Multiple Sclerosis

A tapered approach to natalizumab discontinuation reduced the risk of multiple sclerosis (MS) relapse within 12 months of discontinuation, according to Dr. Bianca Weinstock-Guttman and her associates.

From a group of 50 patients with relapsing MS discontinuing natalizumab, 23 received two subsequent natalizumab infusions before beginning another disease-modifying therapy, while the remaining 27 began a new disease-modifying therapy immediately. In the tapered-discontinuation group, eight relapses were seen in the following 12 months, seven of which occurred within the first 3 months. In the immediate-discontinuation group, 28 relapses were seen, 20 of which occurred within 3 months.

designer491/Thinkstock

A higher number of new T2 lesions were seen in the immediate-discontinuation group, compared with the tapered group, as well as a higher mean T2 lesion volume change after 12 months, and a higher number of new T1 hypointense lesions.

“Receptor saturation may be more relevant to natalizumab effectiveness than natalizumab serum concentration. Based on our study, we postulate that tapering the infusions, instead of immediate discontinuation, may provide a slower rate for VLA4 desaturation that may be of clinical importance,” the investigators noted.

Find the full study in the Journal of Neurology, Neurosurgery & Psychiatry (doi: 10.1136/jnnp-2015-312221).

lfranki@frontlinemedcom.com

A tapered approach to natalizumab discontinuation reduced the risk of multiple sclerosis (MS) relapse within 12 months of discontinuation, according to Dr. Bianca Weinstock-Guttman and her associates.

From a group of 50 patients with relapsing MS discontinuing natalizumab, 23 received two subsequent natalizumab infusions before beginning another disease-modifying therapy, while the remaining 27 began a new disease-modifying therapy immediately. In the tapered-discontinuation group, eight relapses were seen in the following 12 months, seven of which occurred within the first 3 months. In the immediate-discontinuation group, 28 relapses were seen, 20 of which occurred within 3 months.

designer491/Thinkstock

A higher number of new T2 lesions were seen in the immediate-discontinuation group, compared with the tapered group, as well as a higher mean T2 lesion volume change after 12 months, and a higher number of new T1 hypointense lesions.

“Receptor saturation may be more relevant to natalizumab effectiveness than natalizumab serum concentration. Based on our study, we postulate that tapering the infusions, instead of immediate discontinuation, may provide a slower rate for VLA4 desaturation that may be of clinical importance,” the investigators noted.

Find the full study in the Journal of Neurology, Neurosurgery & Psychiatry (doi: 10.1136/jnnp-2015-312221).

lfranki@frontlinemedcom.com

A tapered approach to natalizumab discontinuation reduced the risk of multiple sclerosis (MS) relapse within 12 months of discontinuation, according to Dr. Bianca Weinstock-Guttman and her associates.

From a group of 50 patients with relapsing MS discontinuing natalizumab, 23 received two subsequent natalizumab infusions before beginning another disease-modifying therapy, while the remaining 27 began a new disease-modifying therapy immediately. In the tapered-discontinuation group, eight relapses were seen in the following 12 months, seven of which occurred within the first 3 months. In the immediate-discontinuation group, 28 relapses were seen, 20 of which occurred within 3 months.

designer491/Thinkstock

A higher number of new T2 lesions were seen in the immediate-discontinuation group, compared with the tapered group, as well as a higher mean T2 lesion volume change after 12 months, and a higher number of new T1 hypointense lesions.

“Receptor saturation may be more relevant to natalizumab effectiveness than natalizumab serum concentration. Based on our study, we postulate that tapering the infusions, instead of immediate discontinuation, may provide a slower rate for VLA4 desaturation that may be of clinical importance,” the investigators noted.

Find the full study in the Journal of Neurology, Neurosurgery & Psychiatry (doi: 10.1136/jnnp-2015-312221).

lfranki@frontlinemedcom.com

Glatiramer acetate exposure during the first trimester of pregnancy appears safe and was not associated with a teratogenic effect in a nationwide German Multiple Sclerosis and Pregnancy registry.

In the second largest study of the safety of glatiramer acetate exposure during early pregnancy in multiple sclerosis patients, Sandra Herbstritt, Pharm.D., and her colleagues at Ruhr University Bochum (Germany) reported that exposure to the drug in 151 women with multiple sclerosis was not associated with significant differences in pregnancy or birth outcomes when compared with 95 controls without exposure to disease-modifying therapy (DMT) during pregnancy. All but three of the patients who took glatiramer acetate stopped it in the first trimester (median duration of 31 days; range, 0-154 days). Pregnancies were considered exposed to glatiramer acetate if the last injection was administered after the last menstrual period (Mult Scler. 2016 Jan 11. doi: 10.1177/1352458515623366).

arda savascogullari/Thinkstock.com

Significantly more relapses occurred in women who did not take a DMT during pregnancy than in women who took glatiramer acetate (28 vs. 18, respectively), particularly in the first and third trimesters. A total of 224 live births occurred, including 136 with exposure to glatiramer acetate and 88 without DMT exposure. All but 3 of the 22 pregnancies that did not result in live births were spontaneous abortions in the first trimester.

The only early neonatal death among women who took glatiramer acetate involved an infant who died 30 minutes after birth in gestational week 24 because of a maternal infection. According to the investigators, “the mother received glatiramer acetate for 8 months prior to pregnancy, stopped treatment in the second [gestational week], and was not exposed to other substances during pregnancy.”

A total of nine congenital abnormalities (eight major, one minor) were observed without any specific pattern and included three in glatiramer acetate–exposed neonates and six in unexposed neonates.

No safety signals were reported for glatiramer acetate on the outcome of pregnancy, labor, or delivery in a previous meta-analysis of 97 pregnancies in eight studies. Glatiramer acetate’s manufacturer, Teva, reported no adverse outcomes in a conference abstract of 245 pregnancies exposed to glatiramer acetate, but the company has not published its postmarketing surveillance data in manuscript form, the authors wrote.

“Our results of a lacking adverse effect of glatiramer acetate during early pregnancy exposure are biologically plausible as it is very unlikely that glatiramer acetate passes the placental barrier,” the investigators wrote, because it is not permeable for a large heterogeneous mixture of polypeptides such as glatiramer acetate, which have molecular weights of 5,000-9,000 d.

The German Multiple Sclerosis and Pregnancy registry was partly supported by Bayer Healthcare, Biogen Idec Germany, Merck Serono, Novartis Pharma, Teva Pharma, and Sanofi-Aventis Genzyme Pharmaceuticals, but the sponsors had no role in the registry design, data collection, analyses, or dissemination of results. Two authors reported financial ties to numerous pharmaceutical companies that market MS drugs, and two reported support from the German Research Council. Another author is the site principal investigator for two industry-sponsored randomized clinical trials.

jevans@frontlinemedcom.com

Glatiramer acetate exposure during the first trimester of pregnancy appears safe and was not associated with a teratogenic effect in a nationwide German Multiple Sclerosis and Pregnancy registry.

In the second largest study of the safety of glatiramer acetate exposure during early pregnancy in multiple sclerosis patients, Sandra Herbstritt, Pharm.D., and her colleagues at Ruhr University Bochum (Germany) reported that exposure to the drug in 151 women with multiple sclerosis was not associated with significant differences in pregnancy or birth outcomes when compared with 95 controls without exposure to disease-modifying therapy (DMT) during pregnancy. All but three of the patients who took glatiramer acetate stopped it in the first trimester (median duration of 31 days; range, 0-154 days). Pregnancies were considered exposed to glatiramer acetate if the last injection was administered after the last menstrual period (Mult Scler. 2016 Jan 11. doi: 10.1177/1352458515623366).

arda savascogullari/Thinkstock.com

Significantly more relapses occurred in women who did not take a DMT during pregnancy than in women who took glatiramer acetate (28 vs. 18, respectively), particularly in the first and third trimesters. A total of 224 live births occurred, including 136 with exposure to glatiramer acetate and 88 without DMT exposure. All but 3 of the 22 pregnancies that did not result in live births were spontaneous abortions in the first trimester.

The only early neonatal death among women who took glatiramer acetate involved an infant who died 30 minutes after birth in gestational week 24 because of a maternal infection. According to the investigators, “the mother received glatiramer acetate for 8 months prior to pregnancy, stopped treatment in the second [gestational week], and was not exposed to other substances during pregnancy.”

A total of nine congenital abnormalities (eight major, one minor) were observed without any specific pattern and included three in glatiramer acetate–exposed neonates and six in unexposed neonates.

No safety signals were reported for glatiramer acetate on the outcome of pregnancy, labor, or delivery in a previous meta-analysis of 97 pregnancies in eight studies. Glatiramer acetate’s manufacturer, Teva, reported no adverse outcomes in a conference abstract of 245 pregnancies exposed to glatiramer acetate, but the company has not published its postmarketing surveillance data in manuscript form, the authors wrote.

“Our results of a lacking adverse effect of glatiramer acetate during early pregnancy exposure are biologically plausible as it is very unlikely that glatiramer acetate passes the placental barrier,” the investigators wrote, because it is not permeable for a large heterogeneous mixture of polypeptides such as glatiramer acetate, which have molecular weights of 5,000-9,000 d.

The German Multiple Sclerosis and Pregnancy registry was partly supported by Bayer Healthcare, Biogen Idec Germany, Merck Serono, Novartis Pharma, Teva Pharma, and Sanofi-Aventis Genzyme Pharmaceuticals, but the sponsors had no role in the registry design, data collection, analyses, or dissemination of results. Two authors reported financial ties to numerous pharmaceutical companies that market MS drugs, and two reported support from the German Research Council. Another author is the site principal investigator for two industry-sponsored randomized clinical trials.

jevans@frontlinemedcom.com

Glatiramer acetate exposure during the first trimester of pregnancy appears safe and was not associated with a teratogenic effect in a nationwide German Multiple Sclerosis and Pregnancy registry.

In the second largest study of the safety of glatiramer acetate exposure during early pregnancy in multiple sclerosis patients, Sandra Herbstritt, Pharm.D., and her colleagues at Ruhr University Bochum (Germany) reported that exposure to the drug in 151 women with multiple sclerosis was not associated with significant differences in pregnancy or birth outcomes when compared with 95 controls without exposure to disease-modifying therapy (DMT) during pregnancy. All but three of the patients who took glatiramer acetate stopped it in the first trimester (median duration of 31 days; range, 0-154 days). Pregnancies were considered exposed to glatiramer acetate if the last injection was administered after the last menstrual period (Mult Scler. 2016 Jan 11. doi: 10.1177/1352458515623366).

arda savascogullari/Thinkstock.com

Significantly more relapses occurred in women who did not take a DMT during pregnancy than in women who took glatiramer acetate (28 vs. 18, respectively), particularly in the first and third trimesters. A total of 224 live births occurred, including 136 with exposure to glatiramer acetate and 88 without DMT exposure. All but 3 of the 22 pregnancies that did not result in live births were spontaneous abortions in the first trimester.

The only early neonatal death among women who took glatiramer acetate involved an infant who died 30 minutes after birth in gestational week 24 because of a maternal infection. According to the investigators, “the mother received glatiramer acetate for 8 months prior to pregnancy, stopped treatment in the second [gestational week], and was not exposed to other substances during pregnancy.”

A total of nine congenital abnormalities (eight major, one minor) were observed without any specific pattern and included three in glatiramer acetate–exposed neonates and six in unexposed neonates.

No safety signals were reported for glatiramer acetate on the outcome of pregnancy, labor, or delivery in a previous meta-analysis of 97 pregnancies in eight studies. Glatiramer acetate’s manufacturer, Teva, reported no adverse outcomes in a conference abstract of 245 pregnancies exposed to glatiramer acetate, but the company has not published its postmarketing surveillance data in manuscript form, the authors wrote.

“Our results of a lacking adverse effect of glatiramer acetate during early pregnancy exposure are biologically plausible as it is very unlikely that glatiramer acetate passes the placental barrier,” the investigators wrote, because it is not permeable for a large heterogeneous mixture of polypeptides such as glatiramer acetate, which have molecular weights of 5,000-9,000 d.

The German Multiple Sclerosis and Pregnancy registry was partly supported by Bayer Healthcare, Biogen Idec Germany, Merck Serono, Novartis Pharma, Teva Pharma, and Sanofi-Aventis Genzyme Pharmaceuticals, but the sponsors had no role in the registry design, data collection, analyses, or dissemination of results. Two authors reported financial ties to numerous pharmaceutical companies that market MS drugs, and two reported support from the German Research Council. Another author is the site principal investigator for two industry-sponsored randomized clinical trials.

jevans@frontlinemedcom.com

Humoral response to Epstein-Barr virus (EBV) antigens is associated with more advanced cortical atrophy, accumulation of chronic T1 black holes, and focal white matter lesions in patients with multiple sclerosis, Dr. Robert Zivadinov of the State University of New York, Buffalo, and his colleagues reported in Neurology.

Researchers enrolled 846 participants for the study, including 539 patients with MS (369 with relapsing-remitting MS, 135 with secondary progressive MS, and 35 with primary progressive MS); 66 patients with clinically isolated syndrome (CIS); 63 patients with other neurologic diseases (OND); and 178 healthy controls. They used 3T MRI to scan participants’ brains and evaluated serum samples for IgG antibodies against EBV viral capsid antigen (VCA) and EBV nuclear antigen-1 (EBNA-1), dividing the group into quartiles based on their responses.

More than 30% of patients with MS and CIS presented with the highest quartile of anti–EBV-VCA and anti–EBNA-1 status, compared with 10% or fewer of healthy controls (P less than .001). The figures were 9 (14.3%) and 7 (12.3%) for patients with OND. Patients with MS with the highest quartile of anti–EBV-VCA showed significantly increased T2 lesion volume (P = .001), T1 lesion number (P = .002), and T1 lesion volume (P = .04), as well as decreased gray matter (P = .041) and cortical volumes (P = .043), compared with patients with MS in lower quartiles.

“The results provide evidence for further research aimed at modulating the response of patients with MS to these viruses via drug and vaccine strategies,” the authors wrote.

Read the article in Neurology (2016;3:e190. doi: 10.1212/NXI.0000000000000190).

Humoral response to Epstein-Barr virus (EBV) antigens is associated with more advanced cortical atrophy, accumulation of chronic T1 black holes, and focal white matter lesions in patients with multiple sclerosis, Dr. Robert Zivadinov of the State University of New York, Buffalo, and his colleagues reported in Neurology.

Researchers enrolled 846 participants for the study, including 539 patients with MS (369 with relapsing-remitting MS, 135 with secondary progressive MS, and 35 with primary progressive MS); 66 patients with clinically isolated syndrome (CIS); 63 patients with other neurologic diseases (OND); and 178 healthy controls. They used 3T MRI to scan participants’ brains and evaluated serum samples for IgG antibodies against EBV viral capsid antigen (VCA) and EBV nuclear antigen-1 (EBNA-1), dividing the group into quartiles based on their responses.

More than 30% of patients with MS and CIS presented with the highest quartile of anti–EBV-VCA and anti–EBNA-1 status, compared with 10% or fewer of healthy controls (P less than .001). The figures were 9 (14.3%) and 7 (12.3%) for patients with OND. Patients with MS with the highest quartile of anti–EBV-VCA showed significantly increased T2 lesion volume (P = .001), T1 lesion number (P = .002), and T1 lesion volume (P = .04), as well as decreased gray matter (P = .041) and cortical volumes (P = .043), compared with patients with MS in lower quartiles.

“The results provide evidence for further research aimed at modulating the response of patients with MS to these viruses via drug and vaccine strategies,” the authors wrote.

Read the article in Neurology (2016;3:e190. doi: 10.1212/NXI.0000000000000190).

Humoral response to Epstein-Barr virus (EBV) antigens is associated with more advanced cortical atrophy, accumulation of chronic T1 black holes, and focal white matter lesions in patients with multiple sclerosis, Dr. Robert Zivadinov of the State University of New York, Buffalo, and his colleagues reported in Neurology.

Researchers enrolled 846 participants for the study, including 539 patients with MS (369 with relapsing-remitting MS, 135 with secondary progressive MS, and 35 with primary progressive MS); 66 patients with clinically isolated syndrome (CIS); 63 patients with other neurologic diseases (OND); and 178 healthy controls. They used 3T MRI to scan participants’ brains and evaluated serum samples for IgG antibodies against EBV viral capsid antigen (VCA) and EBV nuclear antigen-1 (EBNA-1), dividing the group into quartiles based on their responses.

More than 30% of patients with MS and CIS presented with the highest quartile of anti–EBV-VCA and anti–EBNA-1 status, compared with 10% or fewer of healthy controls (P less than .001). The figures were 9 (14.3%) and 7 (12.3%) for patients with OND. Patients with MS with the highest quartile of anti–EBV-VCA showed significantly increased T2 lesion volume (P = .001), T1 lesion number (P = .002), and T1 lesion volume (P = .04), as well as decreased gray matter (P = .041) and cortical volumes (P = .043), compared with patients with MS in lower quartiles.

“The results provide evidence for further research aimed at modulating the response of patients with MS to these viruses via drug and vaccine strategies,” the authors wrote.

Read the article in Neurology (2016;3:e190. doi: 10.1212/NXI.0000000000000190).

Specific polymorphisms of the SCN10A gene affect motor coordination and functional status in relapsing-onset multiple sclerosis (MS) patients via the abnormal expression of the voltage-gated Na_v1.8 sodium channel in cerebellar Purkinje neurons, causing dysfunctional cerebellothalamic circuitry, according to findings from a prospective cohort study.

The clinical effects of abnormally expressed Na_v1.8 in cerebellar Purkinje neurons and the polymorphisms’ effect on the activity of the channels in affected patients suggests that “SCN10A genotype may predict an MS subphenotype with significantly greater deficit in motor coordination and cognition and compromised cerebellothalamic functional integrity. This study further supports previous evidence that Na_v1.8 channelopathy is involved in the pathophysiology of cerebellar dysfunction in MS,” Dr. Tina Roostaei of the Tehran (Iran) University of Medical Sciences and her colleagues reported (Neurology. 2016 Jan 6. doi: 10.1212/WNL.0000000000002326). The authors noted that “unlike other clinical abnormalities in MS that tend to be remitting, cerebellar dysfunction tends to become persistent early in the course of the illness and is refractory to either disease-modifying or symptomatic therapy.”

©Eraxion/thinkstockphotos.com

Genotyping for four potentially functional SCN10A polymorphisms in 161 patients with relapsing-onset MS and 94 healthy controls revealed two polymorphisms that proved significantly related to performance on the Multiple Sclerosis Functional Composite and all its subscores, with carriers of one polymorphism (rs6795970^AA) performing worse than carriers of rs6795970^G, regardless of Expanded Disability Status Scale score or cerebellar atrophy. However, carriers of rs6795970^AA did not have significant gross ataxia as indexed by the Scale for the Assessment and Rating of Ataxia and cerebellar functional system score. The poor-performing carriers showed significantly diminished cerebellar functional connectivity with the thalami and midbrain on functional MRI. Similar results occurred for analyses of a separate polymorphism (rs6801957) that was in high-linkage disequilibrium with rs6795970. The effects of the polymorphisms were not seen in the healthy controls.

The effects of abnormal Na_v1.8 channel expression on Purkinje cells is thought to alter their activity because Na_v1.8 channels are normally found on unmyelinated sensory neurons of the dorsal root ganglia and peripheral nerve axons and support their repetitive firing by rapidly recovering from inactivation at depolarized membrane potentials.

The study by Dr. Roostaei and her colleagues and previous research suggests that it may be possible to reverse cerebellar manifestations of MS by blocking Na_v1.8 with drugs currently in development for treating pain caused by pain-signaling cells in dorsal root ganglion neurons, which have been shown to improve clinical function in animal models of MS, wrote Dr. Stephen G. Waxman of Yale University, New Haven, Conn., and Dr. Orhun H. Kantarci of the Mayo Clinic, Rochester, Minn., in an accompanying editorial (Neurology. 2016 Jan 6. doi: 10.1212/WNL.0000000000002338). Additional work needs to be done with higher-resolution tests of cerebellar function to determine the effects of the abnormal presence of Na_v1.8 on Purkinje cells in the cerebellum of MS patients, as well as further experiments to “understand the triggers that lead to upregulation of Na_v1.8 expression in the cerebellum in MS.”

The study was supported by the Tehran University of Medical Sciences and the MS Society of Iran. One author reported receiving financial compensation from Biogen, Merck Serono, Bayer-Schering, Novartis, and CinnaGen for consulting and speaking services. Dr. Waxman reported holding a patent for invention of sodium channel Na_v1.9, serving on the advisory board of SiteOne Therapeutics, and consulting for a variety of pharmaceutical companies. Dr. Kantarci reported receiving funding for travel and/or speaker honoraria from Novartis; research support from the European Regional Development Fund, National Multiple Sclerosis Society, Mayo Foundation, and Hilton Foundation; and participating in grant review for the National Multiple Sclerosis Society.

jevans@frontlinemedcom.com

Specific polymorphisms of the SCN10A gene affect motor coordination and functional status in relapsing-onset multiple sclerosis (MS) patients via the abnormal expression of the voltage-gated Na_v1.8 sodium channel in cerebellar Purkinje neurons, causing dysfunctional cerebellothalamic circuitry, according to findings from a prospective cohort study.

The clinical effects of abnormally expressed Na_v1.8 in cerebellar Purkinje neurons and the polymorphisms’ effect on the activity of the channels in affected patients suggests that “SCN10A genotype may predict an MS subphenotype with significantly greater deficit in motor coordination and cognition and compromised cerebellothalamic functional integrity. This study further supports previous evidence that Na_v1.8 channelopathy is involved in the pathophysiology of cerebellar dysfunction in MS,” Dr. Tina Roostaei of the Tehran (Iran) University of Medical Sciences and her colleagues reported (Neurology. 2016 Jan 6. doi: 10.1212/WNL.0000000000002326). The authors noted that “unlike other clinical abnormalities in MS that tend to be remitting, cerebellar dysfunction tends to become persistent early in the course of the illness and is refractory to either disease-modifying or symptomatic therapy.”

©Eraxion/thinkstockphotos.com

Genotyping for four potentially functional SCN10A polymorphisms in 161 patients with relapsing-onset MS and 94 healthy controls revealed two polymorphisms that proved significantly related to performance on the Multiple Sclerosis Functional Composite and all its subscores, with carriers of one polymorphism (rs6795970^AA) performing worse than carriers of rs6795970^G, regardless of Expanded Disability Status Scale score or cerebellar atrophy. However, carriers of rs6795970^AA did not have significant gross ataxia as indexed by the Scale for the Assessment and Rating of Ataxia and cerebellar functional system score. The poor-performing carriers showed significantly diminished cerebellar functional connectivity with the thalami and midbrain on functional MRI. Similar results occurred for analyses of a separate polymorphism (rs6801957) that was in high-linkage disequilibrium with rs6795970. The effects of the polymorphisms were not seen in the healthy controls.

The effects of abnormal Na_v1.8 channel expression on Purkinje cells is thought to alter their activity because Na_v1.8 channels are normally found on unmyelinated sensory neurons of the dorsal root ganglia and peripheral nerve axons and support their repetitive firing by rapidly recovering from inactivation at depolarized membrane potentials.

The study by Dr. Roostaei and her colleagues and previous research suggests that it may be possible to reverse cerebellar manifestations of MS by blocking Na_v1.8 with drugs currently in development for treating pain caused by pain-signaling cells in dorsal root ganglion neurons, which have been shown to improve clinical function in animal models of MS, wrote Dr. Stephen G. Waxman of Yale University, New Haven, Conn., and Dr. Orhun H. Kantarci of the Mayo Clinic, Rochester, Minn., in an accompanying editorial (Neurology. 2016 Jan 6. doi: 10.1212/WNL.0000000000002338). Additional work needs to be done with higher-resolution tests of cerebellar function to determine the effects of the abnormal presence of Na_v1.8 on Purkinje cells in the cerebellum of MS patients, as well as further experiments to “understand the triggers that lead to upregulation of Na_v1.8 expression in the cerebellum in MS.”

The study was supported by the Tehran University of Medical Sciences and the MS Society of Iran. One author reported receiving financial compensation from Biogen, Merck Serono, Bayer-Schering, Novartis, and CinnaGen for consulting and speaking services. Dr. Waxman reported holding a patent for invention of sodium channel Na_v1.9, serving on the advisory board of SiteOne Therapeutics, and consulting for a variety of pharmaceutical companies. Dr. Kantarci reported receiving funding for travel and/or speaker honoraria from Novartis; research support from the European Regional Development Fund, National Multiple Sclerosis Society, Mayo Foundation, and Hilton Foundation; and participating in grant review for the National Multiple Sclerosis Society.

jevans@frontlinemedcom.com

Specific polymorphisms of the SCN10A gene affect motor coordination and functional status in relapsing-onset multiple sclerosis (MS) patients via the abnormal expression of the voltage-gated Na_v1.8 sodium channel in cerebellar Purkinje neurons, causing dysfunctional cerebellothalamic circuitry, according to findings from a prospective cohort study.

The clinical effects of abnormally expressed Na_v1.8 in cerebellar Purkinje neurons and the polymorphisms’ effect on the activity of the channels in affected patients suggests that “SCN10A genotype may predict an MS subphenotype with significantly greater deficit in motor coordination and cognition and compromised cerebellothalamic functional integrity. This study further supports previous evidence that Na_v1.8 channelopathy is involved in the pathophysiology of cerebellar dysfunction in MS,” Dr. Tina Roostaei of the Tehran (Iran) University of Medical Sciences and her colleagues reported (Neurology. 2016 Jan 6. doi: 10.1212/WNL.0000000000002326). The authors noted that “unlike other clinical abnormalities in MS that tend to be remitting, cerebellar dysfunction tends to become persistent early in the course of the illness and is refractory to either disease-modifying or symptomatic therapy.”

©Eraxion/thinkstockphotos.com

Genotyping for four potentially functional SCN10A polymorphisms in 161 patients with relapsing-onset MS and 94 healthy controls revealed two polymorphisms that proved significantly related to performance on the Multiple Sclerosis Functional Composite and all its subscores, with carriers of one polymorphism (rs6795970^AA) performing worse than carriers of rs6795970^G, regardless of Expanded Disability Status Scale score or cerebellar atrophy. However, carriers of rs6795970^AA did not have significant gross ataxia as indexed by the Scale for the Assessment and Rating of Ataxia and cerebellar functional system score. The poor-performing carriers showed significantly diminished cerebellar functional connectivity with the thalami and midbrain on functional MRI. Similar results occurred for analyses of a separate polymorphism (rs6801957) that was in high-linkage disequilibrium with rs6795970. The effects of the polymorphisms were not seen in the healthy controls.

The effects of abnormal Na_v1.8 channel expression on Purkinje cells is thought to alter their activity because Na_v1.8 channels are normally found on unmyelinated sensory neurons of the dorsal root ganglia and peripheral nerve axons and support their repetitive firing by rapidly recovering from inactivation at depolarized membrane potentials.

The study by Dr. Roostaei and her colleagues and previous research suggests that it may be possible to reverse cerebellar manifestations of MS by blocking Na_v1.8 with drugs currently in development for treating pain caused by pain-signaling cells in dorsal root ganglion neurons, which have been shown to improve clinical function in animal models of MS, wrote Dr. Stephen G. Waxman of Yale University, New Haven, Conn., and Dr. Orhun H. Kantarci of the Mayo Clinic, Rochester, Minn., in an accompanying editorial (Neurology. 2016 Jan 6. doi: 10.1212/WNL.0000000000002338). Additional work needs to be done with higher-resolution tests of cerebellar function to determine the effects of the abnormal presence of Na_v1.8 on Purkinje cells in the cerebellum of MS patients, as well as further experiments to “understand the triggers that lead to upregulation of Na_v1.8 expression in the cerebellum in MS.”

The study was supported by the Tehran University of Medical Sciences and the MS Society of Iran. One author reported receiving financial compensation from Biogen, Merck Serono, Bayer-Schering, Novartis, and CinnaGen for consulting and speaking services. Dr. Waxman reported holding a patent for invention of sodium channel Na_v1.9, serving on the advisory board of SiteOne Therapeutics, and consulting for a variety of pharmaceutical companies. Dr. Kantarci reported receiving funding for travel and/or speaker honoraria from Novartis; research support from the European Regional Development Fund, National Multiple Sclerosis Society, Mayo Foundation, and Hilton Foundation; and participating in grant review for the National Multiple Sclerosis Society.

jevans@frontlinemedcom.com

Canadian researchers have reported the first case of a patient developing multiple sclerosis (MS) while taking tocilizumab for rheumatoid arthritis.

A 48-year-old woman with a 20-year history of rheumatoid arthritis was seen for right hemisensory symptoms that began as numbness and pain on her right foot that spread to her trunk, arm, and face over a week, Dr. Philippe Beauchemin and Dr. Robert Carruthers of the University of British Columbia, Vancouver, noted in Multiple Sclerosis Journal. She had received many treatments for rheumatoid arthritis, including hydroxychloroquine, etanercept, and adalimumab. She also was on methotrexate, vitamin D, naproxen, and dexlansoprazole. MRI showed 20 lesions consistent with the diagnosis of MS. Doctors immediately discontinued tocilizumab and methotrexate. Three months later, another MRI showed two new lesions confirming MS diagnosis.

designer491/Thinkstock

“There is absolutely no proof of a causal relationship between tocilizumab and MS in this patient, but it is also not excluded that tocilizumab might have caused secondary autoimmunity in CNS,” the authors wrote. The drug is in efficacy trials for patients with neuromyelitis optica spectrum disorder.

Two scenarios could explain this potential relationship, according to an accompanying commentary by Dr. Manuel Comabella of the Multiple Sclerosis Center of Catalonia, Vall d’Hebron University Hospital, Barcelona. The patient may have developed demyelinating lesions as a consequence of previous exposure to anti-TNF agents, and MS was later precipitated by treatment with tocilizumab; or that the drug itself can trigger a demyelinating disorder. “IL-6 may have immunosuppressive properties … that when absent by the effect of anti-IL6 agents, predisposes the individual to demyelinating conditions.”

Read the article in Multiple Sclerosis Journal (doi: 10:1177/1352458515623862).

Canadian researchers have reported the first case of a patient developing multiple sclerosis (MS) while taking tocilizumab for rheumatoid arthritis.

A 48-year-old woman with a 20-year history of rheumatoid arthritis was seen for right hemisensory symptoms that began as numbness and pain on her right foot that spread to her trunk, arm, and face over a week, Dr. Philippe Beauchemin and Dr. Robert Carruthers of the University of British Columbia, Vancouver, noted in Multiple Sclerosis Journal. She had received many treatments for rheumatoid arthritis, including hydroxychloroquine, etanercept, and adalimumab. She also was on methotrexate, vitamin D, naproxen, and dexlansoprazole. MRI showed 20 lesions consistent with the diagnosis of MS. Doctors immediately discontinued tocilizumab and methotrexate. Three months later, another MRI showed two new lesions confirming MS diagnosis.

designer491/Thinkstock

“There is absolutely no proof of a causal relationship between tocilizumab and MS in this patient, but it is also not excluded that tocilizumab might have caused secondary autoimmunity in CNS,” the authors wrote. The drug is in efficacy trials for patients with neuromyelitis optica spectrum disorder.

Two scenarios could explain this potential relationship, according to an accompanying commentary by Dr. Manuel Comabella of the Multiple Sclerosis Center of Catalonia, Vall d’Hebron University Hospital, Barcelona. The patient may have developed demyelinating lesions as a consequence of previous exposure to anti-TNF agents, and MS was later precipitated by treatment with tocilizumab; or that the drug itself can trigger a demyelinating disorder. “IL-6 may have immunosuppressive properties … that when absent by the effect of anti-IL6 agents, predisposes the individual to demyelinating conditions.”

Read the article in Multiple Sclerosis Journal (doi: 10:1177/1352458515623862).

Canadian researchers have reported the first case of a patient developing multiple sclerosis (MS) while taking tocilizumab for rheumatoid arthritis.

A 48-year-old woman with a 20-year history of rheumatoid arthritis was seen for right hemisensory symptoms that began as numbness and pain on her right foot that spread to her trunk, arm, and face over a week, Dr. Philippe Beauchemin and Dr. Robert Carruthers of the University of British Columbia, Vancouver, noted in Multiple Sclerosis Journal. She had received many treatments for rheumatoid arthritis, including hydroxychloroquine, etanercept, and adalimumab. She also was on methotrexate, vitamin D, naproxen, and dexlansoprazole. MRI showed 20 lesions consistent with the diagnosis of MS. Doctors immediately discontinued tocilizumab and methotrexate. Three months later, another MRI showed two new lesions confirming MS diagnosis.

designer491/Thinkstock

“There is absolutely no proof of a causal relationship between tocilizumab and MS in this patient, but it is also not excluded that tocilizumab might have caused secondary autoimmunity in CNS,” the authors wrote. The drug is in efficacy trials for patients with neuromyelitis optica spectrum disorder.

Two scenarios could explain this potential relationship, according to an accompanying commentary by Dr. Manuel Comabella of the Multiple Sclerosis Center of Catalonia, Vall d’Hebron University Hospital, Barcelona. The patient may have developed demyelinating lesions as a consequence of previous exposure to anti-TNF agents, and MS was later precipitated by treatment with tocilizumab; or that the drug itself can trigger a demyelinating disorder. “IL-6 may have immunosuppressive properties … that when absent by the effect of anti-IL6 agents, predisposes the individual to demyelinating conditions.”

Read the article in Multiple Sclerosis Journal (doi: 10:1177/1352458515623862).

The recently identified autoantibody target in multiple sclerosis, sperm-associated antigen 16 (SPAG16), occurred most often in patients with primary progressive disease and was associated with faster-progressing disease in a case-control cohort study of Belgian and Spanish patients.

Anti-SPAG16 antibody reactivity to the autoantigen, which occurred in 22% of 374 multiple sclerosis (MS) patients overall in the study, was highest among patients with primary progressive MS (PPMS, 34% of 61), followed by secondary progressive MS (SPMS, 26% of 39) and relapsing-remitting MS (RRMS, 19% of 274). Patients with PPMS also had the highest anti-SPAG16 antibody levels, and seropositive PPMS patients had greater worsening of disease over time, judging from a significantly increased progression index relative to seronegative PPMS patients, Laura de Bock of Hasselt University, Diepenbeek, Belgium, and her colleagues reported (Eur J Neurol. 2015 Dec 26. doi: 10.1111/ene.12925).

©Zerbor/thinkstockphotos.com

Anti-SPAG16 antibody seropositivity had a 93% specificity for MS. A total of 7 out of 106 healthy controls were seropositive, based on a cutoff of 70 arbitrary units (AU) for seropositivity using enzyme-linked immunosorbent assay testing. While the mean anti-SPAG16 antibody levels were 58.7 AU in MS patients overall and 16.6 AU in healthy controls, PPMS patients had significantly higher mean levels than did RRMS patients (77.9 vs. 53.2 AU). However, anti-SPAG16 antibody levels in SPMS patients (67.5 AU) did not differ significantly from the other MS groups. The investigators suggested that the “increase in anti-SPAG16 antibody levels [in PPMS patients] is probably due to the significantly increased proportion of PPMS patients (34%) positive for anti-SPAG16 antibodies compared to RRMS patients (19%)” and that anti-SPAG16 antibody seropositivity overall “is possibly linked to disease stage and pathological subtype.”

Age did not correlate with antibody levels, although PPMS patients were significantly younger than their seronegative counterparts when antibodies were detected (48.4 years vs. 56.0 years), compared with patients with other MS subtypes. The seropositive PPMS patients also had significantly shorter mean disease duration than did seronegative PPMS patients (4.6 years vs. 7.9 years) despite having a similar mean Expanded Disability Status Scale (EDSS) score (4.2 vs. 4.1). This indication of a faster disease progression in seropositive PPMS patients was confirmed by their higher mean progression index, compared with seronegative patients (2.7 vs. 1.0); progression index was also significantly correlated with mean score on the MS severity scale (MSSS). Independent predictors of anti-SPAG16 antibody seropositivity on a logistic regression analysis included female sex (odds ratio, 3.91) and progression index (OR, 1.78).

In the overall cohort of MS patients, seropositivity was associated with a significantly higher mean EDSS score than was seronegative status (2.9 vs. 2.5, respectively), although EDSS did not differ according to serologic status in RRMS and SPMS subtypes. Serologic status in those subtypes also was not influenced by sex, disease duration, progression index, or MSSS score.

“Future follow-up of seropositive and seronegative PPMS patients is essential to conclude whether the presence of anti-SPAG16 antibodies could be a novel prognostic biomarker in PPMS. It would be interesting to investigate anti-SPAG16 antibodies in relation to neurofilament light levels, which have been shown to be higher in PPMS and can be used as a prognostic marker, and to investigate whether anti-SPAG16 antibodies can be used as a biomarker for possible treatment monitoring in PPMS,” the investigators wrote.

SPAG16 is known to be upregulated in astrocytes in MS lesions, the researchers noted. “Interestingly, astrocytes are becoming increasingly recognized as important players in MS progression and targets of autoantibodies in MS. It is possible that anti-SPAG16 antibodies are formed due to cell damage and death of astrocytes which leads to the exposure of intracellular antigens such as SPAG16 (epitope spreading).”

The study received support from the Transnationale Universiteit Limburg, Hasselt University, the Flanders Fund for Scientific Research, the Charcot Foundation (Belgium), and Rotary International. Two authors declared financial relationships with companies marketing MS drugs.

jevans@frontlinemedcom.com

The recently identified autoantibody target in multiple sclerosis, sperm-associated antigen 16 (SPAG16), occurred most often in patients with primary progressive disease and was associated with faster-progressing disease in a case-control cohort study of Belgian and Spanish patients.

Anti-SPAG16 antibody reactivity to the autoantigen, which occurred in 22% of 374 multiple sclerosis (MS) patients overall in the study, was highest among patients with primary progressive MS (PPMS, 34% of 61), followed by secondary progressive MS (SPMS, 26% of 39) and relapsing-remitting MS (RRMS, 19% of 274). Patients with PPMS also had the highest anti-SPAG16 antibody levels, and seropositive PPMS patients had greater worsening of disease over time, judging from a significantly increased progression index relative to seronegative PPMS patients, Laura de Bock of Hasselt University, Diepenbeek, Belgium, and her colleagues reported (Eur J Neurol. 2015 Dec 26. doi: 10.1111/ene.12925).

©Zerbor/thinkstockphotos.com

Anti-SPAG16 antibody seropositivity had a 93% specificity for MS. A total of 7 out of 106 healthy controls were seropositive, based on a cutoff of 70 arbitrary units (AU) for seropositivity using enzyme-linked immunosorbent assay testing. While the mean anti-SPAG16 antibody levels were 58.7 AU in MS patients overall and 16.6 AU in healthy controls, PPMS patients had significantly higher mean levels than did RRMS patients (77.9 vs. 53.2 AU). However, anti-SPAG16 antibody levels in SPMS patients (67.5 AU) did not differ significantly from the other MS groups. The investigators suggested that the “increase in anti-SPAG16 antibody levels [in PPMS patients] is probably due to the significantly increased proportion of PPMS patients (34%) positive for anti-SPAG16 antibodies compared to RRMS patients (19%)” and that anti-SPAG16 antibody seropositivity overall “is possibly linked to disease stage and pathological subtype.”

Age did not correlate with antibody levels, although PPMS patients were significantly younger than their seronegative counterparts when antibodies were detected (48.4 years vs. 56.0 years), compared with patients with other MS subtypes. The seropositive PPMS patients also had significantly shorter mean disease duration than did seronegative PPMS patients (4.6 years vs. 7.9 years) despite having a similar mean Expanded Disability Status Scale (EDSS) score (4.2 vs. 4.1). This indication of a faster disease progression in seropositive PPMS patients was confirmed by their higher mean progression index, compared with seronegative patients (2.7 vs. 1.0); progression index was also significantly correlated with mean score on the MS severity scale (MSSS). Independent predictors of anti-SPAG16 antibody seropositivity on a logistic regression analysis included female sex (odds ratio, 3.91) and progression index (OR, 1.78).

In the overall cohort of MS patients, seropositivity was associated with a significantly higher mean EDSS score than was seronegative status (2.9 vs. 2.5, respectively), although EDSS did not differ according to serologic status in RRMS and SPMS subtypes. Serologic status in those subtypes also was not influenced by sex, disease duration, progression index, or MSSS score.

“Future follow-up of seropositive and seronegative PPMS patients is essential to conclude whether the presence of anti-SPAG16 antibodies could be a novel prognostic biomarker in PPMS. It would be interesting to investigate anti-SPAG16 antibodies in relation to neurofilament light levels, which have been shown to be higher in PPMS and can be used as a prognostic marker, and to investigate whether anti-SPAG16 antibodies can be used as a biomarker for possible treatment monitoring in PPMS,” the investigators wrote.

SPAG16 is known to be upregulated in astrocytes in MS lesions, the researchers noted. “Interestingly, astrocytes are becoming increasingly recognized as important players in MS progression and targets of autoantibodies in MS. It is possible that anti-SPAG16 antibodies are formed due to cell damage and death of astrocytes which leads to the exposure of intracellular antigens such as SPAG16 (epitope spreading).”

The study received support from the Transnationale Universiteit Limburg, Hasselt University, the Flanders Fund for Scientific Research, the Charcot Foundation (Belgium), and Rotary International. Two authors declared financial relationships with companies marketing MS drugs.

jevans@frontlinemedcom.com

The recently identified autoantibody target in multiple sclerosis, sperm-associated antigen 16 (SPAG16), occurred most often in patients with primary progressive disease and was associated with faster-progressing disease in a case-control cohort study of Belgian and Spanish patients.

Anti-SPAG16 antibody reactivity to the autoantigen, which occurred in 22% of 374 multiple sclerosis (MS) patients overall in the study, was highest among patients with primary progressive MS (PPMS, 34% of 61), followed by secondary progressive MS (SPMS, 26% of 39) and relapsing-remitting MS (RRMS, 19% of 274). Patients with PPMS also had the highest anti-SPAG16 antibody levels, and seropositive PPMS patients had greater worsening of disease over time, judging from a significantly increased progression index relative to seronegative PPMS patients, Laura de Bock of Hasselt University, Diepenbeek, Belgium, and her colleagues reported (Eur J Neurol. 2015 Dec 26. doi: 10.1111/ene.12925).

©Zerbor/thinkstockphotos.com

Anti-SPAG16 antibody seropositivity had a 93% specificity for MS. A total of 7 out of 106 healthy controls were seropositive, based on a cutoff of 70 arbitrary units (AU) for seropositivity using enzyme-linked immunosorbent assay testing. While the mean anti-SPAG16 antibody levels were 58.7 AU in MS patients overall and 16.6 AU in healthy controls, PPMS patients had significantly higher mean levels than did RRMS patients (77.9 vs. 53.2 AU). However, anti-SPAG16 antibody levels in SPMS patients (67.5 AU) did not differ significantly from the other MS groups. The investigators suggested that the “increase in anti-SPAG16 antibody levels [in PPMS patients] is probably due to the significantly increased proportion of PPMS patients (34%) positive for anti-SPAG16 antibodies compared to RRMS patients (19%)” and that anti-SPAG16 antibody seropositivity overall “is possibly linked to disease stage and pathological subtype.”

Age did not correlate with antibody levels, although PPMS patients were significantly younger than their seronegative counterparts when antibodies were detected (48.4 years vs. 56.0 years), compared with patients with other MS subtypes. The seropositive PPMS patients also had significantly shorter mean disease duration than did seronegative PPMS patients (4.6 years vs. 7.9 years) despite having a similar mean Expanded Disability Status Scale (EDSS) score (4.2 vs. 4.1). This indication of a faster disease progression in seropositive PPMS patients was confirmed by their higher mean progression index, compared with seronegative patients (2.7 vs. 1.0); progression index was also significantly correlated with mean score on the MS severity scale (MSSS). Independent predictors of anti-SPAG16 antibody seropositivity on a logistic regression analysis included female sex (odds ratio, 3.91) and progression index (OR, 1.78).

In the overall cohort of MS patients, seropositivity was associated with a significantly higher mean EDSS score than was seronegative status (2.9 vs. 2.5, respectively), although EDSS did not differ according to serologic status in RRMS and SPMS subtypes. Serologic status in those subtypes also was not influenced by sex, disease duration, progression index, or MSSS score.

“Future follow-up of seropositive and seronegative PPMS patients is essential to conclude whether the presence of anti-SPAG16 antibodies could be a novel prognostic biomarker in PPMS. It would be interesting to investigate anti-SPAG16 antibodies in relation to neurofilament light levels, which have been shown to be higher in PPMS and can be used as a prognostic marker, and to investigate whether anti-SPAG16 antibodies can be used as a biomarker for possible treatment monitoring in PPMS,” the investigators wrote.

SPAG16 is known to be upregulated in astrocytes in MS lesions, the researchers noted. “Interestingly, astrocytes are becoming increasingly recognized as important players in MS progression and targets of autoantibodies in MS. It is possible that anti-SPAG16 antibodies are formed due to cell damage and death of astrocytes which leads to the exposure of intracellular antigens such as SPAG16 (epitope spreading).”

The study received support from the Transnationale Universiteit Limburg, Hasselt University, the Flanders Fund for Scientific Research, the Charcot Foundation (Belgium), and Rotary International. Two authors declared financial relationships with companies marketing MS drugs.

jevans@frontlinemedcom.com

Cognitive impairment in secondary progressive multiple sclerosis (SPMS) is linked to significantly worse white matter integrity in areas important to cognitive function, according to Dr. Kim A. Meijer and associates.

Compared with a control group of 32 healthy people, the 12 cognitively impaired and 18 cognitively preserved SPMS patients had significant loss of white matter integrity across the white matter skeleton. SPMS patients with cognitive impairment had more severe and extensive damage in several places, including the fornix, superior longitudinal fasciculus, and forceps major.

Poor cognitive function in SPMS patients was associated with lower premorbid IQ, female sex, and higher age. Combined with white matter integrity, these factors accounted for 48% of the difference in cognition between cognitively impaired and cognitively preserved SPMS patients.

“As with [relapsing remitting multiple sclerosis], damage to WM [white matter] tracts also appears to be a potential mechanism for cognitive impairment in SPMS patients. This study shows that the loss of WM integrity assessed using [tract-based spatial statistics] helps to explain cognitive decline and emphasizes the relevance of studying patterns of WM disruption throughout the brain in relation to cognitive deficits,” the investigators concluded.

Find the full study in the Multiple Sclerosis Journal (doi: 10.1177/1352458515622694).

lfranki@frontlinemedcom.com

Cognitive impairment in secondary progressive multiple sclerosis (SPMS) is linked to significantly worse white matter integrity in areas important to cognitive function, according to Dr. Kim A. Meijer and associates.

Compared with a control group of 32 healthy people, the 12 cognitively impaired and 18 cognitively preserved SPMS patients had significant loss of white matter integrity across the white matter skeleton. SPMS patients with cognitive impairment had more severe and extensive damage in several places, including the fornix, superior longitudinal fasciculus, and forceps major.

Poor cognitive function in SPMS patients was associated with lower premorbid IQ, female sex, and higher age. Combined with white matter integrity, these factors accounted for 48% of the difference in cognition between cognitively impaired and cognitively preserved SPMS patients.

“As with [relapsing remitting multiple sclerosis], damage to WM [white matter] tracts also appears to be a potential mechanism for cognitive impairment in SPMS patients. This study shows that the loss of WM integrity assessed using [tract-based spatial statistics] helps to explain cognitive decline and emphasizes the relevance of studying patterns of WM disruption throughout the brain in relation to cognitive deficits,” the investigators concluded.

Find the full study in the Multiple Sclerosis Journal (doi: 10.1177/1352458515622694).

lfranki@frontlinemedcom.com

Cognitive impairment in secondary progressive multiple sclerosis (SPMS) is linked to significantly worse white matter integrity in areas important to cognitive function, according to Dr. Kim A. Meijer and associates.

Compared with a control group of 32 healthy people, the 12 cognitively impaired and 18 cognitively preserved SPMS patients had significant loss of white matter integrity across the white matter skeleton. SPMS patients with cognitive impairment had more severe and extensive damage in several places, including the fornix, superior longitudinal fasciculus, and forceps major.

Poor cognitive function in SPMS patients was associated with lower premorbid IQ, female sex, and higher age. Combined with white matter integrity, these factors accounted for 48% of the difference in cognition between cognitively impaired and cognitively preserved SPMS patients.

“As with [relapsing remitting multiple sclerosis], damage to WM [white matter] tracts also appears to be a potential mechanism for cognitive impairment in SPMS patients. This study shows that the loss of WM integrity assessed using [tract-based spatial statistics] helps to explain cognitive decline and emphasizes the relevance of studying patterns of WM disruption throughout the brain in relation to cognitive deficits,” the investigators concluded.

Find the full study in the Multiple Sclerosis Journal (doi: 10.1177/1352458515622694).

lfranki@frontlinemedcom.com

The morphology of brain lesions can provide strong clues for differentiating patients with multiple sclerosis (MS) with cavitary lesions from patients with vanishing white matter disease (VWMD), suggests a cross-sectional study conducted in France.

The study comprised 14 patients with MS with cavitary lesions and 14 patients with VWMD. Two neuroradiologists reviewed brain MRI scans for the patients.

HUNG KUO CHUN/Thinkstock

All of the patients with MS had ovoid lesions perpendicular to the lateral ventricles and half of such patients had isolated juxtacortical lesions. None of the VWMD patients had either of those types of lesions.

Another of the neuroradiologists’ findings was that 58% of the VWMD patients had symmetrical hyperintensities in the infratentorial region of the brain, mainly involving the middle cerebellar peduncle and cerebellar white matter, while symmetrical hyperintensities were absent from that part of the brain in MS patients.

Other statistically significant differences between the brains of the two groups were the percentages of each group that had hyperintensities located in the midbrain and thalamus. Both were found in more than 70% of MS patients. In contrast, midbrain and thalamus hyperintensities were found in 29% and 7% of the VWMD patients, respectively.

While it is difficult to distinguish MS with cavitary lesions from VWMD, this study “clearly shows some MRI characteristics that seems to be specific and thus help to differentiate these two disorders,” wrote Xavier Ayrignac and his colleagues.

Read the study in the European Journal of Neurology (doi: 10.111/ene.12931).

klennon@frontlinemedcom.com

The morphology of brain lesions can provide strong clues for differentiating patients with multiple sclerosis (MS) with cavitary lesions from patients with vanishing white matter disease (VWMD), suggests a cross-sectional study conducted in France.

The study comprised 14 patients with MS with cavitary lesions and 14 patients with VWMD. Two neuroradiologists reviewed brain MRI scans for the patients.

HUNG KUO CHUN/Thinkstock

All of the patients with MS had ovoid lesions perpendicular to the lateral ventricles and half of such patients had isolated juxtacortical lesions. None of the VWMD patients had either of those types of lesions.

Another of the neuroradiologists’ findings was that 58% of the VWMD patients had symmetrical hyperintensities in the infratentorial region of the brain, mainly involving the middle cerebellar peduncle and cerebellar white matter, while symmetrical hyperintensities were absent from that part of the brain in MS patients.

Other statistically significant differences between the brains of the two groups were the percentages of each group that had hyperintensities located in the midbrain and thalamus. Both were found in more than 70% of MS patients. In contrast, midbrain and thalamus hyperintensities were found in 29% and 7% of the VWMD patients, respectively.

While it is difficult to distinguish MS with cavitary lesions from VWMD, this study “clearly shows some MRI characteristics that seems to be specific and thus help to differentiate these two disorders,” wrote Xavier Ayrignac and his colleagues.

Read the study in the European Journal of Neurology (doi: 10.111/ene.12931).

klennon@frontlinemedcom.com

The morphology of brain lesions can provide strong clues for differentiating patients with multiple sclerosis (MS) with cavitary lesions from patients with vanishing white matter disease (VWMD), suggests a cross-sectional study conducted in France.

The study comprised 14 patients with MS with cavitary lesions and 14 patients with VWMD. Two neuroradiologists reviewed brain MRI scans for the patients.

HUNG KUO CHUN/Thinkstock

All of the patients with MS had ovoid lesions perpendicular to the lateral ventricles and half of such patients had isolated juxtacortical lesions. None of the VWMD patients had either of those types of lesions.

Another of the neuroradiologists’ findings was that 58% of the VWMD patients had symmetrical hyperintensities in the infratentorial region of the brain, mainly involving the middle cerebellar peduncle and cerebellar white matter, while symmetrical hyperintensities were absent from that part of the brain in MS patients.

Other statistically significant differences between the brains of the two groups were the percentages of each group that had hyperintensities located in the midbrain and thalamus. Both were found in more than 70% of MS patients. In contrast, midbrain and thalamus hyperintensities were found in 29% and 7% of the VWMD patients, respectively.

While it is difficult to distinguish MS with cavitary lesions from VWMD, this study “clearly shows some MRI characteristics that seems to be specific and thus help to differentiate these two disorders,” wrote Xavier Ayrignac and his colleagues.

Read the study in the European Journal of Neurology (doi: 10.111/ene.12931).

klennon@frontlinemedcom.com

The expression of l-selectin on specific T cells in peripheral blood from patients with relapsing forms of multiple sclerosis (MS) does not reliably predict risk for progressive multifocal leukoencephalopathy (PML) during natalizumab treatment, according to findings from a Biogen-supported study.

These findings are at odds with those of a previously reported preliminary study that used a different analytical technique. Investigators in the earlier preliminary study had found a drop in the percentage of CD4- and CD3-positive T cells expressing l-selectin (CD62L) at least 4 months and often 2 years prior to PML diagnosis and concluded that measuring the percentage of CD4- and CD3-positive T cells expressing l-selectin (%CD62L) “may improve stratification of patients taking natalizumab who are at risk for developing PML,” according to the study from Biogen, which makes natalizumab (Tysabri).

HUNG KUO CHUN/Thinkstock

Biogen investigators, led by Linda A. Lieberman, Ph.D., sought to confirm the findings, enhance the reproducibility of the %CD62L assay, “and potentially enable the deployment of %CD62L as a biomarker for PML in a global setting.” However, the investigators did not find a significant difference in %CD62L in cryopreserved peripheral blood mononuclear cells in 104 patients with relapsing forms of multiple sclerosis (MS) on natalizumab who did not develop PML, compared with 21 who developed PML (Neurology. 2015 Dec 30. doi: 10.1212/WNL.0000000000002314).

In the current study, the investigators detected a large range in %CD62L (0.31%-68.4%) in a subset of natalizumab-treated MS patients without PML at two time points at least 6 months apart. Because CD62L and the chemokine receptor CCR7 are coexpressed on CD4- and CD3-positive T cells, they also checked the level of variation in simultaneous measurements of %CD62L and %CCR7 on the same cells at two separate time points in the same patients. They found that %CD62L expression varied substantially, whereas %CCR7 varied little, and the difference between the two was significant, “signifying that %CD62L is not a stable outcome measure,” they wrote.

Dr. Lieberman and her colleagues also confirmed a positive correlation between lymphocyte viability and %CD62L expression, which highlights the “technique-driven variability of the assay” that was used in the preliminary study.

In patient samples collected at least 6 months prior to PML diagnosis, %CD62L did not discriminate significantly between non-PML and active PML (defined as 0-6 months prior to diagnosis). The median %CD62L varied according to the viability of cryopreserved CD4- and CD3-positive T cells. Median %CD62L was no different between non-PML and pre-PML samples with lymphocyte viability greater than 75% (25.9% vs. 26.3%, respectively) but was significantly lower than with non-PML and pre-PML samples with lymphocyte viability less than 75% (10.55% and 5.41%). There was no difference in lymphocyte viability between non-PML and pre-PML samples.

In a case-control comparison of patients on natalizumab who had multiple pre-PML samples, nine patients who developed PML had %CD62L values that in most samples fell in the range of nine matched control patients without PML.

Examination of samples from non-MS patients demonstrated that %CD62L also could vary significantly in various disease states, such as after influenza vaccination and during hospitalization for total knee replacement surgery or methicillin-resistant Staphylococcus aureus infection, the researchers found.

jevans@frontlinemedcom.com

The expression of l-selectin on specific T cells in peripheral blood from patients with relapsing forms of multiple sclerosis (MS) does not reliably predict risk for progressive multifocal leukoencephalopathy (PML) during natalizumab treatment, according to findings from a Biogen-supported study.

These findings are at odds with those of a previously reported preliminary study that used a different analytical technique. Investigators in the earlier preliminary study had found a drop in the percentage of CD4- and CD3-positive T cells expressing l-selectin (CD62L) at least 4 months and often 2 years prior to PML diagnosis and concluded that measuring the percentage of CD4- and CD3-positive T cells expressing l-selectin (%CD62L) “may improve stratification of patients taking natalizumab who are at risk for developing PML,” according to the study from Biogen, which makes natalizumab (Tysabri).

HUNG KUO CHUN/Thinkstock

Biogen investigators, led by Linda A. Lieberman, Ph.D., sought to confirm the findings, enhance the reproducibility of the %CD62L assay, “and potentially enable the deployment of %CD62L as a biomarker for PML in a global setting.” However, the investigators did not find a significant difference in %CD62L in cryopreserved peripheral blood mononuclear cells in 104 patients with relapsing forms of multiple sclerosis (MS) on natalizumab who did not develop PML, compared with 21 who developed PML (Neurology. 2015 Dec 30. doi: 10.1212/WNL.0000000000002314).

In the current study, the investigators detected a large range in %CD62L (0.31%-68.4%) in a subset of natalizumab-treated MS patients without PML at two time points at least 6 months apart. Because CD62L and the chemokine receptor CCR7 are coexpressed on CD4- and CD3-positive T cells, they also checked the level of variation in simultaneous measurements of %CD62L and %CCR7 on the same cells at two separate time points in the same patients. They found that %CD62L expression varied substantially, whereas %CCR7 varied little, and the difference between the two was significant, “signifying that %CD62L is not a stable outcome measure,” they wrote.

Dr. Lieberman and her colleagues also confirmed a positive correlation between lymphocyte viability and %CD62L expression, which highlights the “technique-driven variability of the assay” that was used in the preliminary study.

In patient samples collected at least 6 months prior to PML diagnosis, %CD62L did not discriminate significantly between non-PML and active PML (defined as 0-6 months prior to diagnosis). The median %CD62L varied according to the viability of cryopreserved CD4- and CD3-positive T cells. Median %CD62L was no different between non-PML and pre-PML samples with lymphocyte viability greater than 75% (25.9% vs. 26.3%, respectively) but was significantly lower than with non-PML and pre-PML samples with lymphocyte viability less than 75% (10.55% and 5.41%). There was no difference in lymphocyte viability between non-PML and pre-PML samples.

In a case-control comparison of patients on natalizumab who had multiple pre-PML samples, nine patients who developed PML had %CD62L values that in most samples fell in the range of nine matched control patients without PML.

Examination of samples from non-MS patients demonstrated that %CD62L also could vary significantly in various disease states, such as after influenza vaccination and during hospitalization for total knee replacement surgery or methicillin-resistant Staphylococcus aureus infection, the researchers found.

jevans@frontlinemedcom.com

The expression of l-selectin on specific T cells in peripheral blood from patients with relapsing forms of multiple sclerosis (MS) does not reliably predict risk for progressive multifocal leukoencephalopathy (PML) during natalizumab treatment, according to findings from a Biogen-supported study.

These findings are at odds with those of a previously reported preliminary study that used a different analytical technique. Investigators in the earlier preliminary study had found a drop in the percentage of CD4- and CD3-positive T cells expressing l-selectin (CD62L) at least 4 months and often 2 years prior to PML diagnosis and concluded that measuring the percentage of CD4- and CD3-positive T cells expressing l-selectin (%CD62L) “may improve stratification of patients taking natalizumab who are at risk for developing PML,” according to the study from Biogen, which makes natalizumab (Tysabri).

HUNG KUO CHUN/Thinkstock

Biogen investigators, led by Linda A. Lieberman, Ph.D., sought to confirm the findings, enhance the reproducibility of the %CD62L assay, “and potentially enable the deployment of %CD62L as a biomarker for PML in a global setting.” However, the investigators did not find a significant difference in %CD62L in cryopreserved peripheral blood mononuclear cells in 104 patients with relapsing forms of multiple sclerosis (MS) on natalizumab who did not develop PML, compared with 21 who developed PML (Neurology. 2015 Dec 30. doi: 10.1212/WNL.0000000000002314).

In the current study, the investigators detected a large range in %CD62L (0.31%-68.4%) in a subset of natalizumab-treated MS patients without PML at two time points at least 6 months apart. Because CD62L and the chemokine receptor CCR7 are coexpressed on CD4- and CD3-positive T cells, they also checked the level of variation in simultaneous measurements of %CD62L and %CCR7 on the same cells at two separate time points in the same patients. They found that %CD62L expression varied substantially, whereas %CCR7 varied little, and the difference between the two was significant, “signifying that %CD62L is not a stable outcome measure,” they wrote.

Dr. Lieberman and her colleagues also confirmed a positive correlation between lymphocyte viability and %CD62L expression, which highlights the “technique-driven variability of the assay” that was used in the preliminary study.

In patient samples collected at least 6 months prior to PML diagnosis, %CD62L did not discriminate significantly between non-PML and active PML (defined as 0-6 months prior to diagnosis). The median %CD62L varied according to the viability of cryopreserved CD4- and CD3-positive T cells. Median %CD62L was no different between non-PML and pre-PML samples with lymphocyte viability greater than 75% (25.9% vs. 26.3%, respectively) but was significantly lower than with non-PML and pre-PML samples with lymphocyte viability less than 75% (10.55% and 5.41%). There was no difference in lymphocyte viability between non-PML and pre-PML samples.

In a case-control comparison of patients on natalizumab who had multiple pre-PML samples, nine patients who developed PML had %CD62L values that in most samples fell in the range of nine matched control patients without PML.

Examination of samples from non-MS patients demonstrated that %CD62L also could vary significantly in various disease states, such as after influenza vaccination and during hospitalization for total knee replacement surgery or methicillin-resistant Staphylococcus aureus infection, the researchers found.

jevans@frontlinemedcom.com

BARCELONA—Revised consensus criteria have proposed that neuromyelitis optica spectrum disorder (NMOSD) become the new unifying term to replace neuromyelitis optica, and that the condition be further stratified based on serologic testing. In kind, NMOSD treatment may differ based on the goals of either relapse prevention or prevention of acute attacks. NMOSD diagnosis and treatment were discussed at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis.

NMOSD encompasses what previously has been diagnosed as neuromyelitis optica, an inflammatory CNS syndrome distinct from multiple sclerosis (MS), which requires clinical optic neuritis and myelitis. It also includes limited forms (eg, optic neuritis or myelitis alone) and a series of associated conditions such as area postrema syndrome and certain brain syndromes known to occur with other symptoms of neuromyelitis optica, said Brian G. Weinshenker, MD, Professor of Neurology at the Mayo Clinic in Rochester, Minnesota, and a member of the international panel that developed the NMOSD consensus criteria. The criteria were published in the July 14 issue of Neurology. The criteria also include patients who are aquaporin 4 (AQP4) seronegative but have otherwise typical clinical presentations.

Patients who are AQP4 antibody sero­positive should have at least one core clinical characteristic for a diagnosis of NMOSD, according to the criteria. The core clinical characteristics are optic neuritis, acute myelitis, area postrema syndrome (ie, otherwise unexplained hiccups or nausea), acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome with diencephalic lesions typical of NMOSD on MRI, and symptomatic cerebral syndrome.

“There are no exclusionary criteria, but our caveat is that there should be no better explanation for the symptoms,” Dr. Weinshenker noted. “Comorbidities such as lupus or Sjögren’s syndrome do not exclude NMOSD, but some syndromes or comorbidities raise red flags. These red flags are clinical and MRI features that might suggest a diagnosis of MS instead of NMOSD, as well as sarcoidosis, which can cause optic neuritis or myelitis.” Other red flags, according to the criteria, include cancer and chronic infection (eg, HIV or syphilis).

For patients who are AQP4 seronegative or those for whom serologic testing is unavailable, the criteria are similar, but more rigorous. Specifically, at least two core clinical characteristics are required, and one of them must be optic neuritis, acute myelitis with longitudinally extensive transverse myelitis (LETM) lesions, or area postrema syndrome.

“There must be evidence of dissemination in space, and we require additional MRI features to be present,” said Dr. Weinshenker. “For example, in patients with intractable vomiting, we require that they also have associated dorsal medulla/area postrema lesions.” Those with myelitis must have a long spinal cord lesion and those with acute optic neuritis must have a long optic nerve lesion that takes up half or more of the length of the optic nerve or affects the optic chiasm. “Again, there should be no better explanation for the findings,” he said.

The revised criteria align “with our contemporary view of what NMOSD is and captures current expert practice,” Dr. Weinshenker said. “It should facilitate clinical research by allowing for early diagnosis in a larger pool of patients who might be eligible for clinical trials.”

However, as is true for any set of diagnostic criteria, physicians will still need to exercise individual judgment, he said. He noted that despite the high accuracy of enzyme-linked immunosorbent assay (ELISA) testing, the most widely used serologic test in the United States for AQP4 antibodies, there is still about a 5% chance of false positives, particularly among patients with a low pretest probability of NMOSD. In addition, patients who are AQP4 seronegative, who make up approximately 30% of the total NMOSD population, are poorly characterized.

Among the AQP4 seropositive patients are those who have detectable serum myelin oligodendrocyte glycoprotein (MOG) antibodies. They tend to be younger, male, and less likely to relapse than those with AQP4 antibodies “Maybe MOG syndrome will ultimately be considered separately, but currently we consider it to be a form of NMOSD, and future versions of the diagnostic criteria will probably incorporate other biomarkers,” Dr. Weinshenker said.

NMOSD therapy can be stratified into two types: treatment of acute (ie, monophasic) attack and relapse prevention, said Jacqueline Palace, BM, DM, Consultant Neurologist at the University of Oxford, United Kingdom. She noted that her classifications for treatment purposes are not based on the newly revised NMOSD diagnostic criteria, but rather are slightly broader. She pointed out that her treatment recommendations are in line with 2010 guidelines by the European Federation of Neurological Societies.

“AQP4 antibody disease is a relapsing condition when untreated,” said Dr. Palace. “On the other hand, many MOG antibody seropositive patients have monophasic phenotypes.” Other monophasic conditions include LETM or idiopathic transverse myelitis, Devic’s disease, and severe or bilateral optic neuritis.

Patients in the monophasic group may go on to develop relapsing disease (ie, relapsing NMOSD, relapsing optic neuritis, and relapsing LETM), Dr. Palace noted. Among the difficult-to-treat patients are those who have overlap between MS and antibody-negative NMOSD.

Management of an acute attack across all of these monophasic syndromes is similar because the attacks tend to present with more severe relapses than patients with MS, and some patients are left with severe residual disability, said Dr. Palace. “We treat these patients urgently with IV methylprednisolone for three to five days to try to restore function. If there is poor response or significant disability, we follow with plasma exchange.” If plasma exchange is not feasible, patients may be given IV immunoglobulin (IVIG), she suggested. “There is a small proportion of patients who develop severe paraplegia that don’t appear to respond at all to treatment, even if given urgently. In my experience, these patients are monophasic and they are antibody negative for both MOG and AQP4.”

Patients with acute disseminated encephalomyelitis can rebound if given a short course of IV methylprednisolone. Dr. Palace recommended follow-on prednisolone for two months for patients who have such monophasic MOG and AQP4 antibody disorders to prevent rebound, and for longer (ie, six to 12 months) for monophasic patients with MOG antibodies.

Preventing relapse is probably the most important aspect of managing NMOSD. “AQP4 antibody disease is a relapsing condition, and there is no progressive phase as there is in MS,” Dr. Palace said. “There is a high morbidity and mortality associated with relapse.”

In a 2012 review of AQP4 antibody-seropositive patients—many of whom were on corticosteroids or other immunosuppression—researchers found that, among 59 patients in the UK with a median follow-up of five years, 22% had permanent bilateral visual loss with visual acuity of less than 6/36 in the better eye, and nearly 30% were wheelchair-dependent.

Prednisolone cover alone or in conjunction with a steroid-sparing drug (ie, azathioprine, mycophenolate, methotrexate, or rituximab) is the recommended first-line treatment for relapse prevention. “If patients have a relapse on an adequate dose tried for three to six months, then you might consider an alternative first-line drug or other less commonly used immunosuppressive agents such as ciclosporin/tacrolimus, cyclophosphamide, or mitoxantrone. Regular plasma exchange or IVIG is also an option,” said Dr. Palace. “We note that our patients appear less likely to relapse if they are kept on a low background dose of prednisolone when on other immunosuppressants. If they have a relapse, we may increase the background prednisolone dose rather than switch treatments.”

Some MS disease-modifying drugs have been reported to exacerbate NMOSD, including beta-interferon, natalizumab, and fingolimod. In addition, there is a theoretical risk of alemtuzumab being harmful because it is known to precipitate antibody-mediated disease, Dr. Palace said.

—Adriene Marshall

BARCELONA—Revised consensus criteria have proposed that neuromyelitis optica spectrum disorder (NMOSD) become the new unifying term to replace neuromyelitis optica, and that the condition be further stratified based on serologic testing. In kind, NMOSD treatment may differ based on the goals of either relapse prevention or prevention of acute attacks. NMOSD diagnosis and treatment were discussed at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis.

NMOSD encompasses what previously has been diagnosed as neuromyelitis optica, an inflammatory CNS syndrome distinct from multiple sclerosis (MS), which requires clinical optic neuritis and myelitis. It also includes limited forms (eg, optic neuritis or myelitis alone) and a series of associated conditions such as area postrema syndrome and certain brain syndromes known to occur with other symptoms of neuromyelitis optica, said Brian G. Weinshenker, MD, Professor of Neurology at the Mayo Clinic in Rochester, Minnesota, and a member of the international panel that developed the NMOSD consensus criteria. The criteria were published in the July 14 issue of Neurology. The criteria also include patients who are aquaporin 4 (AQP4) seronegative but have otherwise typical clinical presentations.

Patients who are AQP4 antibody sero­positive should have at least one core clinical characteristic for a diagnosis of NMOSD, according to the criteria. The core clinical characteristics are optic neuritis, acute myelitis, area postrema syndrome (ie, otherwise unexplained hiccups or nausea), acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome with diencephalic lesions typical of NMOSD on MRI, and symptomatic cerebral syndrome.

“There are no exclusionary criteria, but our caveat is that there should be no better explanation for the symptoms,” Dr. Weinshenker noted. “Comorbidities such as lupus or Sjögren’s syndrome do not exclude NMOSD, but some syndromes or comorbidities raise red flags. These red flags are clinical and MRI features that might suggest a diagnosis of MS instead of NMOSD, as well as sarcoidosis, which can cause optic neuritis or myelitis.” Other red flags, according to the criteria, include cancer and chronic infection (eg, HIV or syphilis).

For patients who are AQP4 seronegative or those for whom serologic testing is unavailable, the criteria are similar, but more rigorous. Specifically, at least two core clinical characteristics are required, and one of them must be optic neuritis, acute myelitis with longitudinally extensive transverse myelitis (LETM) lesions, or area postrema syndrome.

“There must be evidence of dissemination in space, and we require additional MRI features to be present,” said Dr. Weinshenker. “For example, in patients with intractable vomiting, we require that they also have associated dorsal medulla/area postrema lesions.” Those with myelitis must have a long spinal cord lesion and those with acute optic neuritis must have a long optic nerve lesion that takes up half or more of the length of the optic nerve or affects the optic chiasm. “Again, there should be no better explanation for the findings,” he said.

The revised criteria align “with our contemporary view of what NMOSD is and captures current expert practice,” Dr. Weinshenker said. “It should facilitate clinical research by allowing for early diagnosis in a larger pool of patients who might be eligible for clinical trials.”

However, as is true for any set of diagnostic criteria, physicians will still need to exercise individual judgment, he said. He noted that despite the high accuracy of enzyme-linked immunosorbent assay (ELISA) testing, the most widely used serologic test in the United States for AQP4 antibodies, there is still about a 5% chance of false positives, particularly among patients with a low pretest probability of NMOSD. In addition, patients who are AQP4 seronegative, who make up approximately 30% of the total NMOSD population, are poorly characterized.

Among the AQP4 seropositive patients are those who have detectable serum myelin oligodendrocyte glycoprotein (MOG) antibodies. They tend to be younger, male, and less likely to relapse than those with AQP4 antibodies “Maybe MOG syndrome will ultimately be considered separately, but currently we consider it to be a form of NMOSD, and future versions of the diagnostic criteria will probably incorporate other biomarkers,” Dr. Weinshenker said.

NMOSD therapy can be stratified into two types: treatment of acute (ie, monophasic) attack and relapse prevention, said Jacqueline Palace, BM, DM, Consultant Neurologist at the University of Oxford, United Kingdom. She noted that her classifications for treatment purposes are not based on the newly revised NMOSD diagnostic criteria, but rather are slightly broader. She pointed out that her treatment recommendations are in line with 2010 guidelines by the European Federation of Neurological Societies.

“AQP4 antibody disease is a relapsing condition when untreated,” said Dr. Palace. “On the other hand, many MOG antibody seropositive patients have monophasic phenotypes.” Other monophasic conditions include LETM or idiopathic transverse myelitis, Devic’s disease, and severe or bilateral optic neuritis.

Patients in the monophasic group may go on to develop relapsing disease (ie, relapsing NMOSD, relapsing optic neuritis, and relapsing LETM), Dr. Palace noted. Among the difficult-to-treat patients are those who have overlap between MS and antibody-negative NMOSD.

Management of an acute attack across all of these monophasic syndromes is similar because the attacks tend to present with more severe relapses than patients with MS, and some patients are left with severe residual disability, said Dr. Palace. “We treat these patients urgently with IV methylprednisolone for three to five days to try to restore function. If there is poor response or significant disability, we follow with plasma exchange.” If plasma exchange is not feasible, patients may be given IV immunoglobulin (IVIG), she suggested. “There is a small proportion of patients who develop severe paraplegia that don’t appear to respond at all to treatment, even if given urgently. In my experience, these patients are monophasic and they are antibody negative for both MOG and AQP4.”

Patients with acute disseminated encephalomyelitis can rebound if given a short course of IV methylprednisolone. Dr. Palace recommended follow-on prednisolone for two months for patients who have such monophasic MOG and AQP4 antibody disorders to prevent rebound, and for longer (ie, six to 12 months) for monophasic patients with MOG antibodies.

Preventing relapse is probably the most important aspect of managing NMOSD. “AQP4 antibody disease is a relapsing condition, and there is no progressive phase as there is in MS,” Dr. Palace said. “There is a high morbidity and mortality associated with relapse.”

In a 2012 review of AQP4 antibody-seropositive patients—many of whom were on corticosteroids or other immunosuppression—researchers found that, among 59 patients in the UK with a median follow-up of five years, 22% had permanent bilateral visual loss with visual acuity of less than 6/36 in the better eye, and nearly 30% were wheelchair-dependent.

Prednisolone cover alone or in conjunction with a steroid-sparing drug (ie, azathioprine, mycophenolate, methotrexate, or rituximab) is the recommended first-line treatment for relapse prevention. “If patients have a relapse on an adequate dose tried for three to six months, then you might consider an alternative first-line drug or other less commonly used immunosuppressive agents such as ciclosporin/tacrolimus, cyclophosphamide, or mitoxantrone. Regular plasma exchange or IVIG is also an option,” said Dr. Palace. “We note that our patients appear less likely to relapse if they are kept on a low background dose of prednisolone when on other immunosuppressants. If they have a relapse, we may increase the background prednisolone dose rather than switch treatments.”

Some MS disease-modifying drugs have been reported to exacerbate NMOSD, including beta-interferon, natalizumab, and fingolimod. In addition, there is a theoretical risk of alemtuzumab being harmful because it is known to precipitate antibody-mediated disease, Dr. Palace said.

—Adriene Marshall

BARCELONA—Revised consensus criteria have proposed that neuromyelitis optica spectrum disorder (NMOSD) become the new unifying term to replace neuromyelitis optica, and that the condition be further stratified based on serologic testing. In kind, NMOSD treatment may differ based on the goals of either relapse prevention or prevention of acute attacks. NMOSD diagnosis and treatment were discussed at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis.

NMOSD encompasses what previously has been diagnosed as neuromyelitis optica, an inflammatory CNS syndrome distinct from multiple sclerosis (MS), which requires clinical optic neuritis and myelitis. It also includes limited forms (eg, optic neuritis or myelitis alone) and a series of associated conditions such as area postrema syndrome and certain brain syndromes known to occur with other symptoms of neuromyelitis optica, said Brian G. Weinshenker, MD, Professor of Neurology at the Mayo Clinic in Rochester, Minnesota, and a member of the international panel that developed the NMOSD consensus criteria. The criteria were published in the July 14 issue of Neurology. The criteria also include patients who are aquaporin 4 (AQP4) seronegative but have otherwise typical clinical presentations.

Patients who are AQP4 antibody sero­positive should have at least one core clinical characteristic for a diagnosis of NMOSD, according to the criteria. The core clinical characteristics are optic neuritis, acute myelitis, area postrema syndrome (ie, otherwise unexplained hiccups or nausea), acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome with diencephalic lesions typical of NMOSD on MRI, and symptomatic cerebral syndrome.

“There are no exclusionary criteria, but our caveat is that there should be no better explanation for the symptoms,” Dr. Weinshenker noted. “Comorbidities such as lupus or Sjögren’s syndrome do not exclude NMOSD, but some syndromes or comorbidities raise red flags. These red flags are clinical and MRI features that might suggest a diagnosis of MS instead of NMOSD, as well as sarcoidosis, which can cause optic neuritis or myelitis.” Other red flags, according to the criteria, include cancer and chronic infection (eg, HIV or syphilis).

For patients who are AQP4 seronegative or those for whom serologic testing is unavailable, the criteria are similar, but more rigorous. Specifically, at least two core clinical characteristics are required, and one of them must be optic neuritis, acute myelitis with longitudinally extensive transverse myelitis (LETM) lesions, or area postrema syndrome.

“There must be evidence of dissemination in space, and we require additional MRI features to be present,” said Dr. Weinshenker. “For example, in patients with intractable vomiting, we require that they also have associated dorsal medulla/area postrema lesions.” Those with myelitis must have a long spinal cord lesion and those with acute optic neuritis must have a long optic nerve lesion that takes up half or more of the length of the optic nerve or affects the optic chiasm. “Again, there should be no better explanation for the findings,” he said.

The revised criteria align “with our contemporary view of what NMOSD is and captures current expert practice,” Dr. Weinshenker said. “It should facilitate clinical research by allowing for early diagnosis in a larger pool of patients who might be eligible for clinical trials.”

However, as is true for any set of diagnostic criteria, physicians will still need to exercise individual judgment, he said. He noted that despite the high accuracy of enzyme-linked immunosorbent assay (ELISA) testing, the most widely used serologic test in the United States for AQP4 antibodies, there is still about a 5% chance of false positives, particularly among patients with a low pretest probability of NMOSD. In addition, patients who are AQP4 seronegative, who make up approximately 30% of the total NMOSD population, are poorly characterized.

Among the AQP4 seropositive patients are those who have detectable serum myelin oligodendrocyte glycoprotein (MOG) antibodies. They tend to be younger, male, and less likely to relapse than those with AQP4 antibodies “Maybe MOG syndrome will ultimately be considered separately, but currently we consider it to be a form of NMOSD, and future versions of the diagnostic criteria will probably incorporate other biomarkers,” Dr. Weinshenker said.

NMOSD therapy can be stratified into two types: treatment of acute (ie, monophasic) attack and relapse prevention, said Jacqueline Palace, BM, DM, Consultant Neurologist at the University of Oxford, United Kingdom. She noted that her classifications for treatment purposes are not based on the newly revised NMOSD diagnostic criteria, but rather are slightly broader. She pointed out that her treatment recommendations are in line with 2010 guidelines by the European Federation of Neurological Societies.

“AQP4 antibody disease is a relapsing condition when untreated,” said Dr. Palace. “On the other hand, many MOG antibody seropositive patients have monophasic phenotypes.” Other monophasic conditions include LETM or idiopathic transverse myelitis, Devic’s disease, and severe or bilateral optic neuritis.

Patients in the monophasic group may go on to develop relapsing disease (ie, relapsing NMOSD, relapsing optic neuritis, and relapsing LETM), Dr. Palace noted. Among the difficult-to-treat patients are those who have overlap between MS and antibody-negative NMOSD.

Management of an acute attack across all of these monophasic syndromes is similar because the attacks tend to present with more severe relapses than patients with MS, and some patients are left with severe residual disability, said Dr. Palace. “We treat these patients urgently with IV methylprednisolone for three to five days to try to restore function. If there is poor response or significant disability, we follow with plasma exchange.” If plasma exchange is not feasible, patients may be given IV immunoglobulin (IVIG), she suggested. “There is a small proportion of patients who develop severe paraplegia that don’t appear to respond at all to treatment, even if given urgently. In my experience, these patients are monophasic and they are antibody negative for both MOG and AQP4.”

Patients with acute disseminated encephalomyelitis can rebound if given a short course of IV methylprednisolone. Dr. Palace recommended follow-on prednisolone for two months for patients who have such monophasic MOG and AQP4 antibody disorders to prevent rebound, and for longer (ie, six to 12 months) for monophasic patients with MOG antibodies.

Preventing relapse is probably the most important aspect of managing NMOSD. “AQP4 antibody disease is a relapsing condition, and there is no progressive phase as there is in MS,” Dr. Palace said. “There is a high morbidity and mortality associated with relapse.”

In a 2012 review of AQP4 antibody-seropositive patients—many of whom were on corticosteroids or other immunosuppression—researchers found that, among 59 patients in the UK with a median follow-up of five years, 22% had permanent bilateral visual loss with visual acuity of less than 6/36 in the better eye, and nearly 30% were wheelchair-dependent.

Prednisolone cover alone or in conjunction with a steroid-sparing drug (ie, azathioprine, mycophenolate, methotrexate, or rituximab) is the recommended first-line treatment for relapse prevention. “If patients have a relapse on an adequate dose tried for three to six months, then you might consider an alternative first-line drug or other less commonly used immunosuppressive agents such as ciclosporin/tacrolimus, cyclophosphamide, or mitoxantrone. Regular plasma exchange or IVIG is also an option,” said Dr. Palace. “We note that our patients appear less likely to relapse if they are kept on a low background dose of prednisolone when on other immunosuppressants. If they have a relapse, we may increase the background prednisolone dose rather than switch treatments.”

Some MS disease-modifying drugs have been reported to exacerbate NMOSD, including beta-interferon, natalizumab, and fingolimod. In addition, there is a theoretical risk of alemtuzumab being harmful because it is known to precipitate antibody-mediated disease, Dr. Palace said.

—Adriene Marshall