipoprotein receptor–related protein 1 (LRP1) and higher brain amyloid-β levels. In human brain endothelial cells, normal labile levels of copper caused the downregulation of LRP1 by inducing nitrotyrosination and subsequent proteosomal-dependent degradation, partly because of interactions between copper, cellular prion protein, and LRP1. In APPsw/0 mice, copper downregulated LRP1 in brain capillaries and increased amyloid-b production and neuroinflammation. The effect resulted from the accumulation of copper in brain capillaries and in the parenchyma.
—Erik Greb
Senior Associate Editor
A recent case–control study provides further evidence against the Zamboni hypothesis that chronic cerebrospinal venous insufficiency is involved with multiple sclerosis (MS), researchers reported August 14 in PLOS One. The researchers randomly selected 100 patients with MS between ages 18 and 65 and 100 controls with no known history of MS or other neurologic condition. All participants underwent ultrasound imaging of the veins of the neck and the deep cerebral veins, as well as MRI of the neck veins and brain. The investigators found no evidence of reflux, stenosis, or blockage in the internal jugular veins or vertebral veins in any study participant and no evidence of reflux or cessation of flow in the deep cerebral veins in any subject.
Breastfeeding may reduce a woman’s risk of Alzheimer’s disease, according to research published online ahead of print July 23 in the Journal of Alzheimer’s Disease. Investigators collected reproductive history data from and conducted Alzheimer’s disease diagnostic interviews with a cohort of elderly British women. Analysis using Cox proportional-hazard models indicated that longer breastfeeding duration corresponded to reduced risk of Alzheimer’s disease. Women who breastfed had lower risk of Alzheimer’s disease than women who did not breastfeed. Breastfeeding practices are an important modifier of cumulative endogenous hormone exposure for mothers, according to the researchers. Future studies should consider how reproductive history leads to variation in endogenous hormone exposure and how this variation may influence the relationship between hormones and Alzheimer’s disease, the investigators concluded.
Among older adults, anemia may be associated with an increased risk of dementia, according to a study published August 6 in Neurology. Researchers studied 2,552 older adults (mean age, 76) participating in the Health, Aging, and Body Composition study and who were free of dementia at baseline. Of the total population, 392 participants had anemia at baseline. Over 11 years of follow-up, 455 participants developed dementia. An unadjusted analysis indicated that subjects with baseline anemia had an increased risk of dementia (23% vs 17%) compared with subjects without anemia. The association remained significant after adjusting for demographics, APOE ε4, baseline Modified Mini-Mental State score, comorbidities, and renal function. Additional adjustment for other anemia measures, erythropoietin, and C-reactive protein did not affect the results significantly.
The FDA has approved Trokendi XR, a once-daily extended release formulation of topiramate for the treatment of epilepsy. The agency granted a waiver for certain pediatric study requirements and a deferral for the submission of postmarketing pediatric pharmacokinetic assessments. Trokendi XR is indicated for initial monotherapy in patients ages 10 and older with partial onset or primary generalized tonic–clonic seizures. The drug also is approved as adjunctive therapy in patients ages 6 and older with partial onset or primary generalized tonic–clonic seizures, and as adjunctive therapy in patients ages 6 and older with seizures associated with Lennox–Gastaut syndrome. The product will be available in 25-, 50-, 100- and 200-mg extended-release capsules. Supernus Pharmaceuticals (Rockville, Maryland) expects to launch the product in September 2013.
The FDA has approved scored tablet and oral suspension formulations of ONFI (clobazam) CIV. ONFI is an oral antiepileptic drug of the benzodiazepine class (ie, a 1,5 benzodiazepine). The agency originally approved ONFI in 2011 as a prescription medication to treat seizures associated with Lennox–Gastaut syndrome in adults and children age 2 or older. The new oval-shaped ONFI scored tablets (10 mg and 20 mg) will replace the round, nonscored tablets and are similar in size. The new tablets contain the same ingredients as the round tablet, and the score allows patients or their caregivers to split the tablets in half. ONFI oral suspension (2.5 mg/mL) has a berry flavor. ONFI, manufactured by Lundbeck (Deerfield, Illinois), will no longer be available in a 5-mg tablet.
An incomplete circle of Willis may be more common in patients with migraine with aura than in the general population, according to research published July 26 in PLOS One. Investigators enrolled 56 migraineurs with aura, 61 migraineurs without aura, and 53 controls in an observational study. The researchers performed magnetic resonance angiography to examine subjects’ circle of Willis anatomy and measured cerebral blood flow with arterial spin–labeled perfusion MRI. An incomplete circle of Willis was significantly more common in migraineurs with aura, compared with controls (73% vs 51%). A similar trend was observed among migraineurs without aura (67% vs 51%). Compared with subjects with a complete circle of Willis, subjects with an incomplete circle had greater asymmetry in hemispheric cerebral blood flow.
Some patients with chronic pain diagnosed as fibromyalgia may have unrecognized small-fiber polyneuropathy (SFPN), according to research published online ahead of print June 7 in Pain. Investigators analyzed symptoms associated with SFPN, neurologic examinations, and pathologic and physiologic markers in 27 patients with fibromyalgia and 30 matched normal controls. Study instruments included the Michigan Neuropathy Screening Instrument (MNSI), the Utah Early Neuropathy Scale (UENS), distal-leg neurodiagnostic skin biopsies, and autonomic-function testing (AFT). Approximately 41% of skin biopsies from subjects with fibromyalgia supported a diagnosis of SFPN, compared with 3% of biopsies from control subjects. MNSI and UENS scores were higher in patients with fibromyalgia than in control subjects. Abnormal AFTs were prevalent among patients with fibromyalgia, suggesting that fibromyalgia-associated SFPN is primarily somatic, said the researchers.
High glucose levels may be a risk factor for dementia, even among persons without diabetes, according to a study published August 8 in the New England Journal of Medicine. Researchers examined 35,264 clinical measurements of glucose levels and 10,208 measurements of glycated hemoglobin levels from 2,067 participants (1,228 women) without dementia. Participants’ mean age at baseline was 76. Of the total population, 232 participants had diabetes. During a median follow-up of 6.8 years, 524 participants developed dementia (74 with diabetes). Among participants without diabetes, higher average glucose levels within the preceding five years were related to an increased risk of dementia. A glucose level of 115 mg/dL, compared with 100 mg/dL, was associated with an adjusted hazard ratio for dementia of 1.18.
A majority of Alzheimer’s disease investigators favor disclosing amyloid imaging results to participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), according to a survey published online ahead of print August 21 in Neurology. Shortly before the FDA approved the amyloid-binding radiotracer florbetapir, all ADNI investigators and personnel were asked to complete an anonymous online survey that contained fixed-choice and free-text questions. Although ADNI participants often requested amyloid imaging results, the majority of ADNI investigators (approximately 90%) did not return amyloid imaging results to the participants. Most investigators reported that if the FDA approved florbetapir, they would support the return of amyloid imaging results to participants with mild cognitive impairment and normal cognition, however. ADNI investigators emphasized the need for guidance on how to provide these results to participants.
A sudden decrease of testosterone may induce nigrostriatal pathologies in mice through a decrease in glial-derived neurotrophic factor (GDNF) mediated by inducible nitric-oxide synthase (iNOS), investigators reported in the July 19 Journal of Biological Chemistry. Levels of iNOS, glial markers, and α-synuclein were higher in the nigra of castrated male mice than in normal male mice. After castration, the level of GDNF markedly decreased in the nigra of male mice, however. Subcutaneous implantation of 5 α-dihydrotestosterone pellets reversed nigrostriatal pathologies in castrated male mice, suggesting that the male sex hormone plays a role in castration-induced nigrostriatal pathology. Castrated young male mice may be used as a simple, toxin-free, and nontransgenic animal model to study Parkinson’s disease-related nigrostriatal pathologies, thus facilitating the screening of drugs against Parkinson’s disease, said the researchers.
IV thrombolysis within 90 minutes may be associated with excellent outcomes in patients with moderate and mild stroke, according to research published online ahead of print August 22 in Stroke. Investigators prospectively collected data for consecutive ischemic stroke patients who received IV thrombolysis at 10 European stroke centers. Logistic regression analysis suggested that shorter onset-to-treatment time was significantly associated with excellent outcome. Patients with onset-to-treatment time of 90 minutes or less had lower frequency of intracranial hemorrhage. After adjusting for age, sex, admission glucose level, and year of treatment, the researchers found that onset-to-treatment time of 90 minutes or less was associated with excellent outcome in patients with NIH Stroke Scale (NIHSS) score from 7 to 12, but not in patients with baseline NIHSS score greater than 12 and baseline NIHSS 0 to 6.
A neo-substrate approach involving the adenosine triphosphate (ATP) analog kinetin triphosphate (KTP) can increase the activity of Parkinson’s disease–related mutant PINK1G309D and PINK1WT, according to research published on August 15 in Cell. Investigators found that the normal and mutated versions of PINK1 bind to KTP. The application of KTP precursor kinetin to cells resulted in biologically significant increases in PINK1 activity, which were manifest as higher levels of Parkin recruitment to depolarized mitochondria, reduced mitochondrial motility in axons, and lower levels of apoptosis. Kinetin could treat patients with a known PINK1 mutation and also slow disease progression in patients without a family history of the disease, said the researchers. The search for neo-substrates for kinases could provide a novel way of regulating kinase activity, they concluded.
The effect of copper on brain amyloid-β homeostasis depends on whether it is accumulated in the capillaries or in the parenchyma, researchers reported online ahead of print August 19 in Proceedings of the National Academy of Sciences. In aging mice, the accumulation of copper in brain capillaries was associated with its reduction in low-density lipoprotein receptor–related protein 1 (LRP1) and higher brain amyloid-β levels. In human brain endothelial cells, normal labile levels of copper caused the downregulation of LRP1 by inducing nitrotyrosination and subsequent proteosomal-dependent degradation, partly because of interactions between copper, cellular prion protein, and LRP1. In APPsw/0 mice, copper downregulated LRP1 in brain capillaries and increased amyloid-b production and neuroinflammation. The effect resulted from the accumulation of copper in brain capillaries and in the parenchyma.
—Erik Greb
Senior Associate Editor
A recent case–control study provides further evidence against the Zamboni hypothesis that chronic cerebrospinal venous insufficiency is involved with multiple sclerosis (MS), researchers reported August 14 in PLOS One. The researchers randomly selected 100 patients with MS between ages 18 and 65 and 100 controls with no known history of MS or other neurologic condition. All participants underwent ultrasound imaging of the veins of the neck and the deep cerebral veins, as well as MRI of the neck veins and brain. The investigators found no evidence of reflux, stenosis, or blockage in the internal jugular veins or vertebral veins in any study participant and no evidence of reflux or cessation of flow in the deep cerebral veins in any subject.
Breastfeeding may reduce a woman’s risk of Alzheimer’s disease, according to research published online ahead of print July 23 in the Journal of Alzheimer’s Disease. Investigators collected reproductive history data from and conducted Alzheimer’s disease diagnostic interviews with a cohort of elderly British women. Analysis using Cox proportional-hazard models indicated that longer breastfeeding duration corresponded to reduced risk of Alzheimer’s disease. Women who breastfed had lower risk of Alzheimer’s disease than women who did not breastfeed. Breastfeeding practices are an important modifier of cumulative endogenous hormone exposure for mothers, according to the researchers. Future studies should consider how reproductive history leads to variation in endogenous hormone exposure and how this variation may influence the relationship between hormones and Alzheimer’s disease, the investigators concluded.
Among older adults, anemia may be associated with an increased risk of dementia, according to a study published August 6 in Neurology. Researchers studied 2,552 older adults (mean age, 76) participating in the Health, Aging, and Body Composition study and who were free of dementia at baseline. Of the total population, 392 participants had anemia at baseline. Over 11 years of follow-up, 455 participants developed dementia. An unadjusted analysis indicated that subjects with baseline anemia had an increased risk of dementia (23% vs 17%) compared with subjects without anemia. The association remained significant after adjusting for demographics, APOE ε4, baseline Modified Mini-Mental State score, comorbidities, and renal function. Additional adjustment for other anemia measures, erythropoietin, and C-reactive protein did not affect the results significantly.
The FDA has approved Trokendi XR, a once-daily extended release formulation of topiramate for the treatment of epilepsy. The agency granted a waiver for certain pediatric study requirements and a deferral for the submission of postmarketing pediatric pharmacokinetic assessments. Trokendi XR is indicated for initial monotherapy in patients ages 10 and older with partial onset or primary generalized tonic–clonic seizures. The drug also is approved as adjunctive therapy in patients ages 6 and older with partial onset or primary generalized tonic–clonic seizures, and as adjunctive therapy in patients ages 6 and older with seizures associated with Lennox–Gastaut syndrome. The product will be available in 25-, 50-, 100- and 200-mg extended-release capsules. Supernus Pharmaceuticals (Rockville, Maryland) expects to launch the product in September 2013.
The FDA has approved scored tablet and oral suspension formulations of ONFI (clobazam) CIV. ONFI is an oral antiepileptic drug of the benzodiazepine class (ie, a 1,5 benzodiazepine). The agency originally approved ONFI in 2011 as a prescription medication to treat seizures associated with Lennox–Gastaut syndrome in adults and children age 2 or older. The new oval-shaped ONFI scored tablets (10 mg and 20 mg) will replace the round, nonscored tablets and are similar in size. The new tablets contain the same ingredients as the round tablet, and the score allows patients or their caregivers to split the tablets in half. ONFI oral suspension (2.5 mg/mL) has a berry flavor. ONFI, manufactured by Lundbeck (Deerfield, Illinois), will no longer be available in a 5-mg tablet.
An incomplete circle of Willis may be more common in patients with migraine with aura than in the general population, according to research published July 26 in PLOS One. Investigators enrolled 56 migraineurs with aura, 61 migraineurs without aura, and 53 controls in an observational study. The researchers performed magnetic resonance angiography to examine subjects’ circle of Willis anatomy and measured cerebral blood flow with arterial spin–labeled perfusion MRI. An incomplete circle of Willis was significantly more common in migraineurs with aura, compared with controls (73% vs 51%). A similar trend was observed among migraineurs without aura (67% vs 51%). Compared with subjects with a complete circle of Willis, subjects with an incomplete circle had greater asymmetry in hemispheric cerebral blood flow.
Some patients with chronic pain diagnosed as fibromyalgia may have unrecognized small-fiber polyneuropathy (SFPN), according to research published online ahead of print June 7 in Pain. Investigators analyzed symptoms associated with SFPN, neurologic examinations, and pathologic and physiologic markers in 27 patients with fibromyalgia and 30 matched normal controls. Study instruments included the Michigan Neuropathy Screening Instrument (MNSI), the Utah Early Neuropathy Scale (UENS), distal-leg neurodiagnostic skin biopsies, and autonomic-function testing (AFT). Approximately 41% of skin biopsies from subjects with fibromyalgia supported a diagnosis of SFPN, compared with 3% of biopsies from control subjects. MNSI and UENS scores were higher in patients with fibromyalgia than in control subjects. Abnormal AFTs were prevalent among patients with fibromyalgia, suggesting that fibromyalgia-associated SFPN is primarily somatic, said the researchers.
High glucose levels may be a risk factor for dementia, even among persons without diabetes, according to a study published August 8 in the New England Journal of Medicine. Researchers examined 35,264 clinical measurements of glucose levels and 10,208 measurements of glycated hemoglobin levels from 2,067 participants (1,228 women) without dementia. Participants’ mean age at baseline was 76. Of the total population, 232 participants had diabetes. During a median follow-up of 6.8 years, 524 participants developed dementia (74 with diabetes). Among participants without diabetes, higher average glucose levels within the preceding five years were related to an increased risk of dementia. A glucose level of 115 mg/dL, compared with 100 mg/dL, was associated with an adjusted hazard ratio for dementia of 1.18.
A majority of Alzheimer’s disease investigators favor disclosing amyloid imaging results to participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), according to a survey published online ahead of print August 21 in Neurology. Shortly before the FDA approved the amyloid-binding radiotracer florbetapir, all ADNI investigators and personnel were asked to complete an anonymous online survey that contained fixed-choice and free-text questions. Although ADNI participants often requested amyloid imaging results, the majority of ADNI investigators (approximately 90%) did not return amyloid imaging results to the participants. Most investigators reported that if the FDA approved florbetapir, they would support the return of amyloid imaging results to participants with mild cognitive impairment and normal cognition, however. ADNI investigators emphasized the need for guidance on how to provide these results to participants.
A sudden decrease of testosterone may induce nigrostriatal pathologies in mice through a decrease in glial-derived neurotrophic factor (GDNF) mediated by inducible nitric-oxide synthase (iNOS), investigators reported in the July 19 Journal of Biological Chemistry. Levels of iNOS, glial markers, and α-synuclein were higher in the nigra of castrated male mice than in normal male mice. After castration, the level of GDNF markedly decreased in the nigra of male mice, however. Subcutaneous implantation of 5 α-dihydrotestosterone pellets reversed nigrostriatal pathologies in castrated male mice, suggesting that the male sex hormone plays a role in castration-induced nigrostriatal pathology. Castrated young male mice may be used as a simple, toxin-free, and nontransgenic animal model to study Parkinson’s disease-related nigrostriatal pathologies, thus facilitating the screening of drugs against Parkinson’s disease, said the researchers.
IV thrombolysis within 90 minutes may be associated with excellent outcomes in patients with moderate and mild stroke, according to research published online ahead of print August 22 in Stroke. Investigators prospectively collected data for consecutive ischemic stroke patients who received IV thrombolysis at 10 European stroke centers. Logistic regression analysis suggested that shorter onset-to-treatment time was significantly associated with excellent outcome. Patients with onset-to-treatment time of 90 minutes or less had lower frequency of intracranial hemorrhage. After adjusting for age, sex, admission glucose level, and year of treatment, the researchers found that onset-to-treatment time of 90 minutes or less was associated with excellent outcome in patients with NIH Stroke Scale (NIHSS) score from 7 to 12, but not in patients with baseline NIHSS score greater than 12 and baseline NIHSS 0 to 6.
A neo-substrate approach involving the adenosine triphosphate (ATP) analog kinetin triphosphate (KTP) can increase the activity of Parkinson’s disease–related mutant PINK1G309D and PINK1WT, according to research published on August 15 in Cell. Investigators found that the normal and mutated versions of PINK1 bind to KTP. The application of KTP precursor kinetin to cells resulted in biologically significant increases in PINK1 activity, which were manifest as higher levels of Parkin recruitment to depolarized mitochondria, reduced mitochondrial motility in axons, and lower levels of apoptosis. Kinetin could treat patients with a known PINK1 mutation and also slow disease progression in patients without a family history of the disease, said the researchers. The search for neo-substrates for kinases could provide a novel way of regulating kinase activity, they concluded.
The effect of copper on brain amyloid-β homeostasis depends on whether it is accumulated in the capillaries or in the parenchyma, researchers reported online ahead of print August 19 in Proceedings of the National Academy of Sciences. In aging mice, the accumulation of copper in brain capillaries was associated with its reduction in low-density lipoprotein receptor–related protein 1 (LRP1) and higher brain amyloid-β levels. In human brain endothelial cells, normal labile levels of copper caused the downregulation of LRP1 by inducing nitrotyrosination and subsequent proteosomal-dependent degradation, partly because of interactions between copper, cellular prion protein, and LRP1. In APPsw/0 mice, copper downregulated LRP1 in brain capillaries and increased amyloid-b production and neuroinflammation. The effect resulted from the accumulation of copper in brain capillaries and in the parenchyma.
—Erik Greb
Senior Associate Editor
Heart Effects of Fingolimod May Resolve Within Six Hours
ORLANDO—The first-dose cardiovascular effects of fingolimod 0.5 mg may be transient in most patients with multiple sclerosis (MS). The effects begin to resolve within six hours after administration, according to analyses of two phase III trials and interim results of a phase IV study.
The analyses, which were presented at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS, confirmed that the initiation of treatment with fingolimod is associated with a decrease in heart rate and a slowing of atrioventricular conduction, especially in the first four to six hours. Previously reported cases of bradycardia and atrioventricular block have been mostly transient and self-limited, said the investigators.
All patients who receive fingolimod “should be observed and receive hourly pulse and blood pressure measurement for at least six hours after first dose and undergo ECG predose and after the six-hour observation,” according to the drug’s current prescribing information. The label for fingolimod was revised in May 2012 following reports of sudden or unexplained deaths in the United States and Europe after the drug’s 2010 approval for relapsing forms of MS.
Fingolimod Reduced Heart Rate at Five Hours
In the phase IV EPOC (Evaluate Patient Outcomes, Safety, and Tolerability of Fingolimod) study, 783 patients in the United States and Canada were randomized 3:1 to open-label treatment with once-daily fingolimod 0.5 mg or standard-of-care disease-modifying therapy (DMT) for six months. No patients had taken fingolimod previously, and all received at least one dose of the therapy. Subjects had received continuous treatment with a single standard-of-care DMT for six months or more. Patients’ mean age was 46, and most were white (82%) and female (76%). The mean duration of their MS symptoms was 12 years.
Patients’ mean sitting heart rate decreased from 74.1 bpm at baseline to 65.6 bpm at five hours after administration of fingolimod, said Bruce L. Hughes, MD, Director of Ruan MS Center in Des Moines, Iowa, and his colleagues. Heart rate began to recover by the sixth hour.
Most patients (98.6%) were discharged at six hours after treatment. Ten subjects required extended observations after the sixth hour, and three required a second day of observation and were subsequently discharged.
Twelve patients (1.5%) had bradycardia during the first-dose observation period. Of these patients, eight were symptomatic, four were asymptomatic, and none required treatment, according to the researchers. The mean heart rate in this group decreased to 56.3 ± 8.53 bpm and ranged from 38 to 64 bpm during bradycardia events. The patients recovered to 62.6 ± 9.46 bpm, ranging from 52 to 80 bpm, after the symptoms resolved.
Nearly 18% of the patients (137 of 783) underwent ECG at six hours postdose. In 28 subjects, the second ECG differed from the baseline ECG, and the most common new findings were first-degree atrioventricular block (11 patients) and sinus bradycardia (10 patients). There were no second-degree atrioventricular blocks. Other findings included late anterior hemiblock (one patient), atrial premature complex (two patients), and biphasic T waves (one patient).
Heart-Rate Decrease Was Greater for Patients Without Cardiac Factors
The two other studies reported at the meeting also analyzed the first-dose cardiovascular effects of fingolimod 0.5 mg. The FIRST trial was a four-month, open-label, phase IIIb study of 2,417 patients with relapsing MS, and the FREEDOMS II trial was a two-year, double-blind, placebo-controlled, phase III study of 1,083 patients.
In the FIRST trial, the lowest heart rate occurred at four to five hours postdose. The mean decrease was 7.4 bpm in patients without cardiac factors and 6.5 bpm in those with cardiac factors, said the researchers. The cardiac factors included beta-blocker or calcium channel blocker use (120 patients), resting heart rate of 45 to 54 bpm, Mobitz type I second-degree atrioventricular block, positive tilt test, and recurrent symptomatic bradycardia.
Simrat Randhawa, MD, from Novartis Pharmaceuticals, and her colleagues reported that the mean decrease in heart rate was 7.2 and 7.3 bpm in patients without and with concomitant beta-blocker or calcium channel blocker use, respectively. One patient had a greater than three-second pause in screening and postdose ECG results. One patient discontinued the study drug because of second-degree atrioventricular block, the authors reported.
In the FREEDOMS II trial, the clinician-observed mean maximal decrease in heart rate was 8.5 bpm among patients who received fingolimod. The incidence of Mobitz I second-degree atrioventricular block with fingolimod was 3.7%, compared with 2.0% for placebo. In addition, 2:1 atrioventricular block occurred in 2% of patients taking fingolimod and in no control patients.
Most first-occurrence, second-degree atrioventricular blocks were observed less than six hours after the first dose, according to the researchers. No Mobitz II or third-degree atrioventricular blocks were reported in FIRST or FREEDOMS II.
It is difficult to identify which patients should receive fingolimod, but less difficult to identify patients who should not receive it, said Robert P. Lisak, MD, Professor of Neurology at Wayne State University in Detroit and President-Elect of CMSC. “But once they’re on it, and if they don’t have other contraindications, they should be OK.”
—Naseem S. Miller
IMNG Medical News
Suggested Reading
Cohen JA, Chun J. Mechanisms of fingolimod’s efficacy and adverse effects in multiple sclerosis. Ann Neurol. 2011;69(5):759-777.
Espinosa PS, Berger JR. Delayed fingolimod-associated asystole. Mult Scler. 2011;17(11):1387-1389.
Schmouder R, Hariry S, David OJ. Placebo-controlled study of the effects of fingolimod on cardiac rate and rhythm and pulmonary function in healthy volunteers. Eur J Clin Pharmacol. 2012;68(4):355-362.
ORLANDO—The first-dose cardiovascular effects of fingolimod 0.5 mg may be transient in most patients with multiple sclerosis (MS). The effects begin to resolve within six hours after administration, according to analyses of two phase III trials and interim results of a phase IV study.
The analyses, which were presented at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS, confirmed that the initiation of treatment with fingolimod is associated with a decrease in heart rate and a slowing of atrioventricular conduction, especially in the first four to six hours. Previously reported cases of bradycardia and atrioventricular block have been mostly transient and self-limited, said the investigators.
All patients who receive fingolimod “should be observed and receive hourly pulse and blood pressure measurement for at least six hours after first dose and undergo ECG predose and after the six-hour observation,” according to the drug’s current prescribing information. The label for fingolimod was revised in May 2012 following reports of sudden or unexplained deaths in the United States and Europe after the drug’s 2010 approval for relapsing forms of MS.
Fingolimod Reduced Heart Rate at Five Hours
In the phase IV EPOC (Evaluate Patient Outcomes, Safety, and Tolerability of Fingolimod) study, 783 patients in the United States and Canada were randomized 3:1 to open-label treatment with once-daily fingolimod 0.5 mg or standard-of-care disease-modifying therapy (DMT) for six months. No patients had taken fingolimod previously, and all received at least one dose of the therapy. Subjects had received continuous treatment with a single standard-of-care DMT for six months or more. Patients’ mean age was 46, and most were white (82%) and female (76%). The mean duration of their MS symptoms was 12 years.
Patients’ mean sitting heart rate decreased from 74.1 bpm at baseline to 65.6 bpm at five hours after administration of fingolimod, said Bruce L. Hughes, MD, Director of Ruan MS Center in Des Moines, Iowa, and his colleagues. Heart rate began to recover by the sixth hour.
Most patients (98.6%) were discharged at six hours after treatment. Ten subjects required extended observations after the sixth hour, and three required a second day of observation and were subsequently discharged.
Twelve patients (1.5%) had bradycardia during the first-dose observation period. Of these patients, eight were symptomatic, four were asymptomatic, and none required treatment, according to the researchers. The mean heart rate in this group decreased to 56.3 ± 8.53 bpm and ranged from 38 to 64 bpm during bradycardia events. The patients recovered to 62.6 ± 9.46 bpm, ranging from 52 to 80 bpm, after the symptoms resolved.
Nearly 18% of the patients (137 of 783) underwent ECG at six hours postdose. In 28 subjects, the second ECG differed from the baseline ECG, and the most common new findings were first-degree atrioventricular block (11 patients) and sinus bradycardia (10 patients). There were no second-degree atrioventricular blocks. Other findings included late anterior hemiblock (one patient), atrial premature complex (two patients), and biphasic T waves (one patient).
Heart-Rate Decrease Was Greater for Patients Without Cardiac Factors
The two other studies reported at the meeting also analyzed the first-dose cardiovascular effects of fingolimod 0.5 mg. The FIRST trial was a four-month, open-label, phase IIIb study of 2,417 patients with relapsing MS, and the FREEDOMS II trial was a two-year, double-blind, placebo-controlled, phase III study of 1,083 patients.
In the FIRST trial, the lowest heart rate occurred at four to five hours postdose. The mean decrease was 7.4 bpm in patients without cardiac factors and 6.5 bpm in those with cardiac factors, said the researchers. The cardiac factors included beta-blocker or calcium channel blocker use (120 patients), resting heart rate of 45 to 54 bpm, Mobitz type I second-degree atrioventricular block, positive tilt test, and recurrent symptomatic bradycardia.
Simrat Randhawa, MD, from Novartis Pharmaceuticals, and her colleagues reported that the mean decrease in heart rate was 7.2 and 7.3 bpm in patients without and with concomitant beta-blocker or calcium channel blocker use, respectively. One patient had a greater than three-second pause in screening and postdose ECG results. One patient discontinued the study drug because of second-degree atrioventricular block, the authors reported.
In the FREEDOMS II trial, the clinician-observed mean maximal decrease in heart rate was 8.5 bpm among patients who received fingolimod. The incidence of Mobitz I second-degree atrioventricular block with fingolimod was 3.7%, compared with 2.0% for placebo. In addition, 2:1 atrioventricular block occurred in 2% of patients taking fingolimod and in no control patients.
Most first-occurrence, second-degree atrioventricular blocks were observed less than six hours after the first dose, according to the researchers. No Mobitz II or third-degree atrioventricular blocks were reported in FIRST or FREEDOMS II.
It is difficult to identify which patients should receive fingolimod, but less difficult to identify patients who should not receive it, said Robert P. Lisak, MD, Professor of Neurology at Wayne State University in Detroit and President-Elect of CMSC. “But once they’re on it, and if they don’t have other contraindications, they should be OK.”
—Naseem S. Miller
IMNG Medical News
ORLANDO—The first-dose cardiovascular effects of fingolimod 0.5 mg may be transient in most patients with multiple sclerosis (MS). The effects begin to resolve within six hours after administration, according to analyses of two phase III trials and interim results of a phase IV study.
The analyses, which were presented at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS, confirmed that the initiation of treatment with fingolimod is associated with a decrease in heart rate and a slowing of atrioventricular conduction, especially in the first four to six hours. Previously reported cases of bradycardia and atrioventricular block have been mostly transient and self-limited, said the investigators.
All patients who receive fingolimod “should be observed and receive hourly pulse and blood pressure measurement for at least six hours after first dose and undergo ECG predose and after the six-hour observation,” according to the drug’s current prescribing information. The label for fingolimod was revised in May 2012 following reports of sudden or unexplained deaths in the United States and Europe after the drug’s 2010 approval for relapsing forms of MS.
Fingolimod Reduced Heart Rate at Five Hours
In the phase IV EPOC (Evaluate Patient Outcomes, Safety, and Tolerability of Fingolimod) study, 783 patients in the United States and Canada were randomized 3:1 to open-label treatment with once-daily fingolimod 0.5 mg or standard-of-care disease-modifying therapy (DMT) for six months. No patients had taken fingolimod previously, and all received at least one dose of the therapy. Subjects had received continuous treatment with a single standard-of-care DMT for six months or more. Patients’ mean age was 46, and most were white (82%) and female (76%). The mean duration of their MS symptoms was 12 years.
Patients’ mean sitting heart rate decreased from 74.1 bpm at baseline to 65.6 bpm at five hours after administration of fingolimod, said Bruce L. Hughes, MD, Director of Ruan MS Center in Des Moines, Iowa, and his colleagues. Heart rate began to recover by the sixth hour.
Most patients (98.6%) were discharged at six hours after treatment. Ten subjects required extended observations after the sixth hour, and three required a second day of observation and were subsequently discharged.
Twelve patients (1.5%) had bradycardia during the first-dose observation period. Of these patients, eight were symptomatic, four were asymptomatic, and none required treatment, according to the researchers. The mean heart rate in this group decreased to 56.3 ± 8.53 bpm and ranged from 38 to 64 bpm during bradycardia events. The patients recovered to 62.6 ± 9.46 bpm, ranging from 52 to 80 bpm, after the symptoms resolved.
Nearly 18% of the patients (137 of 783) underwent ECG at six hours postdose. In 28 subjects, the second ECG differed from the baseline ECG, and the most common new findings were first-degree atrioventricular block (11 patients) and sinus bradycardia (10 patients). There were no second-degree atrioventricular blocks. Other findings included late anterior hemiblock (one patient), atrial premature complex (two patients), and biphasic T waves (one patient).
Heart-Rate Decrease Was Greater for Patients Without Cardiac Factors
The two other studies reported at the meeting also analyzed the first-dose cardiovascular effects of fingolimod 0.5 mg. The FIRST trial was a four-month, open-label, phase IIIb study of 2,417 patients with relapsing MS, and the FREEDOMS II trial was a two-year, double-blind, placebo-controlled, phase III study of 1,083 patients.
In the FIRST trial, the lowest heart rate occurred at four to five hours postdose. The mean decrease was 7.4 bpm in patients without cardiac factors and 6.5 bpm in those with cardiac factors, said the researchers. The cardiac factors included beta-blocker or calcium channel blocker use (120 patients), resting heart rate of 45 to 54 bpm, Mobitz type I second-degree atrioventricular block, positive tilt test, and recurrent symptomatic bradycardia.
Simrat Randhawa, MD, from Novartis Pharmaceuticals, and her colleagues reported that the mean decrease in heart rate was 7.2 and 7.3 bpm in patients without and with concomitant beta-blocker or calcium channel blocker use, respectively. One patient had a greater than three-second pause in screening and postdose ECG results. One patient discontinued the study drug because of second-degree atrioventricular block, the authors reported.
In the FREEDOMS II trial, the clinician-observed mean maximal decrease in heart rate was 8.5 bpm among patients who received fingolimod. The incidence of Mobitz I second-degree atrioventricular block with fingolimod was 3.7%, compared with 2.0% for placebo. In addition, 2:1 atrioventricular block occurred in 2% of patients taking fingolimod and in no control patients.
Most first-occurrence, second-degree atrioventricular blocks were observed less than six hours after the first dose, according to the researchers. No Mobitz II or third-degree atrioventricular blocks were reported in FIRST or FREEDOMS II.
It is difficult to identify which patients should receive fingolimod, but less difficult to identify patients who should not receive it, said Robert P. Lisak, MD, Professor of Neurology at Wayne State University in Detroit and President-Elect of CMSC. “But once they’re on it, and if they don’t have other contraindications, they should be OK.”
—Naseem S. Miller
IMNG Medical News
Suggested Reading
Cohen JA, Chun J. Mechanisms of fingolimod’s efficacy and adverse effects in multiple sclerosis. Ann Neurol. 2011;69(5):759-777.
Espinosa PS, Berger JR. Delayed fingolimod-associated asystole. Mult Scler. 2011;17(11):1387-1389.
Schmouder R, Hariry S, David OJ. Placebo-controlled study of the effects of fingolimod on cardiac rate and rhythm and pulmonary function in healthy volunteers. Eur J Clin Pharmacol. 2012;68(4):355-362.
Suggested Reading
Cohen JA, Chun J. Mechanisms of fingolimod’s efficacy and adverse effects in multiple sclerosis. Ann Neurol. 2011;69(5):759-777.
Espinosa PS, Berger JR. Delayed fingolimod-associated asystole. Mult Scler. 2011;17(11):1387-1389.
Schmouder R, Hariry S, David OJ. Placebo-controlled study of the effects of fingolimod on cardiac rate and rhythm and pulmonary function in healthy volunteers. Eur J Clin Pharmacol. 2012;68(4):355-362.
Recommendations Outline How to Improve Dimethyl Fumarate Tolerability in MS
ORLANDO—The flushing frequently reported in conjunction with oral dimethyl fumarate therapy for relapsing forms of multiple sclerosis (MS) is greatly reduced by aspirin pretreatment, J. Theodore Phillips, MD, PhD, reported at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS.
In contrast, slowed titration of dimethyl fumarate does not diminish the gastrointestinal adverse effects, which are common during the first two months of therapy, noted Dr. Phillips, Research Investigator at the MS Research Program, Baylor Institute for Immunology Research in Dallas.
Dr. Phillips was part of a consensus panel that presented recommendations for maximizing the tolerability of dimethyl fumarate, which was approved earlier this year as the third oral agent for the treatment of MS.
In an interview, Dr. Phillips said that the recommendations are largely based on expert opinion rather than on rigorous, evidence-based guidelines. After the pivotal phase III DEFINE and CONFIRM clinical trials were completed, he and four other study leaders decided to ask the investigators who had enrolled at least 10 patients in the trials how they had managed flushing and gastrointestinal upset problems. The flushing and gastrointestinal side effects were reported by 36% and 42%, respectively, of study patients randomized to the drug. The incidence decreased after the first month. These side effects were generally rated by investigators as mild to moderate in nature. Flushing resulted in study dropout of 2.5% of patients, and 4.3% discontinued because of gastrointestinal adverse events.
Thirty of the 84 invited clinical investigators completed the questionnaire. Investigators at Biogen Idec conducted their own randomized, double-blind, phase IIIb study in 172 healthy volunteers, the results of which have been incorporated into the panel’s recommendations. Participants in the eight-week trial were randomized to one of four treatment arms: dimethyl fumarate titrated in standard fashion for one week plus 325 mg of non–enteric-coated aspirin taken 30 minutes beforehand during weeks 1 to 4, replaced by aspirin placebo in weeks 5 to 8; dimethyl fumarate plus aspirin placebo during weeks 1 to 4; dimethyl fumarate slow-titrated during the course of three weeks; and double placebo.
Roughly 80% of subjects who received dimethyl fumarate without aspirin experienced flushing events self-assessed as mild to moderate. Although participants were taking both dimethyl fumarate and aspirin, their flushing frequency and severity were similar to those of participants receiving double placebo. Slow titration of dimethyl fumarate had no impact on gastrointestinal symptoms or flushing frequency or severity.
The panel’s recommendations for managing nausea or vomiting or abdominal pain were to advise taking the drug with food and consider prescribing a proton pump inhibitor or H2 receptor antagonist. Metoclopramide or domperidone is another recommended option for those with nausea or vomiting. For patients who experience medication-related diarrhea, the panel advised loperamide or other standard antidiarrheal agents.
“Vasocutaneous flushing and gastrointestinal upset in association with dosing of [dimethyl fumarate] could for obvious reasons affect a person’s enthusiasm for going on,” Dr. Phillips commented. “The main thing is for the physician to set expectations by acknowledging up front these issues as part of the risk–benefit discussion prior to initiating the drug. Tell the patient that if those side effects were to happen, we’ve got game plans to deal with them.”
—Bruce Jancin
IMNG Medical News
Suggested Reading
Oh J, O’Connor PW. Safety, tolerability, and efficacy of oral therapies for relapsing-remitting multiple sclerosis. CNS Drugs. 2013;27(8):591-609.
ORLANDO—The flushing frequently reported in conjunction with oral dimethyl fumarate therapy for relapsing forms of multiple sclerosis (MS) is greatly reduced by aspirin pretreatment, J. Theodore Phillips, MD, PhD, reported at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS.
In contrast, slowed titration of dimethyl fumarate does not diminish the gastrointestinal adverse effects, which are common during the first two months of therapy, noted Dr. Phillips, Research Investigator at the MS Research Program, Baylor Institute for Immunology Research in Dallas.
Dr. Phillips was part of a consensus panel that presented recommendations for maximizing the tolerability of dimethyl fumarate, which was approved earlier this year as the third oral agent for the treatment of MS.
In an interview, Dr. Phillips said that the recommendations are largely based on expert opinion rather than on rigorous, evidence-based guidelines. After the pivotal phase III DEFINE and CONFIRM clinical trials were completed, he and four other study leaders decided to ask the investigators who had enrolled at least 10 patients in the trials how they had managed flushing and gastrointestinal upset problems. The flushing and gastrointestinal side effects were reported by 36% and 42%, respectively, of study patients randomized to the drug. The incidence decreased after the first month. These side effects were generally rated by investigators as mild to moderate in nature. Flushing resulted in study dropout of 2.5% of patients, and 4.3% discontinued because of gastrointestinal adverse events.
Thirty of the 84 invited clinical investigators completed the questionnaire. Investigators at Biogen Idec conducted their own randomized, double-blind, phase IIIb study in 172 healthy volunteers, the results of which have been incorporated into the panel’s recommendations. Participants in the eight-week trial were randomized to one of four treatment arms: dimethyl fumarate titrated in standard fashion for one week plus 325 mg of non–enteric-coated aspirin taken 30 minutes beforehand during weeks 1 to 4, replaced by aspirin placebo in weeks 5 to 8; dimethyl fumarate plus aspirin placebo during weeks 1 to 4; dimethyl fumarate slow-titrated during the course of three weeks; and double placebo.
Roughly 80% of subjects who received dimethyl fumarate without aspirin experienced flushing events self-assessed as mild to moderate. Although participants were taking both dimethyl fumarate and aspirin, their flushing frequency and severity were similar to those of participants receiving double placebo. Slow titration of dimethyl fumarate had no impact on gastrointestinal symptoms or flushing frequency or severity.
The panel’s recommendations for managing nausea or vomiting or abdominal pain were to advise taking the drug with food and consider prescribing a proton pump inhibitor or H2 receptor antagonist. Metoclopramide or domperidone is another recommended option for those with nausea or vomiting. For patients who experience medication-related diarrhea, the panel advised loperamide or other standard antidiarrheal agents.
“Vasocutaneous flushing and gastrointestinal upset in association with dosing of [dimethyl fumarate] could for obvious reasons affect a person’s enthusiasm for going on,” Dr. Phillips commented. “The main thing is for the physician to set expectations by acknowledging up front these issues as part of the risk–benefit discussion prior to initiating the drug. Tell the patient that if those side effects were to happen, we’ve got game plans to deal with them.”
—Bruce Jancin
IMNG Medical News
ORLANDO—The flushing frequently reported in conjunction with oral dimethyl fumarate therapy for relapsing forms of multiple sclerosis (MS) is greatly reduced by aspirin pretreatment, J. Theodore Phillips, MD, PhD, reported at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS.
In contrast, slowed titration of dimethyl fumarate does not diminish the gastrointestinal adverse effects, which are common during the first two months of therapy, noted Dr. Phillips, Research Investigator at the MS Research Program, Baylor Institute for Immunology Research in Dallas.
Dr. Phillips was part of a consensus panel that presented recommendations for maximizing the tolerability of dimethyl fumarate, which was approved earlier this year as the third oral agent for the treatment of MS.
In an interview, Dr. Phillips said that the recommendations are largely based on expert opinion rather than on rigorous, evidence-based guidelines. After the pivotal phase III DEFINE and CONFIRM clinical trials were completed, he and four other study leaders decided to ask the investigators who had enrolled at least 10 patients in the trials how they had managed flushing and gastrointestinal upset problems. The flushing and gastrointestinal side effects were reported by 36% and 42%, respectively, of study patients randomized to the drug. The incidence decreased after the first month. These side effects were generally rated by investigators as mild to moderate in nature. Flushing resulted in study dropout of 2.5% of patients, and 4.3% discontinued because of gastrointestinal adverse events.
Thirty of the 84 invited clinical investigators completed the questionnaire. Investigators at Biogen Idec conducted their own randomized, double-blind, phase IIIb study in 172 healthy volunteers, the results of which have been incorporated into the panel’s recommendations. Participants in the eight-week trial were randomized to one of four treatment arms: dimethyl fumarate titrated in standard fashion for one week plus 325 mg of non–enteric-coated aspirin taken 30 minutes beforehand during weeks 1 to 4, replaced by aspirin placebo in weeks 5 to 8; dimethyl fumarate plus aspirin placebo during weeks 1 to 4; dimethyl fumarate slow-titrated during the course of three weeks; and double placebo.
Roughly 80% of subjects who received dimethyl fumarate without aspirin experienced flushing events self-assessed as mild to moderate. Although participants were taking both dimethyl fumarate and aspirin, their flushing frequency and severity were similar to those of participants receiving double placebo. Slow titration of dimethyl fumarate had no impact on gastrointestinal symptoms or flushing frequency or severity.
The panel’s recommendations for managing nausea or vomiting or abdominal pain were to advise taking the drug with food and consider prescribing a proton pump inhibitor or H2 receptor antagonist. Metoclopramide or domperidone is another recommended option for those with nausea or vomiting. For patients who experience medication-related diarrhea, the panel advised loperamide or other standard antidiarrheal agents.
“Vasocutaneous flushing and gastrointestinal upset in association with dosing of [dimethyl fumarate] could for obvious reasons affect a person’s enthusiasm for going on,” Dr. Phillips commented. “The main thing is for the physician to set expectations by acknowledging up front these issues as part of the risk–benefit discussion prior to initiating the drug. Tell the patient that if those side effects were to happen, we’ve got game plans to deal with them.”
—Bruce Jancin
IMNG Medical News
Suggested Reading
Oh J, O’Connor PW. Safety, tolerability, and efficacy of oral therapies for relapsing-remitting multiple sclerosis. CNS Drugs. 2013;27(8):591-609.
Suggested Reading
Oh J, O’Connor PW. Safety, tolerability, and efficacy of oral therapies for relapsing-remitting multiple sclerosis. CNS Drugs. 2013;27(8):591-609.
New and Noteworthy Information—August 2013
Patients with Alzheimer’s disease are less likely to have cancer, and patients with cancer are less likely to have Alzheimer’s disease, according to data published online ahead of print July 10 in Neurology. Researchers conducted a cohort study of more than one million people in northern Italy. They derived cancer incidence using the local health authority’s tumor registry and calculated the incidence of Alzheimer’s dementia from registries of drug prescriptions, hospitalizations, and payment exemptions. The risk of cancer in patients with Alzheimer’s dementia was reduced by 50%, and the risk of Alzheimer’s dementia in patients with cancer was reduced by 35%. The investigators observed this relationship in almost all subgroup analyses, suggesting that anticipated potential confounding factors did not significantly influence the results.
Children exposed to antiepileptic drugs in utero may have an increased risk of adverse development within their first three years of life, according to research published online ahead of print July 19 in Epilepsia. From mid-1999 through December 2008, researchers followed children born to mothers who had been recruited at 13 to 17 weeks of pregnancy. Mothers reported their children’s motor development, language, social skills, and autistic traits at 18 months and 36 months. A total of 333 children were exposed to antiepileptic drugs in utero. At 18 months, exposed children had an increased risk of abnormal scores for gross motor skills and autistic traits, compared with nonexposed children. At 36 months, exposed children had an increased risk of abnormal scores for gross motor skills, sentence skills, and autistic traits.
The spatial pattern of amyloid deposition may be related to cognitive performance, according to a study published online ahead of print July 15 in Neurobiology of Aging. Researchers examined the spatial patterns of amyloid deposition throughout the brain using Pittsburgh Compound Blue PET data from the Baltimore Longitudinal Study of Aging. The group approximated spatial patterns of the temporal progression of amyloid plaque deposition from cross-sectional data. Results were consistent with patterns of progression known from autopsy studies. When the investigators categorized participants into subgroups based on longitudinal change in memory performance, they found significantly different spatial patterns of the estimated progression of amyloid deposition between these subgroups. This finding may affect the use of amyloid imaging as a biomarker in research and clinical applications, said the researchers.
A low frequency of physical activity may be associated with an increased risk of stroke, according to data published online ahead of print July 18 in Stroke. Researchers analyzed data for 27,348 participants in the Reasons for Geographic And Racial Differences in Stroke study who had no prior diagnosis of stroke. Participants reported their frequency of moderate-to-vigorous physical activity at baseline according to three categories. Physical inactivity was reported by 33% of participants and was associated with a 20% higher risk of stroke. Adjustment for demographics and socioeconomic factors did not affect the risk, but further adjustment for traditional stroke risk factors completely attenuated the risk. Effects of physical activity are likely to be mediated through the reduction of traditional risk factors, said the researchers.
FTY-720, an immunomodulator for treating multiple sclerosis, may alleviate existing cardiac hypertrophy, according to research published in the July 1 issue of Circulation: Heart Failure. Investigators subjected male C57/Bl6 mice to transverse aortic constriction (TAC) for one week. The researchers treated the mice with FTY-720 for two subsequent weeks while continuing to subject them to TAC. Mice treated with FTY-720 had significantly reduced ventricular mass, ameliorated fibrosis, and improved cardiac performance, compared with mice that received vehicle. Mechanistic studies suggested that FTY-720 appreciably inhibited nuclear factor of activated T-cells activity. In addition, pertussis toxin (Gi-coupled receptor inhibitor) substantially blocked the antihypertrophic effect of FTY-720 in primary rat and human cardiomyocytes. FTY-720 or its analogs could be a promising approach for treating hypertrophic heart disease, said the investigators.
For patients with cardiac arrest who require vasopressors, a combination of vasopressin, epinephrine, and methylprednisolone during cardiopulmonary resuscitation (CPR) and stress-dose hydrocortisone in postresuscitation shock may improve survival to hospital discharge and result in favorable neurologic status, according to data published in the July 17 JAMA. Researchers studied 268 consecutive patients with cardiac arrest requiring epinephrine. Patients received vasopressin plus epinephrine or saline placebo plus epinephrine for the first five CPR cycles after randomization, followed by additional epinephrine if needed. During the first CPR cycle after randomization, patients in the intervention group received methylprednisolone, and patients in the control group received saline placebo. Patients in the treatment arm had higher probability for return of spontaneous circulation of 20 minutes or longer and survival to hospital discharge with cerebral performance category score of 1 or 2.
Chinese people may have a higher risk of stroke than Caucasians, according to research published in the July 16 Neurology. Investigators analyzed studies conducted since 1990 in Chinese populations of first-ever stroke incidence and pathologic types and subtypes of stroke. The team examined hospital- and community-based studies. They also examined community-based stroke studies in Caucasian populations. Age-standardized, annual, first-ever stroke incidence in community-based studies was higher among Chinese than among Caucasian populations. Intracerebral hemorrhage accounted for a larger, more variable proportion of strokes in China than in Taiwan, in Chinese community-based than in hospital-based studies, and in community-based Chinese than in Caucasian studies. The overall proportion of lacunar ischemic stroke was higher in Chinese than in Caucasian populations, but variable study methodologies precluded reliable comparisons.
Narcolepsy in humans may be triggered partly by a proliferation of cells containing histamine, according to data published online ahead of print July 2 in Annals of Neurology. Investigators used immunohistochemistry for histidine decarboxylase (HDC) and quantitative microscopy to detect histamine cells in patients with narcolepsy, Hcrt receptor-2 mutant dogs, and three mouse narcolepsy models. The researchers found an average 64% increase in the number of histamine neurons in human narcolepsy with cataplexy, with no overlap between patients with narcolepsy and controls. The investigators did not observe altered numbers of HDC cells in any of the animal models of narcolepsy, however. The increased histamine cell numbers observed in human narcolepsy may be related to the process causing the human disorder, said the study authors.
Epilepsy may be associated with an early onset of cognitive decline, according to data published online ahead of print on July 8 in JAMA Neurology. Investigators conducted a retrospective observational study of patients at a memory and aging center from 2007 to 2012. Twelve participants had amnestic mild cognitive impairment (aMCI) plus epilepsy, 35 had Alzheimer’s disease plus epilepsy, and seven had Alzheimer’s disease plus subclinical epileptiform activity. Patients with aMCI and epilepsy presented with symptoms of cognitive decline 6.8 years earlier than patients with aMCI who did not have epilepsy. Patients with Alzheimer’s disease who had epilepsy presented with cognitive decline 5.5 years earlier than patients with Alzheimer’s disease who did not have epilepsy. Patients with Alzheimer’s disease and subclinical epileptiform activity also had an early onset of cognitive decline.
Globus pallidus interna (GPi) deep brain stimulation (DBS) may be an effective therapy for DYT1-associated torsion dystonia, according to a study published in the July issue of Neurosurgery. Researchers conducted a retrospective chart review of 47 consecutive patients with DYT1 who were treated by a single surgical team during a 10-year period and followed for up to 96 months. Symptom severity was quantified with the Burke–Fahn–Marsden Dystonia Rating Scale. Motor symptom severity was reduced to less than 20% of baseline after two years of DBS therapy. Disability scores were reduced to less than 30% of baseline. Symptomatic improvement was sustained throughout follow-up. Sixty-one percent of patients had discontinued all dystonia-related medications at their last follow-up. Ninety-one percent had discontinued at least one class of medication.
Concurrent cerebrovascular disease is a common neuropathologic finding in older individuals with dementia, according to an article published online ahead of print July 10 in Brain. Cerebrovascular disease, vascular pathology, and vascular risk factors were studied in 5,715 cases from the National Alzheimer’s Coordinating Centre database who had a single neurodegenerative disease diagnosis based on a neuropathologic examination with or without cerebrovascular disease. After controlling for age and gender, the researchers found a lower prevalence of coincident cerebrovascular disease among patients with α-synucleinopathies, frontotemporal lobar degeneration due to tau and TAR DNA-binding protein 43, and prion disease than among patients with Alzheimer’s disease. This result was more significant in younger patients. Data suggest that these disorders should be targeted by treatments for cerebrovascular disease, according to the researchers.
Athletes who do not get enough sleep the night before undergoing baseline concussion testing may not perform as well as they expect, according to research presented at the 2013 Annual Meeting of the American Orthopaedic Society for Sports Medicine in Chicago. Researchers reviewed 3,686 nonconcussed athletes (1,315 female) with baseline symptom and ImPACT neurocognitive scores. Individuals reported their previous night’s sleep duration as fewer than seven hours, seven to nine hours, or more than nine hours. The study authors observed significant differences in reaction time, verbal memory, and visual memory in the group that had slept less than seven hours. Visual-motor speed scores did not seem to be affected. Significant differences in the total number of reported symptoms were associated with sleeping fewer than seven hours.
Continuation of lipophilic statin therapy may be associated with a decreased risk of Parkinson’s disease, compared with discontinuation, according to research published online ahead of print July 24 in Neurology. Between 2001 and 2008, investigators recruited participants without Parkinson’s disease who had initiated statin therapy. Among 43,810 subjects, the incidence rate for Parkinson’s disease was 1.68 and 3.52 per 1,000,000 person-days for lipophilic and hydrophilic statins, respectively. Continuation of lipophilic statins was associated with a decreased risk of Parkinson’s disease, compared with statin discontinuation. No association between hydrophilic statins and occurrence of Parkinson’s disease was observed. Among lipophilic statins, a significant association was observed for simvastatin and atorvastatin, especially in females. Long-term use of lipophilic or hydrophilic statins was not significantly associated with Parkinson’s disease.
—Erik Greb
Senior Associate Editor
Patients with Alzheimer’s disease are less likely to have cancer, and patients with cancer are less likely to have Alzheimer’s disease, according to data published online ahead of print July 10 in Neurology. Researchers conducted a cohort study of more than one million people in northern Italy. They derived cancer incidence using the local health authority’s tumor registry and calculated the incidence of Alzheimer’s dementia from registries of drug prescriptions, hospitalizations, and payment exemptions. The risk of cancer in patients with Alzheimer’s dementia was reduced by 50%, and the risk of Alzheimer’s dementia in patients with cancer was reduced by 35%. The investigators observed this relationship in almost all subgroup analyses, suggesting that anticipated potential confounding factors did not significantly influence the results.
Children exposed to antiepileptic drugs in utero may have an increased risk of adverse development within their first three years of life, according to research published online ahead of print July 19 in Epilepsia. From mid-1999 through December 2008, researchers followed children born to mothers who had been recruited at 13 to 17 weeks of pregnancy. Mothers reported their children’s motor development, language, social skills, and autistic traits at 18 months and 36 months. A total of 333 children were exposed to antiepileptic drugs in utero. At 18 months, exposed children had an increased risk of abnormal scores for gross motor skills and autistic traits, compared with nonexposed children. At 36 months, exposed children had an increased risk of abnormal scores for gross motor skills, sentence skills, and autistic traits.
The spatial pattern of amyloid deposition may be related to cognitive performance, according to a study published online ahead of print July 15 in Neurobiology of Aging. Researchers examined the spatial patterns of amyloid deposition throughout the brain using Pittsburgh Compound Blue PET data from the Baltimore Longitudinal Study of Aging. The group approximated spatial patterns of the temporal progression of amyloid plaque deposition from cross-sectional data. Results were consistent with patterns of progression known from autopsy studies. When the investigators categorized participants into subgroups based on longitudinal change in memory performance, they found significantly different spatial patterns of the estimated progression of amyloid deposition between these subgroups. This finding may affect the use of amyloid imaging as a biomarker in research and clinical applications, said the researchers.
A low frequency of physical activity may be associated with an increased risk of stroke, according to data published online ahead of print July 18 in Stroke. Researchers analyzed data for 27,348 participants in the Reasons for Geographic And Racial Differences in Stroke study who had no prior diagnosis of stroke. Participants reported their frequency of moderate-to-vigorous physical activity at baseline according to three categories. Physical inactivity was reported by 33% of participants and was associated with a 20% higher risk of stroke. Adjustment for demographics and socioeconomic factors did not affect the risk, but further adjustment for traditional stroke risk factors completely attenuated the risk. Effects of physical activity are likely to be mediated through the reduction of traditional risk factors, said the researchers.
FTY-720, an immunomodulator for treating multiple sclerosis, may alleviate existing cardiac hypertrophy, according to research published in the July 1 issue of Circulation: Heart Failure. Investigators subjected male C57/Bl6 mice to transverse aortic constriction (TAC) for one week. The researchers treated the mice with FTY-720 for two subsequent weeks while continuing to subject them to TAC. Mice treated with FTY-720 had significantly reduced ventricular mass, ameliorated fibrosis, and improved cardiac performance, compared with mice that received vehicle. Mechanistic studies suggested that FTY-720 appreciably inhibited nuclear factor of activated T-cells activity. In addition, pertussis toxin (Gi-coupled receptor inhibitor) substantially blocked the antihypertrophic effect of FTY-720 in primary rat and human cardiomyocytes. FTY-720 or its analogs could be a promising approach for treating hypertrophic heart disease, said the investigators.
For patients with cardiac arrest who require vasopressors, a combination of vasopressin, epinephrine, and methylprednisolone during cardiopulmonary resuscitation (CPR) and stress-dose hydrocortisone in postresuscitation shock may improve survival to hospital discharge and result in favorable neurologic status, according to data published in the July 17 JAMA. Researchers studied 268 consecutive patients with cardiac arrest requiring epinephrine. Patients received vasopressin plus epinephrine or saline placebo plus epinephrine for the first five CPR cycles after randomization, followed by additional epinephrine if needed. During the first CPR cycle after randomization, patients in the intervention group received methylprednisolone, and patients in the control group received saline placebo. Patients in the treatment arm had higher probability for return of spontaneous circulation of 20 minutes or longer and survival to hospital discharge with cerebral performance category score of 1 or 2.
Chinese people may have a higher risk of stroke than Caucasians, according to research published in the July 16 Neurology. Investigators analyzed studies conducted since 1990 in Chinese populations of first-ever stroke incidence and pathologic types and subtypes of stroke. The team examined hospital- and community-based studies. They also examined community-based stroke studies in Caucasian populations. Age-standardized, annual, first-ever stroke incidence in community-based studies was higher among Chinese than among Caucasian populations. Intracerebral hemorrhage accounted for a larger, more variable proportion of strokes in China than in Taiwan, in Chinese community-based than in hospital-based studies, and in community-based Chinese than in Caucasian studies. The overall proportion of lacunar ischemic stroke was higher in Chinese than in Caucasian populations, but variable study methodologies precluded reliable comparisons.
Narcolepsy in humans may be triggered partly by a proliferation of cells containing histamine, according to data published online ahead of print July 2 in Annals of Neurology. Investigators used immunohistochemistry for histidine decarboxylase (HDC) and quantitative microscopy to detect histamine cells in patients with narcolepsy, Hcrt receptor-2 mutant dogs, and three mouse narcolepsy models. The researchers found an average 64% increase in the number of histamine neurons in human narcolepsy with cataplexy, with no overlap between patients with narcolepsy and controls. The investigators did not observe altered numbers of HDC cells in any of the animal models of narcolepsy, however. The increased histamine cell numbers observed in human narcolepsy may be related to the process causing the human disorder, said the study authors.
Epilepsy may be associated with an early onset of cognitive decline, according to data published online ahead of print on July 8 in JAMA Neurology. Investigators conducted a retrospective observational study of patients at a memory and aging center from 2007 to 2012. Twelve participants had amnestic mild cognitive impairment (aMCI) plus epilepsy, 35 had Alzheimer’s disease plus epilepsy, and seven had Alzheimer’s disease plus subclinical epileptiform activity. Patients with aMCI and epilepsy presented with symptoms of cognitive decline 6.8 years earlier than patients with aMCI who did not have epilepsy. Patients with Alzheimer’s disease who had epilepsy presented with cognitive decline 5.5 years earlier than patients with Alzheimer’s disease who did not have epilepsy. Patients with Alzheimer’s disease and subclinical epileptiform activity also had an early onset of cognitive decline.
Globus pallidus interna (GPi) deep brain stimulation (DBS) may be an effective therapy for DYT1-associated torsion dystonia, according to a study published in the July issue of Neurosurgery. Researchers conducted a retrospective chart review of 47 consecutive patients with DYT1 who were treated by a single surgical team during a 10-year period and followed for up to 96 months. Symptom severity was quantified with the Burke–Fahn–Marsden Dystonia Rating Scale. Motor symptom severity was reduced to less than 20% of baseline after two years of DBS therapy. Disability scores were reduced to less than 30% of baseline. Symptomatic improvement was sustained throughout follow-up. Sixty-one percent of patients had discontinued all dystonia-related medications at their last follow-up. Ninety-one percent had discontinued at least one class of medication.
Concurrent cerebrovascular disease is a common neuropathologic finding in older individuals with dementia, according to an article published online ahead of print July 10 in Brain. Cerebrovascular disease, vascular pathology, and vascular risk factors were studied in 5,715 cases from the National Alzheimer’s Coordinating Centre database who had a single neurodegenerative disease diagnosis based on a neuropathologic examination with or without cerebrovascular disease. After controlling for age and gender, the researchers found a lower prevalence of coincident cerebrovascular disease among patients with α-synucleinopathies, frontotemporal lobar degeneration due to tau and TAR DNA-binding protein 43, and prion disease than among patients with Alzheimer’s disease. This result was more significant in younger patients. Data suggest that these disorders should be targeted by treatments for cerebrovascular disease, according to the researchers.
Athletes who do not get enough sleep the night before undergoing baseline concussion testing may not perform as well as they expect, according to research presented at the 2013 Annual Meeting of the American Orthopaedic Society for Sports Medicine in Chicago. Researchers reviewed 3,686 nonconcussed athletes (1,315 female) with baseline symptom and ImPACT neurocognitive scores. Individuals reported their previous night’s sleep duration as fewer than seven hours, seven to nine hours, or more than nine hours. The study authors observed significant differences in reaction time, verbal memory, and visual memory in the group that had slept less than seven hours. Visual-motor speed scores did not seem to be affected. Significant differences in the total number of reported symptoms were associated with sleeping fewer than seven hours.
Continuation of lipophilic statin therapy may be associated with a decreased risk of Parkinson’s disease, compared with discontinuation, according to research published online ahead of print July 24 in Neurology. Between 2001 and 2008, investigators recruited participants without Parkinson’s disease who had initiated statin therapy. Among 43,810 subjects, the incidence rate for Parkinson’s disease was 1.68 and 3.52 per 1,000,000 person-days for lipophilic and hydrophilic statins, respectively. Continuation of lipophilic statins was associated with a decreased risk of Parkinson’s disease, compared with statin discontinuation. No association between hydrophilic statins and occurrence of Parkinson’s disease was observed. Among lipophilic statins, a significant association was observed for simvastatin and atorvastatin, especially in females. Long-term use of lipophilic or hydrophilic statins was not significantly associated with Parkinson’s disease.
—Erik Greb
Senior Associate Editor
Patients with Alzheimer’s disease are less likely to have cancer, and patients with cancer are less likely to have Alzheimer’s disease, according to data published online ahead of print July 10 in Neurology. Researchers conducted a cohort study of more than one million people in northern Italy. They derived cancer incidence using the local health authority’s tumor registry and calculated the incidence of Alzheimer’s dementia from registries of drug prescriptions, hospitalizations, and payment exemptions. The risk of cancer in patients with Alzheimer’s dementia was reduced by 50%, and the risk of Alzheimer’s dementia in patients with cancer was reduced by 35%. The investigators observed this relationship in almost all subgroup analyses, suggesting that anticipated potential confounding factors did not significantly influence the results.
Children exposed to antiepileptic drugs in utero may have an increased risk of adverse development within their first three years of life, according to research published online ahead of print July 19 in Epilepsia. From mid-1999 through December 2008, researchers followed children born to mothers who had been recruited at 13 to 17 weeks of pregnancy. Mothers reported their children’s motor development, language, social skills, and autistic traits at 18 months and 36 months. A total of 333 children were exposed to antiepileptic drugs in utero. At 18 months, exposed children had an increased risk of abnormal scores for gross motor skills and autistic traits, compared with nonexposed children. At 36 months, exposed children had an increased risk of abnormal scores for gross motor skills, sentence skills, and autistic traits.
The spatial pattern of amyloid deposition may be related to cognitive performance, according to a study published online ahead of print July 15 in Neurobiology of Aging. Researchers examined the spatial patterns of amyloid deposition throughout the brain using Pittsburgh Compound Blue PET data from the Baltimore Longitudinal Study of Aging. The group approximated spatial patterns of the temporal progression of amyloid plaque deposition from cross-sectional data. Results were consistent with patterns of progression known from autopsy studies. When the investigators categorized participants into subgroups based on longitudinal change in memory performance, they found significantly different spatial patterns of the estimated progression of amyloid deposition between these subgroups. This finding may affect the use of amyloid imaging as a biomarker in research and clinical applications, said the researchers.
A low frequency of physical activity may be associated with an increased risk of stroke, according to data published online ahead of print July 18 in Stroke. Researchers analyzed data for 27,348 participants in the Reasons for Geographic And Racial Differences in Stroke study who had no prior diagnosis of stroke. Participants reported their frequency of moderate-to-vigorous physical activity at baseline according to three categories. Physical inactivity was reported by 33% of participants and was associated with a 20% higher risk of stroke. Adjustment for demographics and socioeconomic factors did not affect the risk, but further adjustment for traditional stroke risk factors completely attenuated the risk. Effects of physical activity are likely to be mediated through the reduction of traditional risk factors, said the researchers.
FTY-720, an immunomodulator for treating multiple sclerosis, may alleviate existing cardiac hypertrophy, according to research published in the July 1 issue of Circulation: Heart Failure. Investigators subjected male C57/Bl6 mice to transverse aortic constriction (TAC) for one week. The researchers treated the mice with FTY-720 for two subsequent weeks while continuing to subject them to TAC. Mice treated with FTY-720 had significantly reduced ventricular mass, ameliorated fibrosis, and improved cardiac performance, compared with mice that received vehicle. Mechanistic studies suggested that FTY-720 appreciably inhibited nuclear factor of activated T-cells activity. In addition, pertussis toxin (Gi-coupled receptor inhibitor) substantially blocked the antihypertrophic effect of FTY-720 in primary rat and human cardiomyocytes. FTY-720 or its analogs could be a promising approach for treating hypertrophic heart disease, said the investigators.
For patients with cardiac arrest who require vasopressors, a combination of vasopressin, epinephrine, and methylprednisolone during cardiopulmonary resuscitation (CPR) and stress-dose hydrocortisone in postresuscitation shock may improve survival to hospital discharge and result in favorable neurologic status, according to data published in the July 17 JAMA. Researchers studied 268 consecutive patients with cardiac arrest requiring epinephrine. Patients received vasopressin plus epinephrine or saline placebo plus epinephrine for the first five CPR cycles after randomization, followed by additional epinephrine if needed. During the first CPR cycle after randomization, patients in the intervention group received methylprednisolone, and patients in the control group received saline placebo. Patients in the treatment arm had higher probability for return of spontaneous circulation of 20 minutes or longer and survival to hospital discharge with cerebral performance category score of 1 or 2.
Chinese people may have a higher risk of stroke than Caucasians, according to research published in the July 16 Neurology. Investigators analyzed studies conducted since 1990 in Chinese populations of first-ever stroke incidence and pathologic types and subtypes of stroke. The team examined hospital- and community-based studies. They also examined community-based stroke studies in Caucasian populations. Age-standardized, annual, first-ever stroke incidence in community-based studies was higher among Chinese than among Caucasian populations. Intracerebral hemorrhage accounted for a larger, more variable proportion of strokes in China than in Taiwan, in Chinese community-based than in hospital-based studies, and in community-based Chinese than in Caucasian studies. The overall proportion of lacunar ischemic stroke was higher in Chinese than in Caucasian populations, but variable study methodologies precluded reliable comparisons.
Narcolepsy in humans may be triggered partly by a proliferation of cells containing histamine, according to data published online ahead of print July 2 in Annals of Neurology. Investigators used immunohistochemistry for histidine decarboxylase (HDC) and quantitative microscopy to detect histamine cells in patients with narcolepsy, Hcrt receptor-2 mutant dogs, and three mouse narcolepsy models. The researchers found an average 64% increase in the number of histamine neurons in human narcolepsy with cataplexy, with no overlap between patients with narcolepsy and controls. The investigators did not observe altered numbers of HDC cells in any of the animal models of narcolepsy, however. The increased histamine cell numbers observed in human narcolepsy may be related to the process causing the human disorder, said the study authors.
Epilepsy may be associated with an early onset of cognitive decline, according to data published online ahead of print on July 8 in JAMA Neurology. Investigators conducted a retrospective observational study of patients at a memory and aging center from 2007 to 2012. Twelve participants had amnestic mild cognitive impairment (aMCI) plus epilepsy, 35 had Alzheimer’s disease plus epilepsy, and seven had Alzheimer’s disease plus subclinical epileptiform activity. Patients with aMCI and epilepsy presented with symptoms of cognitive decline 6.8 years earlier than patients with aMCI who did not have epilepsy. Patients with Alzheimer’s disease who had epilepsy presented with cognitive decline 5.5 years earlier than patients with Alzheimer’s disease who did not have epilepsy. Patients with Alzheimer’s disease and subclinical epileptiform activity also had an early onset of cognitive decline.
Globus pallidus interna (GPi) deep brain stimulation (DBS) may be an effective therapy for DYT1-associated torsion dystonia, according to a study published in the July issue of Neurosurgery. Researchers conducted a retrospective chart review of 47 consecutive patients with DYT1 who were treated by a single surgical team during a 10-year period and followed for up to 96 months. Symptom severity was quantified with the Burke–Fahn–Marsden Dystonia Rating Scale. Motor symptom severity was reduced to less than 20% of baseline after two years of DBS therapy. Disability scores were reduced to less than 30% of baseline. Symptomatic improvement was sustained throughout follow-up. Sixty-one percent of patients had discontinued all dystonia-related medications at their last follow-up. Ninety-one percent had discontinued at least one class of medication.
Concurrent cerebrovascular disease is a common neuropathologic finding in older individuals with dementia, according to an article published online ahead of print July 10 in Brain. Cerebrovascular disease, vascular pathology, and vascular risk factors were studied in 5,715 cases from the National Alzheimer’s Coordinating Centre database who had a single neurodegenerative disease diagnosis based on a neuropathologic examination with or without cerebrovascular disease. After controlling for age and gender, the researchers found a lower prevalence of coincident cerebrovascular disease among patients with α-synucleinopathies, frontotemporal lobar degeneration due to tau and TAR DNA-binding protein 43, and prion disease than among patients with Alzheimer’s disease. This result was more significant in younger patients. Data suggest that these disorders should be targeted by treatments for cerebrovascular disease, according to the researchers.
Athletes who do not get enough sleep the night before undergoing baseline concussion testing may not perform as well as they expect, according to research presented at the 2013 Annual Meeting of the American Orthopaedic Society for Sports Medicine in Chicago. Researchers reviewed 3,686 nonconcussed athletes (1,315 female) with baseline symptom and ImPACT neurocognitive scores. Individuals reported their previous night’s sleep duration as fewer than seven hours, seven to nine hours, or more than nine hours. The study authors observed significant differences in reaction time, verbal memory, and visual memory in the group that had slept less than seven hours. Visual-motor speed scores did not seem to be affected. Significant differences in the total number of reported symptoms were associated with sleeping fewer than seven hours.
Continuation of lipophilic statin therapy may be associated with a decreased risk of Parkinson’s disease, compared with discontinuation, according to research published online ahead of print July 24 in Neurology. Between 2001 and 2008, investigators recruited participants without Parkinson’s disease who had initiated statin therapy. Among 43,810 subjects, the incidence rate for Parkinson’s disease was 1.68 and 3.52 per 1,000,000 person-days for lipophilic and hydrophilic statins, respectively. Continuation of lipophilic statins was associated with a decreased risk of Parkinson’s disease, compared with statin discontinuation. No association between hydrophilic statins and occurrence of Parkinson’s disease was observed. Among lipophilic statins, a significant association was observed for simvastatin and atorvastatin, especially in females. Long-term use of lipophilic or hydrophilic statins was not significantly associated with Parkinson’s disease.
—Erik Greb
Senior Associate Editor
Monoclonal Antibodies Could Become Popular Treatments for MS
ORLANDO—In the expanding array of disease-modifying therapies for multiple sclerosis (MS), some “old companions” among the parenteral agents likely will fall by the wayside, said Patricia K. Coyle, MD, at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS). Dr. Coyle discussed parenteral agents now in development and described the likely future of the current parenteral drugs.
Interferon Beta and Glatiramer Acetate
Since receiving approval from the FDA for relapsing forms of MS and clinically isolated syndrome, interferon beta and glatiramer acetate have become old standbys. The drugs are fairly well tolerated, and their safety profiles have been thoroughly established during the past two decades. These agents’ big disadvantage, however, is that they must be injected with a needle, said Dr. Coyle, Professor of Clinical Neurology at Stony Brook Medical Center in New York.
“I don’t think the market for interferon beta and glatiramer acetate is going to disappear, but I think it’s going to slowly shrink because now we have oral options,” predicted Dr. Coyle. “The biggest impact is going to be on treatment-naïve, newly diagnosed patients. People are going to opt for an oral agent rather than an injectable. “It’s beginning to become a crowded market among the interferon betas. It’s likely you’re going to see one interferon beta emerge as the dominant option in a shrinking market,” she added.
Natalizumab
Although it is highly effective, natalizumab is associated with a risk of progressive multifocal leukoencephalopathy (PML). Nonetheless, natalizumab use could increase during the coming years because of emerging risk-stratification methods that identify a subset of MS patients at low risk of PML. But once the novel anti-CD20 monoclonal antibodies reach the marketplace, natalizumab use will decline, predicted Dr. Coyle.
Mitoxantrone
A true induction agent with sustained efficacy that lasts after the cessation of treatment, mitoxantrone has FDA approval for all forms of MS except primary progressive MS. The drug’s associated risks of cardiotoxicity and leukemia require lifetime monitoring for the patient, however, and the therapy can only be administered 10 or 11 times. “As far as I can tell, mitoxantrone is not being used for MS at all in the United States any longer,” according to Dr. Coyle.
Rituximab
Rituximab, an IgG1-anti-CD20 chimeric monoclonal antibody, rapidly depletes B cells for four to 12 months. Eventually, naïve B cells return pre-ferentially over memory B cells. Rituximab is marketed for non-Hodgkin’s lymphoma and refractory rheumatoid arthritis. Its manufacturer does not intend to seek an indication for MS, but highly promising phase II studies have spurred intensive development of novel anti-CD20 monoclonal antibodies targeting MS.
Some neurologists use rituximab off label for MS. A common regimen includes 1,000 mg of IV rituximab followed 15 days later by 500 mg, with dosing repeated every six months, said Dr. Coyle.
Parenteral Agents in Development
Of the parenteral agents in development, alemtuzumab is likely to be the first to be marketed, said Dr. Coyle. This agent, which knocks out T cells, is now under FDA review for possible marketing approval based on impressive phase III results. Alemtuzumab, a true induction agent, is administered on eight days over the course of two years. The effects appear to last for several years after the last dose, but the drug does not cure MS, Dr. Coyle emphasized.
Pegylated interferon beta-1a is being evaluated in an ongoing, two-year, phase III trial. The first-year results indicated that self-administered subcutaneous dosing every two weeks may be more effective than dosing every four weeks. It is too early to tell whether pegylated interferon beta-1a will become the dominant interferon-beta in the marketplace, said Dr. Coyle. Generic interferon-beta may become available in the US. A 40-mg dose of glatiramer acetate can be administered subcutaneously three times per week, rather than daily, as with the familiar 20-mg formulation. In the Glatiramer Acetate Low Frequency Administration Study, a 40-mg dose of glatiramer acetate was associated with an annualized relapse rate 34% lower than that of placebo and a 34% reduction in new or relapsing T2 lesions on brain MRI.
Novel Anti-CD20 Agents
Ocrelizumab is the furthest along in development of the novel anti-CD20 agents. The humanized monoclonal antibody is in three phase III clinical trials: two for relapsing MS and one for primary progressive MS. In a phase II study, various doses of ocrelizumab reduced relapses by 73% to 80% and suppressed MRI contrast lesions by 89% to 96%. “The data with ocrelizumab look great. I think it could potentially replace natalizumab, depending on the safety,” said Dr. Coyle. Development of ocrelizumab as a treatment for rheumatoid arthritis and lupus was discontinued because of concerns about an increase in opportunistic infections. “We’ve not really seen that [effect] in the MS cohort. So far, ocrelizumab seems pretty safe,” said Dr. Coyle.
Daclizumab, a humanized IgG1 monoclonal antibody against CD25, is a subcutaneously administered agent on the market for the prevention of transplanted organ rejection. Investigators are comparing the drug with intramuscular interferon beta-1a as a treatment for MS in an ongoing phase III clinical trial. Previous studies raised concerns regarding daclizumab’s safety and tolerability.
Neurologists have long sought biomarkers of efficacy for MS therapies. Daclizumab appears to provide such a biomarker in the form of an increase in CD56 bright natural killer cells.
Other anti-CD20 monoclonal antibodies in development include ofatumumab, which is now marketed for the treatment of refractory chronic lymphocytic leukemia. A second, secukinumab, is an anti-interleukin-17 monoclonal antibody that showed efficacy in terms of MRI lesions in a small study. In addition, an anti-LINGO-1 monoclonal antibody in development is intended to stimulate myelin repair.
Dr. Coyle predicted that more efficacy biomarkers will emerge and that neuroprotection and CNS restoration will be fertile areas for drug development. “A high-efficacy monoclonal antibody, if it’s safe and convenient, could seize the market. The safety will be the critical issue,” she concluded.
—Bruce Jancin
IMNG Medical News
Suggested Reading
Deiß A, Brecht I, Haarmann A, Buttmann M. Treating multiple sclerosis with monoclonal antibodies: a 2013 update. Expert Rev Neurother. 2013;13(3):313-335.
Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676-688.
Hawker K, O’Connor P, Freedman MS, et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009;66(4):460-471.
Kieseier BC, Calabresi PA. PEGylation of interferon-b-1a: a promising strategy in multiple sclerosis. CNS Drugs. 2012;26(3):205-214.
ORLANDO—In the expanding array of disease-modifying therapies for multiple sclerosis (MS), some “old companions” among the parenteral agents likely will fall by the wayside, said Patricia K. Coyle, MD, at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS). Dr. Coyle discussed parenteral agents now in development and described the likely future of the current parenteral drugs.
Interferon Beta and Glatiramer Acetate
Since receiving approval from the FDA for relapsing forms of MS and clinically isolated syndrome, interferon beta and glatiramer acetate have become old standbys. The drugs are fairly well tolerated, and their safety profiles have been thoroughly established during the past two decades. These agents’ big disadvantage, however, is that they must be injected with a needle, said Dr. Coyle, Professor of Clinical Neurology at Stony Brook Medical Center in New York.
“I don’t think the market for interferon beta and glatiramer acetate is going to disappear, but I think it’s going to slowly shrink because now we have oral options,” predicted Dr. Coyle. “The biggest impact is going to be on treatment-naïve, newly diagnosed patients. People are going to opt for an oral agent rather than an injectable. “It’s beginning to become a crowded market among the interferon betas. It’s likely you’re going to see one interferon beta emerge as the dominant option in a shrinking market,” she added.
Natalizumab
Although it is highly effective, natalizumab is associated with a risk of progressive multifocal leukoencephalopathy (PML). Nonetheless, natalizumab use could increase during the coming years because of emerging risk-stratification methods that identify a subset of MS patients at low risk of PML. But once the novel anti-CD20 monoclonal antibodies reach the marketplace, natalizumab use will decline, predicted Dr. Coyle.
Mitoxantrone
A true induction agent with sustained efficacy that lasts after the cessation of treatment, mitoxantrone has FDA approval for all forms of MS except primary progressive MS. The drug’s associated risks of cardiotoxicity and leukemia require lifetime monitoring for the patient, however, and the therapy can only be administered 10 or 11 times. “As far as I can tell, mitoxantrone is not being used for MS at all in the United States any longer,” according to Dr. Coyle.
Rituximab
Rituximab, an IgG1-anti-CD20 chimeric monoclonal antibody, rapidly depletes B cells for four to 12 months. Eventually, naïve B cells return pre-ferentially over memory B cells. Rituximab is marketed for non-Hodgkin’s lymphoma and refractory rheumatoid arthritis. Its manufacturer does not intend to seek an indication for MS, but highly promising phase II studies have spurred intensive development of novel anti-CD20 monoclonal antibodies targeting MS.
Some neurologists use rituximab off label for MS. A common regimen includes 1,000 mg of IV rituximab followed 15 days later by 500 mg, with dosing repeated every six months, said Dr. Coyle.
Parenteral Agents in Development
Of the parenteral agents in development, alemtuzumab is likely to be the first to be marketed, said Dr. Coyle. This agent, which knocks out T cells, is now under FDA review for possible marketing approval based on impressive phase III results. Alemtuzumab, a true induction agent, is administered on eight days over the course of two years. The effects appear to last for several years after the last dose, but the drug does not cure MS, Dr. Coyle emphasized.
Pegylated interferon beta-1a is being evaluated in an ongoing, two-year, phase III trial. The first-year results indicated that self-administered subcutaneous dosing every two weeks may be more effective than dosing every four weeks. It is too early to tell whether pegylated interferon beta-1a will become the dominant interferon-beta in the marketplace, said Dr. Coyle. Generic interferon-beta may become available in the US. A 40-mg dose of glatiramer acetate can be administered subcutaneously three times per week, rather than daily, as with the familiar 20-mg formulation. In the Glatiramer Acetate Low Frequency Administration Study, a 40-mg dose of glatiramer acetate was associated with an annualized relapse rate 34% lower than that of placebo and a 34% reduction in new or relapsing T2 lesions on brain MRI.
Novel Anti-CD20 Agents
Ocrelizumab is the furthest along in development of the novel anti-CD20 agents. The humanized monoclonal antibody is in three phase III clinical trials: two for relapsing MS and one for primary progressive MS. In a phase II study, various doses of ocrelizumab reduced relapses by 73% to 80% and suppressed MRI contrast lesions by 89% to 96%. “The data with ocrelizumab look great. I think it could potentially replace natalizumab, depending on the safety,” said Dr. Coyle. Development of ocrelizumab as a treatment for rheumatoid arthritis and lupus was discontinued because of concerns about an increase in opportunistic infections. “We’ve not really seen that [effect] in the MS cohort. So far, ocrelizumab seems pretty safe,” said Dr. Coyle.
Daclizumab, a humanized IgG1 monoclonal antibody against CD25, is a subcutaneously administered agent on the market for the prevention of transplanted organ rejection. Investigators are comparing the drug with intramuscular interferon beta-1a as a treatment for MS in an ongoing phase III clinical trial. Previous studies raised concerns regarding daclizumab’s safety and tolerability.
Neurologists have long sought biomarkers of efficacy for MS therapies. Daclizumab appears to provide such a biomarker in the form of an increase in CD56 bright natural killer cells.
Other anti-CD20 monoclonal antibodies in development include ofatumumab, which is now marketed for the treatment of refractory chronic lymphocytic leukemia. A second, secukinumab, is an anti-interleukin-17 monoclonal antibody that showed efficacy in terms of MRI lesions in a small study. In addition, an anti-LINGO-1 monoclonal antibody in development is intended to stimulate myelin repair.
Dr. Coyle predicted that more efficacy biomarkers will emerge and that neuroprotection and CNS restoration will be fertile areas for drug development. “A high-efficacy monoclonal antibody, if it’s safe and convenient, could seize the market. The safety will be the critical issue,” she concluded.
—Bruce Jancin
IMNG Medical News
ORLANDO—In the expanding array of disease-modifying therapies for multiple sclerosis (MS), some “old companions” among the parenteral agents likely will fall by the wayside, said Patricia K. Coyle, MD, at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS). Dr. Coyle discussed parenteral agents now in development and described the likely future of the current parenteral drugs.
Interferon Beta and Glatiramer Acetate
Since receiving approval from the FDA for relapsing forms of MS and clinically isolated syndrome, interferon beta and glatiramer acetate have become old standbys. The drugs are fairly well tolerated, and their safety profiles have been thoroughly established during the past two decades. These agents’ big disadvantage, however, is that they must be injected with a needle, said Dr. Coyle, Professor of Clinical Neurology at Stony Brook Medical Center in New York.
“I don’t think the market for interferon beta and glatiramer acetate is going to disappear, but I think it’s going to slowly shrink because now we have oral options,” predicted Dr. Coyle. “The biggest impact is going to be on treatment-naïve, newly diagnosed patients. People are going to opt for an oral agent rather than an injectable. “It’s beginning to become a crowded market among the interferon betas. It’s likely you’re going to see one interferon beta emerge as the dominant option in a shrinking market,” she added.
Natalizumab
Although it is highly effective, natalizumab is associated with a risk of progressive multifocal leukoencephalopathy (PML). Nonetheless, natalizumab use could increase during the coming years because of emerging risk-stratification methods that identify a subset of MS patients at low risk of PML. But once the novel anti-CD20 monoclonal antibodies reach the marketplace, natalizumab use will decline, predicted Dr. Coyle.
Mitoxantrone
A true induction agent with sustained efficacy that lasts after the cessation of treatment, mitoxantrone has FDA approval for all forms of MS except primary progressive MS. The drug’s associated risks of cardiotoxicity and leukemia require lifetime monitoring for the patient, however, and the therapy can only be administered 10 or 11 times. “As far as I can tell, mitoxantrone is not being used for MS at all in the United States any longer,” according to Dr. Coyle.
Rituximab
Rituximab, an IgG1-anti-CD20 chimeric monoclonal antibody, rapidly depletes B cells for four to 12 months. Eventually, naïve B cells return pre-ferentially over memory B cells. Rituximab is marketed for non-Hodgkin’s lymphoma and refractory rheumatoid arthritis. Its manufacturer does not intend to seek an indication for MS, but highly promising phase II studies have spurred intensive development of novel anti-CD20 monoclonal antibodies targeting MS.
Some neurologists use rituximab off label for MS. A common regimen includes 1,000 mg of IV rituximab followed 15 days later by 500 mg, with dosing repeated every six months, said Dr. Coyle.
Parenteral Agents in Development
Of the parenteral agents in development, alemtuzumab is likely to be the first to be marketed, said Dr. Coyle. This agent, which knocks out T cells, is now under FDA review for possible marketing approval based on impressive phase III results. Alemtuzumab, a true induction agent, is administered on eight days over the course of two years. The effects appear to last for several years after the last dose, but the drug does not cure MS, Dr. Coyle emphasized.
Pegylated interferon beta-1a is being evaluated in an ongoing, two-year, phase III trial. The first-year results indicated that self-administered subcutaneous dosing every two weeks may be more effective than dosing every four weeks. It is too early to tell whether pegylated interferon beta-1a will become the dominant interferon-beta in the marketplace, said Dr. Coyle. Generic interferon-beta may become available in the US. A 40-mg dose of glatiramer acetate can be administered subcutaneously three times per week, rather than daily, as with the familiar 20-mg formulation. In the Glatiramer Acetate Low Frequency Administration Study, a 40-mg dose of glatiramer acetate was associated with an annualized relapse rate 34% lower than that of placebo and a 34% reduction in new or relapsing T2 lesions on brain MRI.
Novel Anti-CD20 Agents
Ocrelizumab is the furthest along in development of the novel anti-CD20 agents. The humanized monoclonal antibody is in three phase III clinical trials: two for relapsing MS and one for primary progressive MS. In a phase II study, various doses of ocrelizumab reduced relapses by 73% to 80% and suppressed MRI contrast lesions by 89% to 96%. “The data with ocrelizumab look great. I think it could potentially replace natalizumab, depending on the safety,” said Dr. Coyle. Development of ocrelizumab as a treatment for rheumatoid arthritis and lupus was discontinued because of concerns about an increase in opportunistic infections. “We’ve not really seen that [effect] in the MS cohort. So far, ocrelizumab seems pretty safe,” said Dr. Coyle.
Daclizumab, a humanized IgG1 monoclonal antibody against CD25, is a subcutaneously administered agent on the market for the prevention of transplanted organ rejection. Investigators are comparing the drug with intramuscular interferon beta-1a as a treatment for MS in an ongoing phase III clinical trial. Previous studies raised concerns regarding daclizumab’s safety and tolerability.
Neurologists have long sought biomarkers of efficacy for MS therapies. Daclizumab appears to provide such a biomarker in the form of an increase in CD56 bright natural killer cells.
Other anti-CD20 monoclonal antibodies in development include ofatumumab, which is now marketed for the treatment of refractory chronic lymphocytic leukemia. A second, secukinumab, is an anti-interleukin-17 monoclonal antibody that showed efficacy in terms of MRI lesions in a small study. In addition, an anti-LINGO-1 monoclonal antibody in development is intended to stimulate myelin repair.
Dr. Coyle predicted that more efficacy biomarkers will emerge and that neuroprotection and CNS restoration will be fertile areas for drug development. “A high-efficacy monoclonal antibody, if it’s safe and convenient, could seize the market. The safety will be the critical issue,” she concluded.
—Bruce Jancin
IMNG Medical News
Suggested Reading
Deiß A, Brecht I, Haarmann A, Buttmann M. Treating multiple sclerosis with monoclonal antibodies: a 2013 update. Expert Rev Neurother. 2013;13(3):313-335.
Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676-688.
Hawker K, O’Connor P, Freedman MS, et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009;66(4):460-471.
Kieseier BC, Calabresi PA. PEGylation of interferon-b-1a: a promising strategy in multiple sclerosis. CNS Drugs. 2012;26(3):205-214.
Suggested Reading
Deiß A, Brecht I, Haarmann A, Buttmann M. Treating multiple sclerosis with monoclonal antibodies: a 2013 update. Expert Rev Neurother. 2013;13(3):313-335.
Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676-688.
Hawker K, O’Connor P, Freedman MS, et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009;66(4):460-471.
Kieseier BC, Calabresi PA. PEGylation of interferon-b-1a: a promising strategy in multiple sclerosis. CNS Drugs. 2012;26(3):205-214.
Mark Freedman, MD
Simvastatin May Reduce Brain Atrophy in Patients With Secondary Progressive MS
SAN DIEGO—Simvastatin may reduce the rate of brain atrophy by approximately 40% in patients with secondary progressive multiple sclerosis (SPMS), according to data presented at the 65th Annual Meeting of the American Academy of Neurology. The effect may be apparent after one year of treatment. Simvastatin also may affect physician- and patient-reported outcomes for these individuals.
Patients Did Not Take MS Drugs
In the MS-STAT trial, Jeremy Chataway, PhD, Consultant Neurologist at the Queen Square MS Centre, National Hospital for Neurology and Neurosurgery in London, and colleagues randomized 140 patients with SPMS in a one-to-one ratio. Patients underwent an MRI at baseline and initially received 40 mg per day of simvastatin or placebo. After one month, the dose was increased to 80 mg, and the treatment continued for two years. One month after the end of treatment, patients underwent a second MRI. The baseline and final MRIs were taken while the patients were off medication to avoid possible pseudoatrophy effects of simvastatin, said Dr. Chataway. The study’s primary outcome was the annualized rate of brain atrophy.
Participants responded to the MS Impact Scale-29 (MSIS-29) at baseline and at 24 months. At the same times, the researchers administered the Expanded Disability Status Scale (EDSS) and MS Functional Composite (MSFC).
At baseline, subjects with SPMS had been actively progressing for at least two years, could walk as far as 500 meters (EDSS 4.0) or at least 20 meters with bilateral assistance (6.5), and had a mean EDSS score of 5.8 and a median EDSS score of 6.0. No patients were taking disease-modifying treatments. Average disease duration was 20 years, and patients had had secondary progression for about seven years. Patients’ mean age was about 50.
Simvastatin Lessened the Impact of MS
More than 90% of patients returned for their second MRI, and a majority of patients were compliant with the medication. The mean rate of change in brain volume was about 0.6% per year among controls, compared with 0.3% per year among patients taking simvastatin.
Approximately 55% of patients taking placebo had higher EDSS scores after two years, compared with 40% of patients in the statin arm. At two years, patients taking simvastatin had lower MSIS-29 scores than patients taking placebo. Simvastatin did not affect MSFC scores, however.
The drug was associated with a 30% reduction in the accumulation of T2 lesions, but the difference was not statistically significant. The researchers found no difference in adverse events or serious adverse events between the two treatment arms.
The statin appeared not to affect any of the T-cell outcomes that the investigators measured. The lack of an effect suggests that simvastatin may work through a vascular, microvascular, or permeability mechanism, concluded Dr. Chataway.
—Erik Greb
Senior Associate Editor
Suggested Reading
Sorensen PS, Lycke J, Erälinna JP, et al. Simvastatin as add-on therapy to interferon b-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial. Lancet Neurol. 2011;10(8):691-701.
Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004;363(9421):1607-1608.
Zamvil SS, Steinman, L. Cholesterol-lowering statins possess anti-inflammatory activity that might be useful for treatment of MS.
SAN DIEGO—Simvastatin may reduce the rate of brain atrophy by approximately 40% in patients with secondary progressive multiple sclerosis (SPMS), according to data presented at the 65th Annual Meeting of the American Academy of Neurology. The effect may be apparent after one year of treatment. Simvastatin also may affect physician- and patient-reported outcomes for these individuals.
Patients Did Not Take MS Drugs
In the MS-STAT trial, Jeremy Chataway, PhD, Consultant Neurologist at the Queen Square MS Centre, National Hospital for Neurology and Neurosurgery in London, and colleagues randomized 140 patients with SPMS in a one-to-one ratio. Patients underwent an MRI at baseline and initially received 40 mg per day of simvastatin or placebo. After one month, the dose was increased to 80 mg, and the treatment continued for two years. One month after the end of treatment, patients underwent a second MRI. The baseline and final MRIs were taken while the patients were off medication to avoid possible pseudoatrophy effects of simvastatin, said Dr. Chataway. The study’s primary outcome was the annualized rate of brain atrophy.
Participants responded to the MS Impact Scale-29 (MSIS-29) at baseline and at 24 months. At the same times, the researchers administered the Expanded Disability Status Scale (EDSS) and MS Functional Composite (MSFC).
At baseline, subjects with SPMS had been actively progressing for at least two years, could walk as far as 500 meters (EDSS 4.0) or at least 20 meters with bilateral assistance (6.5), and had a mean EDSS score of 5.8 and a median EDSS score of 6.0. No patients were taking disease-modifying treatments. Average disease duration was 20 years, and patients had had secondary progression for about seven years. Patients’ mean age was about 50.
Simvastatin Lessened the Impact of MS
More than 90% of patients returned for their second MRI, and a majority of patients were compliant with the medication. The mean rate of change in brain volume was about 0.6% per year among controls, compared with 0.3% per year among patients taking simvastatin.
Approximately 55% of patients taking placebo had higher EDSS scores after two years, compared with 40% of patients in the statin arm. At two years, patients taking simvastatin had lower MSIS-29 scores than patients taking placebo. Simvastatin did not affect MSFC scores, however.
The drug was associated with a 30% reduction in the accumulation of T2 lesions, but the difference was not statistically significant. The researchers found no difference in adverse events or serious adverse events between the two treatment arms.
The statin appeared not to affect any of the T-cell outcomes that the investigators measured. The lack of an effect suggests that simvastatin may work through a vascular, microvascular, or permeability mechanism, concluded Dr. Chataway.
—Erik Greb
Senior Associate Editor
Suggested Reading
Sorensen PS, Lycke J, Erälinna JP, et al. Simvastatin as add-on therapy to interferon b-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial. Lancet Neurol. 2011;10(8):691-701.
Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004;363(9421):1607-1608.
Zamvil SS, Steinman, L. Cholesterol-lowering statins possess anti-inflammatory activity that might be useful for treatment of MS.
SAN DIEGO—Simvastatin may reduce the rate of brain atrophy by approximately 40% in patients with secondary progressive multiple sclerosis (SPMS), according to data presented at the 65th Annual Meeting of the American Academy of Neurology. The effect may be apparent after one year of treatment. Simvastatin also may affect physician- and patient-reported outcomes for these individuals.
Patients Did Not Take MS Drugs
In the MS-STAT trial, Jeremy Chataway, PhD, Consultant Neurologist at the Queen Square MS Centre, National Hospital for Neurology and Neurosurgery in London, and colleagues randomized 140 patients with SPMS in a one-to-one ratio. Patients underwent an MRI at baseline and initially received 40 mg per day of simvastatin or placebo. After one month, the dose was increased to 80 mg, and the treatment continued for two years. One month after the end of treatment, patients underwent a second MRI. The baseline and final MRIs were taken while the patients were off medication to avoid possible pseudoatrophy effects of simvastatin, said Dr. Chataway. The study’s primary outcome was the annualized rate of brain atrophy.
Participants responded to the MS Impact Scale-29 (MSIS-29) at baseline and at 24 months. At the same times, the researchers administered the Expanded Disability Status Scale (EDSS) and MS Functional Composite (MSFC).
At baseline, subjects with SPMS had been actively progressing for at least two years, could walk as far as 500 meters (EDSS 4.0) or at least 20 meters with bilateral assistance (6.5), and had a mean EDSS score of 5.8 and a median EDSS score of 6.0. No patients were taking disease-modifying treatments. Average disease duration was 20 years, and patients had had secondary progression for about seven years. Patients’ mean age was about 50.
Simvastatin Lessened the Impact of MS
More than 90% of patients returned for their second MRI, and a majority of patients were compliant with the medication. The mean rate of change in brain volume was about 0.6% per year among controls, compared with 0.3% per year among patients taking simvastatin.
Approximately 55% of patients taking placebo had higher EDSS scores after two years, compared with 40% of patients in the statin arm. At two years, patients taking simvastatin had lower MSIS-29 scores than patients taking placebo. Simvastatin did not affect MSFC scores, however.
The drug was associated with a 30% reduction in the accumulation of T2 lesions, but the difference was not statistically significant. The researchers found no difference in adverse events or serious adverse events between the two treatment arms.
The statin appeared not to affect any of the T-cell outcomes that the investigators measured. The lack of an effect suggests that simvastatin may work through a vascular, microvascular, or permeability mechanism, concluded Dr. Chataway.
—Erik Greb
Senior Associate Editor
Suggested Reading
Sorensen PS, Lycke J, Erälinna JP, et al. Simvastatin as add-on therapy to interferon b-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial. Lancet Neurol. 2011;10(8):691-701.
Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004;363(9421):1607-1608.
Zamvil SS, Steinman, L. Cholesterol-lowering statins possess anti-inflammatory activity that might be useful for treatment of MS.
Fingolimod Slows MS Brain Atrophy Within Six Months
SAN DIEGO—Fingolimod slows brain atrophy in patients with multiple sclerosis (MS) and is the only approved drug that does so within the first six months of treatment, reported Jeffrey Cohen, MD, at the 65th Annual Meeting of the American Academy of Neurology.
The findings come from a combined analysis of the drug’s three clinical trials—FREEDOMS (Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis) and FREEDOMS II, which compared 0.5 mg and 1.25 mg daily against placebo for two years, and TRANSFORMS (FREEDOMS With Optional Extension Phase), which compared those doses against weekly intramuscular interferon beta-1a for a year. Brain volumes were assessed by MRI SIENA (structural image evaluation using normalization of atrophy) at baseline and at six, 12, and 24 months. More than 3,000 patients ages 18 to 55 with clinically active relapsing-remitting MS participated.
“There was a consistent” 31% to 36% reduction in the rate of brain volume loss with both doses of fingolimod “compared to placebo and interferon beta-1a,” said Dr. Cohen. “There was no clear-cut dose effect between the two” doses. Dr. Cohen is Director of Experimental Therapeutics at the Mellen Center for MS Treatment and Research, Cleveland Clinic.
In the two trials with placebo arms, patients who had received fingolimod had volume losses of about 0.85%, compared with 1.31% in patients who had received placebo. In the remaining trial, brain volume loss was about 0.31% with fingolimod and about 0.45% with interferon beta-1a.
The “benefit was seen as early as six months, in both FREEDOMS and FREEDOMS II,” said Dr. Cohen. “In this analysis of the overall study cohort, there was no apparent early acceleration of brain volume loss—in other words, no pseudoatrophy.”
Other approved MS therapies have shown either no significant effect on brain atrophy or a benefit only in the second year of treatment, as with natalizumab and glatiramer acetate, he noted.
The study investigators found that baseline brain atrophy correlated best with baseline T1 and T2 lesion volume, disability, age, and disease duration and severity. Both high baseline T2 lesion volume and active gadolinium-enhancing T1 lesions predicted brain volume loss during the trial. Volume loss in the study correlated best with worsening disability and increasing numbers of T2 lesions.
The drug seemed to protect brain volume in patients who received it, regardless of baseline characteristics, according to Dr. Cohen.
Weak correlations were observed between accumulations of T2 lesions and disability during the study, perhaps because “brain volume and measures of disability don’t change much over two years,” Dr. Cohen said.
—M. Alexander Otto
IMNG Medical News
SAN DIEGO—Fingolimod slows brain atrophy in patients with multiple sclerosis (MS) and is the only approved drug that does so within the first six months of treatment, reported Jeffrey Cohen, MD, at the 65th Annual Meeting of the American Academy of Neurology.
The findings come from a combined analysis of the drug’s three clinical trials—FREEDOMS (Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis) and FREEDOMS II, which compared 0.5 mg and 1.25 mg daily against placebo for two years, and TRANSFORMS (FREEDOMS With Optional Extension Phase), which compared those doses against weekly intramuscular interferon beta-1a for a year. Brain volumes were assessed by MRI SIENA (structural image evaluation using normalization of atrophy) at baseline and at six, 12, and 24 months. More than 3,000 patients ages 18 to 55 with clinically active relapsing-remitting MS participated.
“There was a consistent” 31% to 36% reduction in the rate of brain volume loss with both doses of fingolimod “compared to placebo and interferon beta-1a,” said Dr. Cohen. “There was no clear-cut dose effect between the two” doses. Dr. Cohen is Director of Experimental Therapeutics at the Mellen Center for MS Treatment and Research, Cleveland Clinic.
In the two trials with placebo arms, patients who had received fingolimod had volume losses of about 0.85%, compared with 1.31% in patients who had received placebo. In the remaining trial, brain volume loss was about 0.31% with fingolimod and about 0.45% with interferon beta-1a.
The “benefit was seen as early as six months, in both FREEDOMS and FREEDOMS II,” said Dr. Cohen. “In this analysis of the overall study cohort, there was no apparent early acceleration of brain volume loss—in other words, no pseudoatrophy.”
Other approved MS therapies have shown either no significant effect on brain atrophy or a benefit only in the second year of treatment, as with natalizumab and glatiramer acetate, he noted.
The study investigators found that baseline brain atrophy correlated best with baseline T1 and T2 lesion volume, disability, age, and disease duration and severity. Both high baseline T2 lesion volume and active gadolinium-enhancing T1 lesions predicted brain volume loss during the trial. Volume loss in the study correlated best with worsening disability and increasing numbers of T2 lesions.
The drug seemed to protect brain volume in patients who received it, regardless of baseline characteristics, according to Dr. Cohen.
Weak correlations were observed between accumulations of T2 lesions and disability during the study, perhaps because “brain volume and measures of disability don’t change much over two years,” Dr. Cohen said.
—M. Alexander Otto
IMNG Medical News
SAN DIEGO—Fingolimod slows brain atrophy in patients with multiple sclerosis (MS) and is the only approved drug that does so within the first six months of treatment, reported Jeffrey Cohen, MD, at the 65th Annual Meeting of the American Academy of Neurology.
The findings come from a combined analysis of the drug’s three clinical trials—FREEDOMS (Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis) and FREEDOMS II, which compared 0.5 mg and 1.25 mg daily against placebo for two years, and TRANSFORMS (FREEDOMS With Optional Extension Phase), which compared those doses against weekly intramuscular interferon beta-1a for a year. Brain volumes were assessed by MRI SIENA (structural image evaluation using normalization of atrophy) at baseline and at six, 12, and 24 months. More than 3,000 patients ages 18 to 55 with clinically active relapsing-remitting MS participated.
“There was a consistent” 31% to 36% reduction in the rate of brain volume loss with both doses of fingolimod “compared to placebo and interferon beta-1a,” said Dr. Cohen. “There was no clear-cut dose effect between the two” doses. Dr. Cohen is Director of Experimental Therapeutics at the Mellen Center for MS Treatment and Research, Cleveland Clinic.
In the two trials with placebo arms, patients who had received fingolimod had volume losses of about 0.85%, compared with 1.31% in patients who had received placebo. In the remaining trial, brain volume loss was about 0.31% with fingolimod and about 0.45% with interferon beta-1a.
The “benefit was seen as early as six months, in both FREEDOMS and FREEDOMS II,” said Dr. Cohen. “In this analysis of the overall study cohort, there was no apparent early acceleration of brain volume loss—in other words, no pseudoatrophy.”
Other approved MS therapies have shown either no significant effect on brain atrophy or a benefit only in the second year of treatment, as with natalizumab and glatiramer acetate, he noted.
The study investigators found that baseline brain atrophy correlated best with baseline T1 and T2 lesion volume, disability, age, and disease duration and severity. Both high baseline T2 lesion volume and active gadolinium-enhancing T1 lesions predicted brain volume loss during the trial. Volume loss in the study correlated best with worsening disability and increasing numbers of T2 lesions.
The drug seemed to protect brain volume in patients who received it, regardless of baseline characteristics, according to Dr. Cohen.
Weak correlations were observed between accumulations of T2 lesions and disability during the study, perhaps because “brain volume and measures of disability don’t change much over two years,” Dr. Cohen said.
—M. Alexander Otto
IMNG Medical News
Anti-JCV Antibody Index May Further Define PML Risk
ORLANDO—In anti-JCV antibody–positive natalizumab-treated patients with multiple sclerosis (MS) and no prior immunosuppressant (IS) use, a higher anti-JCV antibody index correlates with an increased risk of progressive multifocal leukoencephalopathy (PML), according to research presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Tatiana Plavina, PhD, Meena Subramanyam, PhD, and colleagues from Biogen Idec, Inc, examined the association between anti-JCV antibody index (anti-JCV antibody level as measured using the STRATIFY JCV DxSelect assay [Focus Diagnostics, Cypress, California]) and PML risk in anti-JCV–positive patients enrolled in natalizumab clinical studies and from postmarketing settings. Anti-JCV antibody index data were available from 71 natalizumab-treated PML patients at least six months prior to PML diagnosis and from 2,522 non-PML anti-JCV antibody–positive patients.
Low Index, Lower Risk
In cross-sectional analyses, anti-JCV antibody index was not associated with duration of natalizumab treatment (less than or equal to 24 versus more than 24 infusions) or prior IS use but was significantly associated with PML risk. A different relationship was observed between anti-JCV antibody index and PML by prior IS use. Hence, the association between anti-JCV antibody index and PML risk was assessed using all available longitudinal data in anti-JCV–positive patients without prior IS use, and estimated odds ratios across a range of thresholds of interest varied from 7 to 23 for the occurrence of PML at higher versus lower index.
According to previous work by Bloomgren et al, risk of PML in natalizumab-treated anti-JCV antibody–negative patients with MS is less than or equal to 0.1/1000. Anti-JCV antibody–positive patients with no prior IS use who have low anti-JCV antibody index may have severalfold lower PML risk, compared with current risk estimates assigned to all anti-JCV antibody–positive patients with no prior IS use as per the current algorithm. The researchers concluded that “anti-JCV antibody index may further differentiate PML risk for natalizumab-treated anti-JCV antibody–positive MS patients with no prior IS use.”
Stability of the Index Over Time
The researchers also looked at the longitudinal stability of the anti-JCV antibody index. In the AFFIRM and STRATIFY-1 study cohorts, of those patients who tested anti-JCV antibody-negative at baseline, 87% remained consistently negative and 96% remained consistently at lower risk (anti-JCV antibody index less than or equal to 0.9, 1.2, or 1.5) for a period of 18 months, with testing every six months. “These analyses may potentially better inform PML risk in patients who seroconvert or test intermittently positive,” the researchers said. Further, the investigators noted that 96% of natalizumab-treated patients who developed PML and had two or more samples available (n = 25) had pre-PML samples with an index consistently above 0.9.
—Glenn S. Williams
VP/Group Editor
Suggested Reading
Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366(20):1870-1880.
Lee P Plavina T, Castro A, et al. A second-generation ELISA (STRATIFY JCV DxSelect) for detection of JC virus antibodies in human serum and plasma to support progressive multifocal leukoencephalopathy risk stratification. J Clin Virol. 2013;57(2):141-146.
Plavina T, Berman M, Njenga M, et al. Multi-site analytical validation of an assay to detect anti-JCV antibodies in human serum and plasma.
ORLANDO—In anti-JCV antibody–positive natalizumab-treated patients with multiple sclerosis (MS) and no prior immunosuppressant (IS) use, a higher anti-JCV antibody index correlates with an increased risk of progressive multifocal leukoencephalopathy (PML), according to research presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Tatiana Plavina, PhD, Meena Subramanyam, PhD, and colleagues from Biogen Idec, Inc, examined the association between anti-JCV antibody index (anti-JCV antibody level as measured using the STRATIFY JCV DxSelect assay [Focus Diagnostics, Cypress, California]) and PML risk in anti-JCV–positive patients enrolled in natalizumab clinical studies and from postmarketing settings. Anti-JCV antibody index data were available from 71 natalizumab-treated PML patients at least six months prior to PML diagnosis and from 2,522 non-PML anti-JCV antibody–positive patients.
Low Index, Lower Risk
In cross-sectional analyses, anti-JCV antibody index was not associated with duration of natalizumab treatment (less than or equal to 24 versus more than 24 infusions) or prior IS use but was significantly associated with PML risk. A different relationship was observed between anti-JCV antibody index and PML by prior IS use. Hence, the association between anti-JCV antibody index and PML risk was assessed using all available longitudinal data in anti-JCV–positive patients without prior IS use, and estimated odds ratios across a range of thresholds of interest varied from 7 to 23 for the occurrence of PML at higher versus lower index.
According to previous work by Bloomgren et al, risk of PML in natalizumab-treated anti-JCV antibody–negative patients with MS is less than or equal to 0.1/1000. Anti-JCV antibody–positive patients with no prior IS use who have low anti-JCV antibody index may have severalfold lower PML risk, compared with current risk estimates assigned to all anti-JCV antibody–positive patients with no prior IS use as per the current algorithm. The researchers concluded that “anti-JCV antibody index may further differentiate PML risk for natalizumab-treated anti-JCV antibody–positive MS patients with no prior IS use.”
Stability of the Index Over Time
The researchers also looked at the longitudinal stability of the anti-JCV antibody index. In the AFFIRM and STRATIFY-1 study cohorts, of those patients who tested anti-JCV antibody-negative at baseline, 87% remained consistently negative and 96% remained consistently at lower risk (anti-JCV antibody index less than or equal to 0.9, 1.2, or 1.5) for a period of 18 months, with testing every six months. “These analyses may potentially better inform PML risk in patients who seroconvert or test intermittently positive,” the researchers said. Further, the investigators noted that 96% of natalizumab-treated patients who developed PML and had two or more samples available (n = 25) had pre-PML samples with an index consistently above 0.9.
—Glenn S. Williams
VP/Group Editor
Suggested Reading
Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366(20):1870-1880.
Lee P Plavina T, Castro A, et al. A second-generation ELISA (STRATIFY JCV DxSelect) for detection of JC virus antibodies in human serum and plasma to support progressive multifocal leukoencephalopathy risk stratification. J Clin Virol. 2013;57(2):141-146.
Plavina T, Berman M, Njenga M, et al. Multi-site analytical validation of an assay to detect anti-JCV antibodies in human serum and plasma.
ORLANDO—In anti-JCV antibody–positive natalizumab-treated patients with multiple sclerosis (MS) and no prior immunosuppressant (IS) use, a higher anti-JCV antibody index correlates with an increased risk of progressive multifocal leukoencephalopathy (PML), according to research presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Tatiana Plavina, PhD, Meena Subramanyam, PhD, and colleagues from Biogen Idec, Inc, examined the association between anti-JCV antibody index (anti-JCV antibody level as measured using the STRATIFY JCV DxSelect assay [Focus Diagnostics, Cypress, California]) and PML risk in anti-JCV–positive patients enrolled in natalizumab clinical studies and from postmarketing settings. Anti-JCV antibody index data were available from 71 natalizumab-treated PML patients at least six months prior to PML diagnosis and from 2,522 non-PML anti-JCV antibody–positive patients.
Low Index, Lower Risk
In cross-sectional analyses, anti-JCV antibody index was not associated with duration of natalizumab treatment (less than or equal to 24 versus more than 24 infusions) or prior IS use but was significantly associated with PML risk. A different relationship was observed between anti-JCV antibody index and PML by prior IS use. Hence, the association between anti-JCV antibody index and PML risk was assessed using all available longitudinal data in anti-JCV–positive patients without prior IS use, and estimated odds ratios across a range of thresholds of interest varied from 7 to 23 for the occurrence of PML at higher versus lower index.
According to previous work by Bloomgren et al, risk of PML in natalizumab-treated anti-JCV antibody–negative patients with MS is less than or equal to 0.1/1000. Anti-JCV antibody–positive patients with no prior IS use who have low anti-JCV antibody index may have severalfold lower PML risk, compared with current risk estimates assigned to all anti-JCV antibody–positive patients with no prior IS use as per the current algorithm. The researchers concluded that “anti-JCV antibody index may further differentiate PML risk for natalizumab-treated anti-JCV antibody–positive MS patients with no prior IS use.”
Stability of the Index Over Time
The researchers also looked at the longitudinal stability of the anti-JCV antibody index. In the AFFIRM and STRATIFY-1 study cohorts, of those patients who tested anti-JCV antibody-negative at baseline, 87% remained consistently negative and 96% remained consistently at lower risk (anti-JCV antibody index less than or equal to 0.9, 1.2, or 1.5) for a period of 18 months, with testing every six months. “These analyses may potentially better inform PML risk in patients who seroconvert or test intermittently positive,” the researchers said. Further, the investigators noted that 96% of natalizumab-treated patients who developed PML and had two or more samples available (n = 25) had pre-PML samples with an index consistently above 0.9.
—Glenn S. Williams
VP/Group Editor
Suggested Reading
Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366(20):1870-1880.
Lee P Plavina T, Castro A, et al. A second-generation ELISA (STRATIFY JCV DxSelect) for detection of JC virus antibodies in human serum and plasma to support progressive multifocal leukoencephalopathy risk stratification. J Clin Virol. 2013;57(2):141-146.
Plavina T, Berman M, Njenga M, et al. Multi-site analytical validation of an assay to detect anti-JCV antibodies in human serum and plasma.
News Briefs From the Fifth Cooperative Meeting of CMSC/ACTRIMS
Disease-Modifying Therapies Affect Quality of Life Differently for Men and Women
After three years of disease-modifying therapy (DMT) for multiple sclerosis (MS), physical health-related quality of life (HRQL) declines were experienced by both men and women, but especially in men, according to a study presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). Karen V. L. Turpin, MSc, BScN, a PhD student at the University of Alberta in Edmonton, Canada, and colleagues examined the course of changes in HRQL over a three-year period in men and women with relapsing-remitting MS who were being treated with DMTs. The researchers used data from a study of 185 patients with relapsing-remitting MS carried out in Saskatchewan, Canada, that was designed to evaluate the long-term impact of DMTs. Study participants completed the SF-36 HRQL survey at three time points: pre-DMT, follow-up at one year, and follow-up at three years. The researchers investigated the course of changes over time in SF-36 subscale scores and the summary scale scores stratified by sex.
The majority of the sample was female (70.3%). The average age of the sample at the study initiation was 39.2, and the average Expanded Disability Status Scale (EDSS) score was 2.4 (ambulatory with minimal to mild disability). For women, there were initial improvements in all scores at one year. At two years, all scores had decreased and three of the physical health subtest scores (but not the mental health scores) had fallen below initial values. Men showed improvement at one year on role limitations due to physical and mental health problems and on the mental health summary scale. Most men’s gains were retained through year three, but there were substantial declines in the physical HRQL domain scores that were greater than declines experienced by women.
Overall, the researchers found that, compared with pre-DMT scores, there were sustained improvements in mental health at three years, but declines in physical health. Sex differences were apparent in the patterns of improvement and worsening over the course of the three-year follow-up, with the degree of improvement and worsening being especially marked for men. The sustained improvement in mental health scores suggests that, despite a worsening physical health, DMTs may lead to better mental and social health. This is important, the researchers said, because psychosocial well-being has been reported to be the most salient aspect of health for persons with relapsing-remitting MS.
Exercise Training Reduces Fatigue in Patients With MS
Exercise training is associated with a significant moderate reduction in fatigue among patients with multiple sclerosis (MS), according to data presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Lara A. Pilutti, PhD, from the University of Illinois at Urbana-Champaign, and colleagues conducted a meta-analysis to provide a quantitative review of randomized controlled trials examining the effects of exercise training on symptomatic fatigue in persons with MS. Electronic databases (eg, Web of Science, PubMed, PsycINFO, and Google Scholar) were searched for articles published between 1960 and October 2012 using the key words fatigue, tiredness, energy, mood, or lassitude in combination with exercise, physical activity, rehabilitation, or fitness with the additional search term multiple sclerosis. The initial search resulted in 311 articles, of which 74 were reviewed in detail, and 17 met inclusion criteria and provided enough data to compute effect sizes.
The 43 effect sizes from 17 randomized controlled trials with 568 MS participants yielded a weighted mean effect size of 0.45. The weighted mean effect size was slightly heterogeneous. Exploratory moderator analyses indicated that study location, disease duration, training supervision, and mode of exercise might be important variables for understanding the effects of exercise training on symptomatic fatigue.
Overall, exercise training was associated with a significant, nearly one-half standard deviation reduction in symptomatic fatigue among persons with MS. The overall effect size was substantially higher than that reported in other meta-analyses examining the effect of exercise training on walking mobility and quality of life. Further, the researchers reported that the overall effect size found in this study represents a clinically significant change in fatigue with exercise training based on a one-point change in Fatigue Severity Scale scores.
The cumulative evidence supports the association of exercise training with a significant, moderate reduction in fatigue among persons with MS. Based on their findings, the researchers recommend that exercise training should be considered as an effective alternative therapy for the management of fatigue in persons with MS.
Multipotent Adult Progenitor Cells May Become a Viable Treatment for MS
Treatment of patients with multiple sclerosis (MS) with human multipotent adult progenitor cells (MAPCs) may provide clinical benefit through modulation of immune status and promotion of remyelination, according to basic science research presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Stem cell therapies are currently being investigated as potential therapeutic treatments for autoimmune disorders such as MS. However, the mechanistic interaction between the diseased tissue environment and transplanted cells is often poorly understood, leading to inefficient or inappropriate applications of cell therapies that may not afford significant health benefits.
Jason A. Hamilton, PhD, from Athersys, Inc, and colleagues investigated the potential use of human MAPCs as a cellular therapeutic for the treatment of MS. Their research evaluated the cells’ efficacy, dose, window of therapeutic benefit, and effects upon remyelination.
Experimental allergic encephalomyelitis (EAE) was induced in C57Bl/6 mice. Efficacy was examined after administering 1, 3, or 9 million cells IV, compared to control animals administered vehicle. Cells or vehicle was administered after significant symptom onset, and behavior was monitored for 28 days by a blinded observer. Window of therapeutic benefit was examined by administering 1 million cells IV at different time points in the course of disease. Myelin content was examined via luxol fast blue (LFB) staining and electron microscopy (EM). Investigation of the direct effects of MAPC upon remyelination was achieved via direct injection of cells or vehicle into lysolecithin (LPC) lesions in adult rat spinal cords. Lesions were characterized via LFB staining and immunocytochemistry.
Significant and sustained behavioral improvement was observed in response to all cell doses tested, when administered after symptom onset. Presymptomatic treatment did not prevent disease onset. Examination of myelination status demonstrated decreased average area of demyelinated lesions in spinal cords of cell-treated animals, as well as a significant decrease in the number of complete lesions. Further analysis via EM showed abundant evidence of newly remyelinated axons within cell-treated animals. Subsequent studies in LPC-lesioned rat spinal cords demonstrated increased remyelination in cell-treated lesions associated with significant induction of M2 macrophages in the core of the lesion.
According to the researchers, the results of their studies suggest that treatment with MAPCs may provide clinical benefit to patients with MS.
—Glenn S. Williams
Vice President, Group Editor
Disease-Modifying Therapies Affect Quality of Life Differently for Men and Women
After three years of disease-modifying therapy (DMT) for multiple sclerosis (MS), physical health-related quality of life (HRQL) declines were experienced by both men and women, but especially in men, according to a study presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). Karen V. L. Turpin, MSc, BScN, a PhD student at the University of Alberta in Edmonton, Canada, and colleagues examined the course of changes in HRQL over a three-year period in men and women with relapsing-remitting MS who were being treated with DMTs. The researchers used data from a study of 185 patients with relapsing-remitting MS carried out in Saskatchewan, Canada, that was designed to evaluate the long-term impact of DMTs. Study participants completed the SF-36 HRQL survey at three time points: pre-DMT, follow-up at one year, and follow-up at three years. The researchers investigated the course of changes over time in SF-36 subscale scores and the summary scale scores stratified by sex.
The majority of the sample was female (70.3%). The average age of the sample at the study initiation was 39.2, and the average Expanded Disability Status Scale (EDSS) score was 2.4 (ambulatory with minimal to mild disability). For women, there were initial improvements in all scores at one year. At two years, all scores had decreased and three of the physical health subtest scores (but not the mental health scores) had fallen below initial values. Men showed improvement at one year on role limitations due to physical and mental health problems and on the mental health summary scale. Most men’s gains were retained through year three, but there were substantial declines in the physical HRQL domain scores that were greater than declines experienced by women.
Overall, the researchers found that, compared with pre-DMT scores, there were sustained improvements in mental health at three years, but declines in physical health. Sex differences were apparent in the patterns of improvement and worsening over the course of the three-year follow-up, with the degree of improvement and worsening being especially marked for men. The sustained improvement in mental health scores suggests that, despite a worsening physical health, DMTs may lead to better mental and social health. This is important, the researchers said, because psychosocial well-being has been reported to be the most salient aspect of health for persons with relapsing-remitting MS.
Exercise Training Reduces Fatigue in Patients With MS
Exercise training is associated with a significant moderate reduction in fatigue among patients with multiple sclerosis (MS), according to data presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Lara A. Pilutti, PhD, from the University of Illinois at Urbana-Champaign, and colleagues conducted a meta-analysis to provide a quantitative review of randomized controlled trials examining the effects of exercise training on symptomatic fatigue in persons with MS. Electronic databases (eg, Web of Science, PubMed, PsycINFO, and Google Scholar) were searched for articles published between 1960 and October 2012 using the key words fatigue, tiredness, energy, mood, or lassitude in combination with exercise, physical activity, rehabilitation, or fitness with the additional search term multiple sclerosis. The initial search resulted in 311 articles, of which 74 were reviewed in detail, and 17 met inclusion criteria and provided enough data to compute effect sizes.
The 43 effect sizes from 17 randomized controlled trials with 568 MS participants yielded a weighted mean effect size of 0.45. The weighted mean effect size was slightly heterogeneous. Exploratory moderator analyses indicated that study location, disease duration, training supervision, and mode of exercise might be important variables for understanding the effects of exercise training on symptomatic fatigue.
Overall, exercise training was associated with a significant, nearly one-half standard deviation reduction in symptomatic fatigue among persons with MS. The overall effect size was substantially higher than that reported in other meta-analyses examining the effect of exercise training on walking mobility and quality of life. Further, the researchers reported that the overall effect size found in this study represents a clinically significant change in fatigue with exercise training based on a one-point change in Fatigue Severity Scale scores.
The cumulative evidence supports the association of exercise training with a significant, moderate reduction in fatigue among persons with MS. Based on their findings, the researchers recommend that exercise training should be considered as an effective alternative therapy for the management of fatigue in persons with MS.
Multipotent Adult Progenitor Cells May Become a Viable Treatment for MS
Treatment of patients with multiple sclerosis (MS) with human multipotent adult progenitor cells (MAPCs) may provide clinical benefit through modulation of immune status and promotion of remyelination, according to basic science research presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Stem cell therapies are currently being investigated as potential therapeutic treatments for autoimmune disorders such as MS. However, the mechanistic interaction between the diseased tissue environment and transplanted cells is often poorly understood, leading to inefficient or inappropriate applications of cell therapies that may not afford significant health benefits.
Jason A. Hamilton, PhD, from Athersys, Inc, and colleagues investigated the potential use of human MAPCs as a cellular therapeutic for the treatment of MS. Their research evaluated the cells’ efficacy, dose, window of therapeutic benefit, and effects upon remyelination.
Experimental allergic encephalomyelitis (EAE) was induced in C57Bl/6 mice. Efficacy was examined after administering 1, 3, or 9 million cells IV, compared to control animals administered vehicle. Cells or vehicle was administered after significant symptom onset, and behavior was monitored for 28 days by a blinded observer. Window of therapeutic benefit was examined by administering 1 million cells IV at different time points in the course of disease. Myelin content was examined via luxol fast blue (LFB) staining and electron microscopy (EM). Investigation of the direct effects of MAPC upon remyelination was achieved via direct injection of cells or vehicle into lysolecithin (LPC) lesions in adult rat spinal cords. Lesions were characterized via LFB staining and immunocytochemistry.
Significant and sustained behavioral improvement was observed in response to all cell doses tested, when administered after symptom onset. Presymptomatic treatment did not prevent disease onset. Examination of myelination status demonstrated decreased average area of demyelinated lesions in spinal cords of cell-treated animals, as well as a significant decrease in the number of complete lesions. Further analysis via EM showed abundant evidence of newly remyelinated axons within cell-treated animals. Subsequent studies in LPC-lesioned rat spinal cords demonstrated increased remyelination in cell-treated lesions associated with significant induction of M2 macrophages in the core of the lesion.
According to the researchers, the results of their studies suggest that treatment with MAPCs may provide clinical benefit to patients with MS.
—Glenn S. Williams
Vice President, Group Editor
Disease-Modifying Therapies Affect Quality of Life Differently for Men and Women
After three years of disease-modifying therapy (DMT) for multiple sclerosis (MS), physical health-related quality of life (HRQL) declines were experienced by both men and women, but especially in men, according to a study presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). Karen V. L. Turpin, MSc, BScN, a PhD student at the University of Alberta in Edmonton, Canada, and colleagues examined the course of changes in HRQL over a three-year period in men and women with relapsing-remitting MS who were being treated with DMTs. The researchers used data from a study of 185 patients with relapsing-remitting MS carried out in Saskatchewan, Canada, that was designed to evaluate the long-term impact of DMTs. Study participants completed the SF-36 HRQL survey at three time points: pre-DMT, follow-up at one year, and follow-up at three years. The researchers investigated the course of changes over time in SF-36 subscale scores and the summary scale scores stratified by sex.
The majority of the sample was female (70.3%). The average age of the sample at the study initiation was 39.2, and the average Expanded Disability Status Scale (EDSS) score was 2.4 (ambulatory with minimal to mild disability). For women, there were initial improvements in all scores at one year. At two years, all scores had decreased and three of the physical health subtest scores (but not the mental health scores) had fallen below initial values. Men showed improvement at one year on role limitations due to physical and mental health problems and on the mental health summary scale. Most men’s gains were retained through year three, but there were substantial declines in the physical HRQL domain scores that were greater than declines experienced by women.
Overall, the researchers found that, compared with pre-DMT scores, there were sustained improvements in mental health at three years, but declines in physical health. Sex differences were apparent in the patterns of improvement and worsening over the course of the three-year follow-up, with the degree of improvement and worsening being especially marked for men. The sustained improvement in mental health scores suggests that, despite a worsening physical health, DMTs may lead to better mental and social health. This is important, the researchers said, because psychosocial well-being has been reported to be the most salient aspect of health for persons with relapsing-remitting MS.
Exercise Training Reduces Fatigue in Patients With MS
Exercise training is associated with a significant moderate reduction in fatigue among patients with multiple sclerosis (MS), according to data presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Lara A. Pilutti, PhD, from the University of Illinois at Urbana-Champaign, and colleagues conducted a meta-analysis to provide a quantitative review of randomized controlled trials examining the effects of exercise training on symptomatic fatigue in persons with MS. Electronic databases (eg, Web of Science, PubMed, PsycINFO, and Google Scholar) were searched for articles published between 1960 and October 2012 using the key words fatigue, tiredness, energy, mood, or lassitude in combination with exercise, physical activity, rehabilitation, or fitness with the additional search term multiple sclerosis. The initial search resulted in 311 articles, of which 74 were reviewed in detail, and 17 met inclusion criteria and provided enough data to compute effect sizes.
The 43 effect sizes from 17 randomized controlled trials with 568 MS participants yielded a weighted mean effect size of 0.45. The weighted mean effect size was slightly heterogeneous. Exploratory moderator analyses indicated that study location, disease duration, training supervision, and mode of exercise might be important variables for understanding the effects of exercise training on symptomatic fatigue.
Overall, exercise training was associated with a significant, nearly one-half standard deviation reduction in symptomatic fatigue among persons with MS. The overall effect size was substantially higher than that reported in other meta-analyses examining the effect of exercise training on walking mobility and quality of life. Further, the researchers reported that the overall effect size found in this study represents a clinically significant change in fatigue with exercise training based on a one-point change in Fatigue Severity Scale scores.
The cumulative evidence supports the association of exercise training with a significant, moderate reduction in fatigue among persons with MS. Based on their findings, the researchers recommend that exercise training should be considered as an effective alternative therapy for the management of fatigue in persons with MS.
Multipotent Adult Progenitor Cells May Become a Viable Treatment for MS
Treatment of patients with multiple sclerosis (MS) with human multipotent adult progenitor cells (MAPCs) may provide clinical benefit through modulation of immune status and promotion of remyelination, according to basic science research presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Stem cell therapies are currently being investigated as potential therapeutic treatments for autoimmune disorders such as MS. However, the mechanistic interaction between the diseased tissue environment and transplanted cells is often poorly understood, leading to inefficient or inappropriate applications of cell therapies that may not afford significant health benefits.
Jason A. Hamilton, PhD, from Athersys, Inc, and colleagues investigated the potential use of human MAPCs as a cellular therapeutic for the treatment of MS. Their research evaluated the cells’ efficacy, dose, window of therapeutic benefit, and effects upon remyelination.
Experimental allergic encephalomyelitis (EAE) was induced in C57Bl/6 mice. Efficacy was examined after administering 1, 3, or 9 million cells IV, compared to control animals administered vehicle. Cells or vehicle was administered after significant symptom onset, and behavior was monitored for 28 days by a blinded observer. Window of therapeutic benefit was examined by administering 1 million cells IV at different time points in the course of disease. Myelin content was examined via luxol fast blue (LFB) staining and electron microscopy (EM). Investigation of the direct effects of MAPC upon remyelination was achieved via direct injection of cells or vehicle into lysolecithin (LPC) lesions in adult rat spinal cords. Lesions were characterized via LFB staining and immunocytochemistry.
Significant and sustained behavioral improvement was observed in response to all cell doses tested, when administered after symptom onset. Presymptomatic treatment did not prevent disease onset. Examination of myelination status demonstrated decreased average area of demyelinated lesions in spinal cords of cell-treated animals, as well as a significant decrease in the number of complete lesions. Further analysis via EM showed abundant evidence of newly remyelinated axons within cell-treated animals. Subsequent studies in LPC-lesioned rat spinal cords demonstrated increased remyelination in cell-treated lesions associated with significant induction of M2 macrophages in the core of the lesion.
According to the researchers, the results of their studies suggest that treatment with MAPCs may provide clinical benefit to patients with MS.
—Glenn S. Williams
Vice President, Group Editor