Multiple Sclerosis Hub

A second brain death examination in patients older than 1 year is largely unecessary and may negatively affect organ donation, according to a report in the January 11 online Neurology. “In practice, observation time to a second neurologic examination was three times longer than the proposed guideline and associated with substantial intensive care unit costs and loss of viable organs,” researchers stated. The investigators reviewed data for 1,229 adult and 82 pediatric patients who had been pronounced brain-dead. No patients who were declared brain-dead regained brainstem function after repeat examination. The mean brain death declaration interval between the two examinations was 19.2 hours. Consent for organ donation decreased from 57% to 45% as the brain death declaration interval increased. However, refusal of organ donation increased from 23% to 36% as the brain death interval increased. A total of 166 patients (12%) sustained a cardiac arrest between the two examinations or after the second examination.

Most antiepileptic drugs (AEDs) were associated with an increased risk of nontraumatic fractures in patients 50 and older, according to a study in the January Archives of Neurology. A total of 15,792 persons with nontraumatic fractures of the wrist, hip, and vertebra were analyzed. Each patient was matched for age, sex, ethnicity, and comorbidity with as many as three controls (n = 47,289). Prior AED use among participants included carbamazepine, clonazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, topiramate, valproic acid, and vigabatrin. The researchers found a significant increase in fracture risk for most of the AEDs (carbamazepine, clonazepam, gabapentin, phenobarbital, and phenytoin). The adjusted odds ratios (ORs) ranged from 1.24 for clonazepam use to 1.91 for phenytoin use. Valproic acid (adjusted OR, 1.10) was the only AED not associated with an increased fracture risk. “Further studies are warranted to assess the risk of nontraumatic fractures with the newer AEDs and to determine the efficacy of osteoprotective medications in this population,” the researchers stated.

Although some pediatric patients with multiple sclerosis (MS) refractory to initial treatment may effectively switch between first-line disease-modifying therapies (DMTs), some may require second-line therapeutic interventions, per a report in the December 13, 2010, online Archives of Neurology. Researchers reviewed the records of 258 children with a confirmed diagnosis of MS and who had taken DMTs. Interferon beta and glatiramer acetate were the two most frequently used first-line DMTs. Overall, 144 children (55.8%) continued to receive one therapy, while 65 (25.2%) received two sequential therapies, 29 (11.2%) received three therapies, and 20 (7.8%) received four or more therapies during a mean observation period of 3.9 years. “Second-line DMT use was restricted to interferon beta and glatiramer acetate in 203 children (78.7%), whereas other treatments such as broad-spectrum chemotherapies (cyclophosphamide, mitoxantrone hydrochloride), natalizumab, corticosteroids (monthly), and daclizumab were used at some point during the observation period for disease management in 55 children (21.3%),” stated the investigators.

Transient pregnancy restless legs syndrome is a significant risk factor for developing a future chronic idiopathic restless legs syndrome form, and for a new transient symptomatology in a future pregnancy, according to a study in the December 7, 2010, Neurology. Seventy-four women who experienced restless legs syndrome during a previous pregnancy, and 133 who did not, were included in the study. The incidence of restless legs syndrome was 56% person/year in women who experienced the transient pregnancy restless legs syndrome form, versus 12.6% person/year in women who did not, with a significant fourfold increased risk of developing chronic restless legs syndrome in women who presented with restless legs syndrome in their previous pregnancy. “Considering further new pregnancies during the follow-up period, restless legs symptoms reappeared in 58% of the cases, while they emerged for the first time in only 3% of women who had never experienced restless legs syndrome,” stated the authors. 

The cancer drug paclitaxel may promote the regeneration of injured nerve cells in the CNS after spinal cord injury, according to a study in the online January 27 Science. Researchers found that the drug has a dual role in spinal cord repair in rodents, stabilizing the microtuble so that injured nerve cells regain their ability to grow and preventing the production of inhibitory substances in the scar tissue. Moderate microtubule stabilization decreased scar formation via various cellular mechanisms, including dampening of transforming growth factor-β signaling. “It prevented accumulation of chondroitin sulfate proteoglycans and rendered the lesion site permissive for axon regeneration of growth competent sensory neurons,” stated the investigators. “Microtubule stabilization also promoted growth of CNS axons of the Raphe-spinal tract and led to functional improvement.”

Among patients with acute ischemic stroke, blacks have a lower mortality than whites, which may be attributable to differences in receiving life-sustaining interventions and end-of-life care, researchers reported in the February 1 Annals of Internal Medicine. The findings are based on 5,319 black and 18,340 white patients 18 and older who were hospitalized with acute ischemic stroke. The overall in-hospital mortality rate was lower for black patients than for white patients (5.0% vs 7.4%), as was all-cause mortality at 30 days (6.1% vs 11.4%) and one year (16.5% vs 24.4%). After propensity score adjustment, black race was independently associated with lower in-hospital mortality (odds ratio [OR], 0.77) and all-cause mortality up to one year (OR, 0.86). “After adjustment for the probability of dying in the hospital, black patients with stroke were more likely to receive life-sustaining interventions (OR, 1.22) but less likely to be discharged to hospice (OR, 0.25),” the researchers concluded.

A second brain death examination in patients older than 1 year is largely unecessary and may negatively affect organ donation, according to a report in the January 11 online Neurology. “In practice, observation time to a second neurologic examination was three times longer than the proposed guideline and associated with substantial intensive care unit costs and loss of viable organs,” researchers stated. The investigators reviewed data for 1,229 adult and 82 pediatric patients who had been pronounced brain-dead. No patients who were declared brain-dead regained brainstem function after repeat examination. The mean brain death declaration interval between the two examinations was 19.2 hours. Consent for organ donation decreased from 57% to 45% as the brain death declaration interval increased. However, refusal of organ donation increased from 23% to 36% as the brain death interval increased. A total of 166 patients (12%) sustained a cardiac arrest between the two examinations or after the second examination.

Most antiepileptic drugs (AEDs) were associated with an increased risk of nontraumatic fractures in patients 50 and older, according to a study in the January Archives of Neurology. A total of 15,792 persons with nontraumatic fractures of the wrist, hip, and vertebra were analyzed. Each patient was matched for age, sex, ethnicity, and comorbidity with as many as three controls (n = 47,289). Prior AED use among participants included carbamazepine, clonazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, topiramate, valproic acid, and vigabatrin. The researchers found a significant increase in fracture risk for most of the AEDs (carbamazepine, clonazepam, gabapentin, phenobarbital, and phenytoin). The adjusted odds ratios (ORs) ranged from 1.24 for clonazepam use to 1.91 for phenytoin use. Valproic acid (adjusted OR, 1.10) was the only AED not associated with an increased fracture risk. “Further studies are warranted to assess the risk of nontraumatic fractures with the newer AEDs and to determine the efficacy of osteoprotective medications in this population,” the researchers stated.

Although some pediatric patients with multiple sclerosis (MS) refractory to initial treatment may effectively switch between first-line disease-modifying therapies (DMTs), some may require second-line therapeutic interventions, per a report in the December 13, 2010, online Archives of Neurology. Researchers reviewed the records of 258 children with a confirmed diagnosis of MS and who had taken DMTs. Interferon beta and glatiramer acetate were the two most frequently used first-line DMTs. Overall, 144 children (55.8%) continued to receive one therapy, while 65 (25.2%) received two sequential therapies, 29 (11.2%) received three therapies, and 20 (7.8%) received four or more therapies during a mean observation period of 3.9 years. “Second-line DMT use was restricted to interferon beta and glatiramer acetate in 203 children (78.7%), whereas other treatments such as broad-spectrum chemotherapies (cyclophosphamide, mitoxantrone hydrochloride), natalizumab, corticosteroids (monthly), and daclizumab were used at some point during the observation period for disease management in 55 children (21.3%),” stated the investigators.

Transient pregnancy restless legs syndrome is a significant risk factor for developing a future chronic idiopathic restless legs syndrome form, and for a new transient symptomatology in a future pregnancy, according to a study in the December 7, 2010, Neurology. Seventy-four women who experienced restless legs syndrome during a previous pregnancy, and 133 who did not, were included in the study. The incidence of restless legs syndrome was 56% person/year in women who experienced the transient pregnancy restless legs syndrome form, versus 12.6% person/year in women who did not, with a significant fourfold increased risk of developing chronic restless legs syndrome in women who presented with restless legs syndrome in their previous pregnancy. “Considering further new pregnancies during the follow-up period, restless legs symptoms reappeared in 58% of the cases, while they emerged for the first time in only 3% of women who had never experienced restless legs syndrome,” stated the authors. 

The cancer drug paclitaxel may promote the regeneration of injured nerve cells in the CNS after spinal cord injury, according to a study in the online January 27 Science. Researchers found that the drug has a dual role in spinal cord repair in rodents, stabilizing the microtuble so that injured nerve cells regain their ability to grow and preventing the production of inhibitory substances in the scar tissue. Moderate microtubule stabilization decreased scar formation via various cellular mechanisms, including dampening of transforming growth factor-β signaling. “It prevented accumulation of chondroitin sulfate proteoglycans and rendered the lesion site permissive for axon regeneration of growth competent sensory neurons,” stated the investigators. “Microtubule stabilization also promoted growth of CNS axons of the Raphe-spinal tract and led to functional improvement.”

Among patients with acute ischemic stroke, blacks have a lower mortality than whites, which may be attributable to differences in receiving life-sustaining interventions and end-of-life care, researchers reported in the February 1 Annals of Internal Medicine. The findings are based on 5,319 black and 18,340 white patients 18 and older who were hospitalized with acute ischemic stroke. The overall in-hospital mortality rate was lower for black patients than for white patients (5.0% vs 7.4%), as was all-cause mortality at 30 days (6.1% vs 11.4%) and one year (16.5% vs 24.4%). After propensity score adjustment, black race was independently associated with lower in-hospital mortality (odds ratio [OR], 0.77) and all-cause mortality up to one year (OR, 0.86). “After adjustment for the probability of dying in the hospital, black patients with stroke were more likely to receive life-sustaining interventions (OR, 1.22) but less likely to be discharged to hospice (OR, 0.25),” the researchers concluded.

A second brain death examination in patients older than 1 year is largely unecessary and may negatively affect organ donation, according to a report in the January 11 online Neurology. “In practice, observation time to a second neurologic examination was three times longer than the proposed guideline and associated with substantial intensive care unit costs and loss of viable organs,” researchers stated. The investigators reviewed data for 1,229 adult and 82 pediatric patients who had been pronounced brain-dead. No patients who were declared brain-dead regained brainstem function after repeat examination. The mean brain death declaration interval between the two examinations was 19.2 hours. Consent for organ donation decreased from 57% to 45% as the brain death declaration interval increased. However, refusal of organ donation increased from 23% to 36% as the brain death interval increased. A total of 166 patients (12%) sustained a cardiac arrest between the two examinations or after the second examination.

Most antiepileptic drugs (AEDs) were associated with an increased risk of nontraumatic fractures in patients 50 and older, according to a study in the January Archives of Neurology. A total of 15,792 persons with nontraumatic fractures of the wrist, hip, and vertebra were analyzed. Each patient was matched for age, sex, ethnicity, and comorbidity with as many as three controls (n = 47,289). Prior AED use among participants included carbamazepine, clonazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, topiramate, valproic acid, and vigabatrin. The researchers found a significant increase in fracture risk for most of the AEDs (carbamazepine, clonazepam, gabapentin, phenobarbital, and phenytoin). The adjusted odds ratios (ORs) ranged from 1.24 for clonazepam use to 1.91 for phenytoin use. Valproic acid (adjusted OR, 1.10) was the only AED not associated with an increased fracture risk. “Further studies are warranted to assess the risk of nontraumatic fractures with the newer AEDs and to determine the efficacy of osteoprotective medications in this population,” the researchers stated.

Although some pediatric patients with multiple sclerosis (MS) refractory to initial treatment may effectively switch between first-line disease-modifying therapies (DMTs), some may require second-line therapeutic interventions, per a report in the December 13, 2010, online Archives of Neurology. Researchers reviewed the records of 258 children with a confirmed diagnosis of MS and who had taken DMTs. Interferon beta and glatiramer acetate were the two most frequently used first-line DMTs. Overall, 144 children (55.8%) continued to receive one therapy, while 65 (25.2%) received two sequential therapies, 29 (11.2%) received three therapies, and 20 (7.8%) received four or more therapies during a mean observation period of 3.9 years. “Second-line DMT use was restricted to interferon beta and glatiramer acetate in 203 children (78.7%), whereas other treatments such as broad-spectrum chemotherapies (cyclophosphamide, mitoxantrone hydrochloride), natalizumab, corticosteroids (monthly), and daclizumab were used at some point during the observation period for disease management in 55 children (21.3%),” stated the investigators.

Transient pregnancy restless legs syndrome is a significant risk factor for developing a future chronic idiopathic restless legs syndrome form, and for a new transient symptomatology in a future pregnancy, according to a study in the December 7, 2010, Neurology. Seventy-four women who experienced restless legs syndrome during a previous pregnancy, and 133 who did not, were included in the study. The incidence of restless legs syndrome was 56% person/year in women who experienced the transient pregnancy restless legs syndrome form, versus 12.6% person/year in women who did not, with a significant fourfold increased risk of developing chronic restless legs syndrome in women who presented with restless legs syndrome in their previous pregnancy. “Considering further new pregnancies during the follow-up period, restless legs symptoms reappeared in 58% of the cases, while they emerged for the first time in only 3% of women who had never experienced restless legs syndrome,” stated the authors. 

The cancer drug paclitaxel may promote the regeneration of injured nerve cells in the CNS after spinal cord injury, according to a study in the online January 27 Science. Researchers found that the drug has a dual role in spinal cord repair in rodents, stabilizing the microtuble so that injured nerve cells regain their ability to grow and preventing the production of inhibitory substances in the scar tissue. Moderate microtubule stabilization decreased scar formation via various cellular mechanisms, including dampening of transforming growth factor-β signaling. “It prevented accumulation of chondroitin sulfate proteoglycans and rendered the lesion site permissive for axon regeneration of growth competent sensory neurons,” stated the investigators. “Microtubule stabilization also promoted growth of CNS axons of the Raphe-spinal tract and led to functional improvement.”

Among patients with acute ischemic stroke, blacks have a lower mortality than whites, which may be attributable to differences in receiving life-sustaining interventions and end-of-life care, researchers reported in the February 1 Annals of Internal Medicine. The findings are based on 5,319 black and 18,340 white patients 18 and older who were hospitalized with acute ischemic stroke. The overall in-hospital mortality rate was lower for black patients than for white patients (5.0% vs 7.4%), as was all-cause mortality at 30 days (6.1% vs 11.4%) and one year (16.5% vs 24.4%). After propensity score adjustment, black race was independently associated with lower in-hospital mortality (odds ratio [OR], 0.77) and all-cause mortality up to one year (OR, 0.86). “After adjustment for the probability of dying in the hospital, black patients with stroke were more likely to receive life-sustaining interventions (OR, 1.22) but less likely to be discharged to hospice (OR, 0.25),” the researchers concluded.

Depression, fatigue, and lack of physical activity are associated with decreased bone mineral density in patients with MS and replete vitamin D level, researchers report. 

In ambulatory patients with multiple sclerosis (MS) who have adequate vitamin D stores, depression, fatigue, and a lack of moderate physical activity are associated with decreased femoral and lumbar bone mineral density, according to research presented at the 24th Annual Meeting of the Consortium of Multiple Sclerosis Centers.
Alexander Ng, PhD, Associate Professor of Exercise Science, Marquette University, Milwaukee, and colleagues examined 23 patients with MS and 22 healthy controls. Study participants underwent Dual Energy X-ray Absorptiometry (DEXA) of femoral, neck, lumbar, and total body, and resting supine EKGs. In addition, data were collected with use of the MS Functional Composite Measure, Expanded Disability Status Scale (EDSS), Fatigue Impact Scale, and Beck Depression Inventory, and levels of salivary cortisol and serum vitamin D were measured.
Depression and Fatigue in Patients With MS
The researchers found that patients with MS reported greater levels of depression and fatigue than did controls, and subjects also had lower MS Functional Composite Measure scores. No differences were observed between subjects and controls in measures of vitamin D, cortisol, mineral bone density, or heart rate variability.
Levels of moderate but not total physical activity differed between the two groups. Moderate activity was directly correlated to femoral bone mineral density in the MS group, but not in controls. EDSS also correlated to femoral bone mineral density. Depression and fatigue both correlated with femoral and lumbar bone mineral density in the MS group but not in controls.
“Young women and men with MS are at an increased risk for decreased bone mineral density, which, if combined with decreased balance, could lead to an increased risk of bone fractures due to falling or otherwise,” Dr. Ng told Neurology Reviews.
“Appropriate weight-bearing exercise of moderate intensity in persons with MS could be an effective nonpharmacologic countermeasure to this bone mineral density risk,” he added.
The Benefits of Exercise
"Exercise is already recommended for persons with MS for fitness and health risk reduction,” he continued. “Maintaining or increasing bone density is yet another potential benefit of exercise for persons with MS. Intense or hard exercise may not be necessary to improve bone mineral density, although easy exercise may not provide enough of an osteogenic stimulus.”

Depression, fatigue, and lack of physical activity are associated with decreased bone mineral density in patients with MS and replete vitamin D level, researchers report. 

In ambulatory patients with multiple sclerosis (MS) who have adequate vitamin D stores, depression, fatigue, and a lack of moderate physical activity are associated with decreased femoral and lumbar bone mineral density, according to research presented at the 24th Annual Meeting of the Consortium of Multiple Sclerosis Centers.
Alexander Ng, PhD, Associate Professor of Exercise Science, Marquette University, Milwaukee, and colleagues examined 23 patients with MS and 22 healthy controls. Study participants underwent Dual Energy X-ray Absorptiometry (DEXA) of femoral, neck, lumbar, and total body, and resting supine EKGs. In addition, data were collected with use of the MS Functional Composite Measure, Expanded Disability Status Scale (EDSS), Fatigue Impact Scale, and Beck Depression Inventory, and levels of salivary cortisol and serum vitamin D were measured.
Depression and Fatigue in Patients With MS
The researchers found that patients with MS reported greater levels of depression and fatigue than did controls, and subjects also had lower MS Functional Composite Measure scores. No differences were observed between subjects and controls in measures of vitamin D, cortisol, mineral bone density, or heart rate variability.
Levels of moderate but not total physical activity differed between the two groups. Moderate activity was directly correlated to femoral bone mineral density in the MS group, but not in controls. EDSS also correlated to femoral bone mineral density. Depression and fatigue both correlated with femoral and lumbar bone mineral density in the MS group but not in controls.
“Young women and men with MS are at an increased risk for decreased bone mineral density, which, if combined with decreased balance, could lead to an increased risk of bone fractures due to falling or otherwise,” Dr. Ng told Neurology Reviews.
“Appropriate weight-bearing exercise of moderate intensity in persons with MS could be an effective nonpharmacologic countermeasure to this bone mineral density risk,” he added.
The Benefits of Exercise
"Exercise is already recommended for persons with MS for fitness and health risk reduction,” he continued. “Maintaining or increasing bone density is yet another potential benefit of exercise for persons with MS. Intense or hard exercise may not be necessary to improve bone mineral density, although easy exercise may not provide enough of an osteogenic stimulus.”

Depression, fatigue, and lack of physical activity are associated with decreased bone mineral density in patients with MS and replete vitamin D level, researchers report. 

In ambulatory patients with multiple sclerosis (MS) who have adequate vitamin D stores, depression, fatigue, and a lack of moderate physical activity are associated with decreased femoral and lumbar bone mineral density, according to research presented at the 24th Annual Meeting of the Consortium of Multiple Sclerosis Centers.
Alexander Ng, PhD, Associate Professor of Exercise Science, Marquette University, Milwaukee, and colleagues examined 23 patients with MS and 22 healthy controls. Study participants underwent Dual Energy X-ray Absorptiometry (DEXA) of femoral, neck, lumbar, and total body, and resting supine EKGs. In addition, data were collected with use of the MS Functional Composite Measure, Expanded Disability Status Scale (EDSS), Fatigue Impact Scale, and Beck Depression Inventory, and levels of salivary cortisol and serum vitamin D were measured.
Depression and Fatigue in Patients With MS
The researchers found that patients with MS reported greater levels of depression and fatigue than did controls, and subjects also had lower MS Functional Composite Measure scores. No differences were observed between subjects and controls in measures of vitamin D, cortisol, mineral bone density, or heart rate variability.
Levels of moderate but not total physical activity differed between the two groups. Moderate activity was directly correlated to femoral bone mineral density in the MS group, but not in controls. EDSS also correlated to femoral bone mineral density. Depression and fatigue both correlated with femoral and lumbar bone mineral density in the MS group but not in controls.
“Young women and men with MS are at an increased risk for decreased bone mineral density, which, if combined with decreased balance, could lead to an increased risk of bone fractures due to falling or otherwise,” Dr. Ng told Neurology Reviews.
“Appropriate weight-bearing exercise of moderate intensity in persons with MS could be an effective nonpharmacologic countermeasure to this bone mineral density risk,” he added.
The Benefits of Exercise
"Exercise is already recommended for persons with MS for fitness and health risk reduction,” he continued. “Maintaining or increasing bone density is yet another potential benefit of exercise for persons with MS. Intense or hard exercise may not be necessary to improve bone mineral density, although easy exercise may not provide enough of an osteogenic stimulus.”

Pregnancy and breastfeeding are strongly associated with low vitamin D levels in women with MS, but these low vitamin D levels are not associated with an increased risk of postpartum MS relapses.

Women with multiple sclerosis (MS) have lower vitamin D levels during pregnancy and while breastfeeding; however, according to a November 8 online report released by the Archives of Neurology, these low vitamin D levels were not associated with a greater risk of MS relapse postpartum.  
“During the last decade, low level of vitamin D, a potent immunomodulator, has emerged as an important risk factor for MS as well as other autoimmune diseases and certain cancers,” said Annette Langer-Gould, MD, PhD, and colleagues. “The observation that healthy pregnant and lactating women are at particularly high risk of vitamin D insufficiency, regardless of race, suggests that pregnant and nursing mothers with MS may have a higher risk of relapses.” However, they pointed out, it has already been well established that the risk of MS relapse decreases during pregnancy and increases during the postpartum period and that breastfeeding does not increase the risk of relapses.
Dr. Langer-Gould, at the time of the study at Stanford University School of Medicine and now at Kaiser Permanente Southern California’s Department of Research and Evaluation in Pasadena, and colleagues studied 28 pregnant women with MS identified through membership records of Kaiser Permanente Northern California or Stanford University outpatient neurology clinics. Participants donated blood and completed questionnaires at the beginning of the study, during their remaining trimesters of pregnancy, and regularly through the first year after birth.
Fluctuating Vitamin D Levels
Of the 28 women, 14 (50%) breastfed exclusively and 12 (43%) relapsed within six months after giving birth. During pregnancy, average blood levels of 25-hydroxyvitamin D (25[OH]D) were 25.4 ng/mL and were associated with season. After birth, levels remained low among women who were exclusively breastfeeding but rose significantly in the nonexclusive breastfeeding group regardless of season. By four and six months after childbirth, 25(OH)D levels were an average of 5 ng/mL lower among women who breastfed exclusively than among those who did not. However, these low postpartum vitamin D levels were not associated with risk of MS relapse. “If anything, by three to six months after childbirth, 25(OH)D levels were marginally higher among the women who relapsed within the first six months after childbirth compared with women who were relapse-free during the same period,” the researchers said. “We do not believe that higher vitamin D levels increase the risk of postpartum relapses, as the rise we observed did not appear to occur prior to the onset of symptoms and the findings were of marginal statistical significance after accounting for season. Instead, we think this apparent inverse association is a reflection of the fact that most of the women who relapsed in the study also did not breastfeed or did so only briefly.”
The Bottom Line for Women With MS
“Our finding that low vitamin D is not a risk factor for MS relapse in pregnant and lactating women suggests that increasing vitamin D levels during pregnancy and the postpartum period in women with MS is unlikely to affect the risk of postpartum relapse,” the researchers concluded. “Therefore, our findings imply that the recommended dose of vitamin D supplementation for women with MS during pregnancy and lactation should be the same as for women who are not.”

Pregnancy and breastfeeding are strongly associated with low vitamin D levels in women with MS, but these low vitamin D levels are not associated with an increased risk of postpartum MS relapses.

Women with multiple sclerosis (MS) have lower vitamin D levels during pregnancy and while breastfeeding; however, according to a November 8 online report released by the Archives of Neurology, these low vitamin D levels were not associated with a greater risk of MS relapse postpartum.  
“During the last decade, low level of vitamin D, a potent immunomodulator, has emerged as an important risk factor for MS as well as other autoimmune diseases and certain cancers,” said Annette Langer-Gould, MD, PhD, and colleagues. “The observation that healthy pregnant and lactating women are at particularly high risk of vitamin D insufficiency, regardless of race, suggests that pregnant and nursing mothers with MS may have a higher risk of relapses.” However, they pointed out, it has already been well established that the risk of MS relapse decreases during pregnancy and increases during the postpartum period and that breastfeeding does not increase the risk of relapses.
Dr. Langer-Gould, at the time of the study at Stanford University School of Medicine and now at Kaiser Permanente Southern California’s Department of Research and Evaluation in Pasadena, and colleagues studied 28 pregnant women with MS identified through membership records of Kaiser Permanente Northern California or Stanford University outpatient neurology clinics. Participants donated blood and completed questionnaires at the beginning of the study, during their remaining trimesters of pregnancy, and regularly through the first year after birth.
Fluctuating Vitamin D Levels
Of the 28 women, 14 (50%) breastfed exclusively and 12 (43%) relapsed within six months after giving birth. During pregnancy, average blood levels of 25-hydroxyvitamin D (25[OH]D) were 25.4 ng/mL and were associated with season. After birth, levels remained low among women who were exclusively breastfeeding but rose significantly in the nonexclusive breastfeeding group regardless of season. By four and six months after childbirth, 25(OH)D levels were an average of 5 ng/mL lower among women who breastfed exclusively than among those who did not. However, these low postpartum vitamin D levels were not associated with risk of MS relapse. “If anything, by three to six months after childbirth, 25(OH)D levels were marginally higher among the women who relapsed within the first six months after childbirth compared with women who were relapse-free during the same period,” the researchers said. “We do not believe that higher vitamin D levels increase the risk of postpartum relapses, as the rise we observed did not appear to occur prior to the onset of symptoms and the findings were of marginal statistical significance after accounting for season. Instead, we think this apparent inverse association is a reflection of the fact that most of the women who relapsed in the study also did not breastfeed or did so only briefly.”
The Bottom Line for Women With MS
“Our finding that low vitamin D is not a risk factor for MS relapse in pregnant and lactating women suggests that increasing vitamin D levels during pregnancy and the postpartum period in women with MS is unlikely to affect the risk of postpartum relapse,” the researchers concluded. “Therefore, our findings imply that the recommended dose of vitamin D supplementation for women with MS during pregnancy and lactation should be the same as for women who are not.”

Pregnancy and breastfeeding are strongly associated with low vitamin D levels in women with MS, but these low vitamin D levels are not associated with an increased risk of postpartum MS relapses.

Women with multiple sclerosis (MS) have lower vitamin D levels during pregnancy and while breastfeeding; however, according to a November 8 online report released by the Archives of Neurology, these low vitamin D levels were not associated with a greater risk of MS relapse postpartum.  
“During the last decade, low level of vitamin D, a potent immunomodulator, has emerged as an important risk factor for MS as well as other autoimmune diseases and certain cancers,” said Annette Langer-Gould, MD, PhD, and colleagues. “The observation that healthy pregnant and lactating women are at particularly high risk of vitamin D insufficiency, regardless of race, suggests that pregnant and nursing mothers with MS may have a higher risk of relapses.” However, they pointed out, it has already been well established that the risk of MS relapse decreases during pregnancy and increases during the postpartum period and that breastfeeding does not increase the risk of relapses.
Dr. Langer-Gould, at the time of the study at Stanford University School of Medicine and now at Kaiser Permanente Southern California’s Department of Research and Evaluation in Pasadena, and colleagues studied 28 pregnant women with MS identified through membership records of Kaiser Permanente Northern California or Stanford University outpatient neurology clinics. Participants donated blood and completed questionnaires at the beginning of the study, during their remaining trimesters of pregnancy, and regularly through the first year after birth.
Fluctuating Vitamin D Levels
Of the 28 women, 14 (50%) breastfed exclusively and 12 (43%) relapsed within six months after giving birth. During pregnancy, average blood levels of 25-hydroxyvitamin D (25[OH]D) were 25.4 ng/mL and were associated with season. After birth, levels remained low among women who were exclusively breastfeeding but rose significantly in the nonexclusive breastfeeding group regardless of season. By four and six months after childbirth, 25(OH)D levels were an average of 5 ng/mL lower among women who breastfed exclusively than among those who did not. However, these low postpartum vitamin D levels were not associated with risk of MS relapse. “If anything, by three to six months after childbirth, 25(OH)D levels were marginally higher among the women who relapsed within the first six months after childbirth compared with women who were relapse-free during the same period,” the researchers said. “We do not believe that higher vitamin D levels increase the risk of postpartum relapses, as the rise we observed did not appear to occur prior to the onset of symptoms and the findings were of marginal statistical significance after accounting for season. Instead, we think this apparent inverse association is a reflection of the fact that most of the women who relapsed in the study also did not breastfeed or did so only briefly.”
The Bottom Line for Women With MS
“Our finding that low vitamin D is not a risk factor for MS relapse in pregnant and lactating women suggests that increasing vitamin D levels during pregnancy and the postpartum period in women with MS is unlikely to affect the risk of postpartum relapse,” the researchers concluded. “Therefore, our findings imply that the recommended dose of vitamin D supplementation for women with MS during pregnancy and lactation should be the same as for women who are not.”

Findings support a pathogenic role for an autoantibody of AQP4 specificity in neuromyelitis optica.

SAN FRANCISCO—A complement activating aquaporin-4 (AQP4)-specific autoantibody has a pathogenic role in initiating neuromyelitis optica (NMO) lesions and distinguishes NMO from multiple sclerosis (MS), according to research presented at the 135th Annual Meeting of the American Neurological Association.
Clinical presentation of NMO differs from MS in a number of ways, explained Claudia Lucchinetti, MD, of the Mayo Clinic Rochester in Minnesota, and member of the Mayo Clinic NMO Consortium. NMO onset tends to occur at an older age, affects more females than males, and is more common in non-Caucasians. NMO is typically a relapsing disease, and unlike MS, a progressive course is distinctly unusual. In contrast to MS, brain MRI scans are often normal early in the disease, while spinal cord MRIs typically show long lesions spanning three or more intervertebral segments, which are not typically seen in adult MS. Oligoclonal bands in the spinal fluid are rare in NMO, whereas pleocytosis is common. NMO can be associated with other autoimmune disorders, including myasthenia gravis. Patients with active NMO respond favorably to antibody-depleting therapies.
In 2002, Dr. Lucchinetti and colleagues described the presence of deposits of immunoglobulin G (IgG) and immunoglobulin M (IgM) co-localizing with products of complement activation in a vasculocentric pattern around thickened hyalinized blood vessels in active NMO lesions, suggesting a pathogenic role for humoral immunity targeting an antigen in the perivascular space. In 2004, Vanda Lennon, MD, PhD, and colleagues at the Mayo Clinic reported a specific serum autoantibody marker that was 73% sensitive and more than 90% specific for clinically defined NMO. Its selective binding to the abluminal face of microvessels, pia, subpia and Virchow-Robin sheaths was reminiscent of the localization of immune complexes in NMO patients’ spinal cord tissues described by Lucchinetti and colleagues.
“With the discovery of the biomarker, a spectrum of neurologic disorders has been identified associated with the presence of NMO-IgG, including not only NMO, but also isolated or recurrent longitudinally extensive transverse myelitis, or optic neuritis, encephalopathy, intractable nausea and vomiting, a posterior reversible leukoencephalopathy (PRES)-like syndrome, endocrinopathies, and even narcolepsy,” she said.
Aquaporin-4
Subsequent studies led by Dr. Lennon identified AQP4 as the target auto-antigen in NMO. AQP4 is the dominant CNS water channel, which regulates bidirectional water flux between the blood and brain, and the brain and spinal fluid, and is concentrated at the astrocytic end-feet. It is expressed in two isoforms, M1 and M23, and consists of six membranes that determine the channel’s selectivity for water molecules, Dr. Lucchinetti said.
AQP4 is found on the surfaces of astrocytes, concentrated in periventricular regions, circumventricular organs, and spinal cord gray matter in healthy controls. Normal AQP4 expression parallels the classic ring and rosette staining pattern of immune complex deposition observed in active NMO lesions. In contrast to active MS lesions, which show an increase in AQP4 immunoreactivity, NMO lesions show a striking loss of AQP4, she explained. “Interestingly, myelin may be relatively preserved in some of these lesions, despite the profound loss of AQP4,” said Dr. Lucchinetti.
Brain Lesions in NMO
MRI detects brain lesions in 60% of NMO patients, which include NMO-specific brain lesions in regions of high AQP4 expression (eg, area postrema, hypothalamus), as well as supratentorial lesions that are either nonspecific or MS-like in appearance. The presence of these supratentorial brain lesions has suggested a possible pathologic overlap of NMO and MS. However, comparison of supratentorial (ST) NMO lesions with opticospinal (OS) NMO lesions, as well as supratentorial MS lesions, confirmed that the pathology of NMO ST lesions is similar to NMO OS lesions with respect to type of inflammation, presence of perivascular immune complex deposits and AQP4 loss. Dr. Lucchinetti suggests these findings indicate that NMO ST and OS lesions have a shared pathogenesis.
Clinical reports have also described intractable hiccups, nausea, and vomiting in NMO. NMO specific medullary lesions have been observed in the area postrema, which are characterized by a selective and targeted loss of AQP4, and likely reflect the pathologic substrate of intractable nausea and vomiting reported in some NMO patients. A study in press by members of the Mayo Clinic NMO consortium suggests that the area postrema may even be the first point of attack in NMO in at least 12% of NMO cases, Dr. Lucchinetti reported.
The Role of NMO IgG
In vitro studies demonstrate that NMO-IgG binds selectively to the surface of living target cell membranes expressing AQP4, a prerequisite for IgG to affect organ-specific pathogenicity. This binding initiates two potentially competing outcomes: 1) rapid downregulation of AQP4 via endocytosis/degradation; and 2) activation of the lytic complement cascade. The relative predominance of antigenic modulation and complement activation that represent competing sequelae of IgG binding to the surface AQP4 may determine an individual’s clinical presentation, response to therapy, and disease course. The rapid endocytosis and degradation of surface AQP4 initiated by IgG binding coupled with the rapid replenishment of newly synthesized AQP4 also supports a potentially reversible insult, at least during early disease stages.
A recent study further demonstrated that exposure to NMO patient serum and active complement compromised the membrane integrity of CNS-derived astrocytes. Without complement, astrocyte membranes remained intact, but AQP4 was endocytosed with concomitant loss of sodium-dependent glutamate transport and loss of the excitatory transporter, EAAT2. These findings suggest that EAAT2 and AQP4 exist in astrocytic membranes as a macromolecular complex. Furthermore, Dr. Lucchinetti reported that NMO lesions demonstrated marked reduction in EAAT2 in regions of AQP4 loss. In summary, binding of NMO-IgG to astrocytic AQP4 initiates not only complement activation, but AQP4 and EAAT2 downregulation, which would be expected to disrupt glutamate homeostasis. This could lead to injury of oligodendrocytes that express calcium-permeable glutamate receptors.
Dr. Lucchinetti discussed several possible mechanisms that might initiate demyelination in NMO. First, oligodendrocyte are more susceptible than astrocytes to lethal injury by noxious stimuli, and would be expected to be injured at the paranode where they directly contact AQP4 containing astrocytic foot processes. Second, demyelination could be secondary as a result of axonal injury due to alterations in the ionic microenvironment at the internode. Third, glutamate toxicity may contribute to demyelination.
“NMO IgG can produce three potentially pathogenic outcomes—AQP4 and EAAT2 modulation, complement activation, and reduced glutamate uptake,” she said. “Treatment strategies targeting complement activation and glutamate excitotoxicity may prove effective."

Suggested Reading
Hinson SR, Roemer SF, Lucchinetti CF, et al. Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2. J Exp Med. 2008;205(11):2473-2481.
Lennon VA, Kryzer TJ, Pittock SJ, et al. IgG marker of optic-spinal MS binds to the aquaporin-4 water channel. J Exp Med. 2005;202(4):473-477.
Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: Distinction from multiple sclerosis. Lancet. 2004;364(9451):2106-2112.
McKeon A, Fryer JP, Apiwattanakul M, et al. Diagnosis of neuromyelitis spectrum disorders: comparative sensitivities and specificities of immunohistochemical and immunoprecipitation assays. Arch Neurol. 2009;66(9):1134-1138.
Pittock SJ, Lennon VA, Krecke K, et al. Brain abnormalities in neuromyelitis optica. Arch Neurol. 2006;63(3):390-396.
Pittock SJ, Weinshenker BG, Lucchinetti CF, et al. Neuromyelitis optica brain lesions localized to sites of high aquaporin 4 expression. Arch Neurol. 2006;63(7):964-968.
Roemer SF, Parisi JE, Lennon VA, et al. Pattern specific loss of aquaporin 4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Brain. 2007;130(Pt 5):1194-1205.
Wingerchuk Dean M, Lennon V, et al. The spectrum of neuromyelitis optica. Lancet Neurol. 2007;6(9):805-815.

Paroxysmal Dystonia Is Associated With Neuromyelitis Optica

SAN FRANCISCO—Paroxysmal dystonia occurs in 14% of patients with neuromyelitis optica, according to research presented at the 135th Annual Meeting of the American Neurological Association. The rate is similar to its association with multiple sclerosis (MS) and may be a presenting sign in both neuromyelitis optica and MS, reported Nida Usmani, MD, and colleagues.

“The pathogenesis of paroxysmal dystonia in neuromyelitis optica is unknown,” stated Dr. Usmani, of the Department of Neurology at the University of Miami. “In MS, it has been hypothesized to be due to ephaptic transmission in demyelinated axons.”

The researchers conducted a retrospective, longitudinal study of 57 patients with neuromyelitis optica. Eight patients had paroxysmal dystonia, which was defined as spontaneous brief, frequent, stereotyped episodes of abnormal posturing of an extremity, face, or neck. The mean age of onset was 37.4 (range, 13.8 to 54.2), with a seven-to-one ratio of females to males. Neuromyelitis optica antibody was found in one of five patients.

Paroxysmal dystonia appeared after a mean of 24.6 months of diagnosis of neuromyelitis optica. In two patients, paroxysmal dystonia was their initial presentation, and the average interval between onset of paroxysmal dystonia and development of other neurologic deficit was 2.5 months. Five patients had single limbs affected, two patients had ipsilateral arm and leg involvement, and one patient had tonic spasms. Two patients had cervical spine lesions on MRI. Seven patients responded to carbamazepine within one week.

“The incidence of paroxysmal dystonia in our neuromyelitis optica case series was 14%, which is similar to reports of its association with MS—3.8% to 17%,” stated Dr. Usmani. “Heretofore, only one well characterized case of neuromyelitis optica with paroxysmal dystonia has been reported. Unfamiliarity with this association can lead to a diagnostic dilemma, especially in cases of paroxysmal dystonia as a presenting symptom.”

Findings support a pathogenic role for an autoantibody of AQP4 specificity in neuromyelitis optica.

SAN FRANCISCO—A complement activating aquaporin-4 (AQP4)-specific autoantibody has a pathogenic role in initiating neuromyelitis optica (NMO) lesions and distinguishes NMO from multiple sclerosis (MS), according to research presented at the 135th Annual Meeting of the American Neurological Association.
Clinical presentation of NMO differs from MS in a number of ways, explained Claudia Lucchinetti, MD, of the Mayo Clinic Rochester in Minnesota, and member of the Mayo Clinic NMO Consortium. NMO onset tends to occur at an older age, affects more females than males, and is more common in non-Caucasians. NMO is typically a relapsing disease, and unlike MS, a progressive course is distinctly unusual. In contrast to MS, brain MRI scans are often normal early in the disease, while spinal cord MRIs typically show long lesions spanning three or more intervertebral segments, which are not typically seen in adult MS. Oligoclonal bands in the spinal fluid are rare in NMO, whereas pleocytosis is common. NMO can be associated with other autoimmune disorders, including myasthenia gravis. Patients with active NMO respond favorably to antibody-depleting therapies.
In 2002, Dr. Lucchinetti and colleagues described the presence of deposits of immunoglobulin G (IgG) and immunoglobulin M (IgM) co-localizing with products of complement activation in a vasculocentric pattern around thickened hyalinized blood vessels in active NMO lesions, suggesting a pathogenic role for humoral immunity targeting an antigen in the perivascular space. In 2004, Vanda Lennon, MD, PhD, and colleagues at the Mayo Clinic reported a specific serum autoantibody marker that was 73% sensitive and more than 90% specific for clinically defined NMO. Its selective binding to the abluminal face of microvessels, pia, subpia and Virchow-Robin sheaths was reminiscent of the localization of immune complexes in NMO patients’ spinal cord tissues described by Lucchinetti and colleagues.
“With the discovery of the biomarker, a spectrum of neurologic disorders has been identified associated with the presence of NMO-IgG, including not only NMO, but also isolated or recurrent longitudinally extensive transverse myelitis, or optic neuritis, encephalopathy, intractable nausea and vomiting, a posterior reversible leukoencephalopathy (PRES)-like syndrome, endocrinopathies, and even narcolepsy,” she said.
Aquaporin-4
Subsequent studies led by Dr. Lennon identified AQP4 as the target auto-antigen in NMO. AQP4 is the dominant CNS water channel, which regulates bidirectional water flux between the blood and brain, and the brain and spinal fluid, and is concentrated at the astrocytic end-feet. It is expressed in two isoforms, M1 and M23, and consists of six membranes that determine the channel’s selectivity for water molecules, Dr. Lucchinetti said.
AQP4 is found on the surfaces of astrocytes, concentrated in periventricular regions, circumventricular organs, and spinal cord gray matter in healthy controls. Normal AQP4 expression parallels the classic ring and rosette staining pattern of immune complex deposition observed in active NMO lesions. In contrast to active MS lesions, which show an increase in AQP4 immunoreactivity, NMO lesions show a striking loss of AQP4, she explained. “Interestingly, myelin may be relatively preserved in some of these lesions, despite the profound loss of AQP4,” said Dr. Lucchinetti.
Brain Lesions in NMO
MRI detects brain lesions in 60% of NMO patients, which include NMO-specific brain lesions in regions of high AQP4 expression (eg, area postrema, hypothalamus), as well as supratentorial lesions that are either nonspecific or MS-like in appearance. The presence of these supratentorial brain lesions has suggested a possible pathologic overlap of NMO and MS. However, comparison of supratentorial (ST) NMO lesions with opticospinal (OS) NMO lesions, as well as supratentorial MS lesions, confirmed that the pathology of NMO ST lesions is similar to NMO OS lesions with respect to type of inflammation, presence of perivascular immune complex deposits and AQP4 loss. Dr. Lucchinetti suggests these findings indicate that NMO ST and OS lesions have a shared pathogenesis.
Clinical reports have also described intractable hiccups, nausea, and vomiting in NMO. NMO specific medullary lesions have been observed in the area postrema, which are characterized by a selective and targeted loss of AQP4, and likely reflect the pathologic substrate of intractable nausea and vomiting reported in some NMO patients. A study in press by members of the Mayo Clinic NMO consortium suggests that the area postrema may even be the first point of attack in NMO in at least 12% of NMO cases, Dr. Lucchinetti reported.
The Role of NMO IgG
In vitro studies demonstrate that NMO-IgG binds selectively to the surface of living target cell membranes expressing AQP4, a prerequisite for IgG to affect organ-specific pathogenicity. This binding initiates two potentially competing outcomes: 1) rapid downregulation of AQP4 via endocytosis/degradation; and 2) activation of the lytic complement cascade. The relative predominance of antigenic modulation and complement activation that represent competing sequelae of IgG binding to the surface AQP4 may determine an individual’s clinical presentation, response to therapy, and disease course. The rapid endocytosis and degradation of surface AQP4 initiated by IgG binding coupled with the rapid replenishment of newly synthesized AQP4 also supports a potentially reversible insult, at least during early disease stages.
A recent study further demonstrated that exposure to NMO patient serum and active complement compromised the membrane integrity of CNS-derived astrocytes. Without complement, astrocyte membranes remained intact, but AQP4 was endocytosed with concomitant loss of sodium-dependent glutamate transport and loss of the excitatory transporter, EAAT2. These findings suggest that EAAT2 and AQP4 exist in astrocytic membranes as a macromolecular complex. Furthermore, Dr. Lucchinetti reported that NMO lesions demonstrated marked reduction in EAAT2 in regions of AQP4 loss. In summary, binding of NMO-IgG to astrocytic AQP4 initiates not only complement activation, but AQP4 and EAAT2 downregulation, which would be expected to disrupt glutamate homeostasis. This could lead to injury of oligodendrocytes that express calcium-permeable glutamate receptors.
Dr. Lucchinetti discussed several possible mechanisms that might initiate demyelination in NMO. First, oligodendrocyte are more susceptible than astrocytes to lethal injury by noxious stimuli, and would be expected to be injured at the paranode where they directly contact AQP4 containing astrocytic foot processes. Second, demyelination could be secondary as a result of axonal injury due to alterations in the ionic microenvironment at the internode. Third, glutamate toxicity may contribute to demyelination.
“NMO IgG can produce three potentially pathogenic outcomes—AQP4 and EAAT2 modulation, complement activation, and reduced glutamate uptake,” she said. “Treatment strategies targeting complement activation and glutamate excitotoxicity may prove effective."

Suggested Reading
Hinson SR, Roemer SF, Lucchinetti CF, et al. Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2. J Exp Med. 2008;205(11):2473-2481.
Lennon VA, Kryzer TJ, Pittock SJ, et al. IgG marker of optic-spinal MS binds to the aquaporin-4 water channel. J Exp Med. 2005;202(4):473-477.
Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: Distinction from multiple sclerosis. Lancet. 2004;364(9451):2106-2112.
McKeon A, Fryer JP, Apiwattanakul M, et al. Diagnosis of neuromyelitis spectrum disorders: comparative sensitivities and specificities of immunohistochemical and immunoprecipitation assays. Arch Neurol. 2009;66(9):1134-1138.
Pittock SJ, Lennon VA, Krecke K, et al. Brain abnormalities in neuromyelitis optica. Arch Neurol. 2006;63(3):390-396.
Pittock SJ, Weinshenker BG, Lucchinetti CF, et al. Neuromyelitis optica brain lesions localized to sites of high aquaporin 4 expression. Arch Neurol. 2006;63(7):964-968.
Roemer SF, Parisi JE, Lennon VA, et al. Pattern specific loss of aquaporin 4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Brain. 2007;130(Pt 5):1194-1205.
Wingerchuk Dean M, Lennon V, et al. The spectrum of neuromyelitis optica. Lancet Neurol. 2007;6(9):805-815.

Paroxysmal Dystonia Is Associated With Neuromyelitis Optica

SAN FRANCISCO—Paroxysmal dystonia occurs in 14% of patients with neuromyelitis optica, according to research presented at the 135th Annual Meeting of the American Neurological Association. The rate is similar to its association with multiple sclerosis (MS) and may be a presenting sign in both neuromyelitis optica and MS, reported Nida Usmani, MD, and colleagues.

“The pathogenesis of paroxysmal dystonia in neuromyelitis optica is unknown,” stated Dr. Usmani, of the Department of Neurology at the University of Miami. “In MS, it has been hypothesized to be due to ephaptic transmission in demyelinated axons.”

The researchers conducted a retrospective, longitudinal study of 57 patients with neuromyelitis optica. Eight patients had paroxysmal dystonia, which was defined as spontaneous brief, frequent, stereotyped episodes of abnormal posturing of an extremity, face, or neck. The mean age of onset was 37.4 (range, 13.8 to 54.2), with a seven-to-one ratio of females to males. Neuromyelitis optica antibody was found in one of five patients.

Paroxysmal dystonia appeared after a mean of 24.6 months of diagnosis of neuromyelitis optica. In two patients, paroxysmal dystonia was their initial presentation, and the average interval between onset of paroxysmal dystonia and development of other neurologic deficit was 2.5 months. Five patients had single limbs affected, two patients had ipsilateral arm and leg involvement, and one patient had tonic spasms. Two patients had cervical spine lesions on MRI. Seven patients responded to carbamazepine within one week.

“The incidence of paroxysmal dystonia in our neuromyelitis optica case series was 14%, which is similar to reports of its association with MS—3.8% to 17%,” stated Dr. Usmani. “Heretofore, only one well characterized case of neuromyelitis optica with paroxysmal dystonia has been reported. Unfamiliarity with this association can lead to a diagnostic dilemma, especially in cases of paroxysmal dystonia as a presenting symptom.”

Findings support a pathogenic role for an autoantibody of AQP4 specificity in neuromyelitis optica.

SAN FRANCISCO—A complement activating aquaporin-4 (AQP4)-specific autoantibody has a pathogenic role in initiating neuromyelitis optica (NMO) lesions and distinguishes NMO from multiple sclerosis (MS), according to research presented at the 135th Annual Meeting of the American Neurological Association.
Clinical presentation of NMO differs from MS in a number of ways, explained Claudia Lucchinetti, MD, of the Mayo Clinic Rochester in Minnesota, and member of the Mayo Clinic NMO Consortium. NMO onset tends to occur at an older age, affects more females than males, and is more common in non-Caucasians. NMO is typically a relapsing disease, and unlike MS, a progressive course is distinctly unusual. In contrast to MS, brain MRI scans are often normal early in the disease, while spinal cord MRIs typically show long lesions spanning three or more intervertebral segments, which are not typically seen in adult MS. Oligoclonal bands in the spinal fluid are rare in NMO, whereas pleocytosis is common. NMO can be associated with other autoimmune disorders, including myasthenia gravis. Patients with active NMO respond favorably to antibody-depleting therapies.
In 2002, Dr. Lucchinetti and colleagues described the presence of deposits of immunoglobulin G (IgG) and immunoglobulin M (IgM) co-localizing with products of complement activation in a vasculocentric pattern around thickened hyalinized blood vessels in active NMO lesions, suggesting a pathogenic role for humoral immunity targeting an antigen in the perivascular space. In 2004, Vanda Lennon, MD, PhD, and colleagues at the Mayo Clinic reported a specific serum autoantibody marker that was 73% sensitive and more than 90% specific for clinically defined NMO. Its selective binding to the abluminal face of microvessels, pia, subpia and Virchow-Robin sheaths was reminiscent of the localization of immune complexes in NMO patients’ spinal cord tissues described by Lucchinetti and colleagues.
“With the discovery of the biomarker, a spectrum of neurologic disorders has been identified associated with the presence of NMO-IgG, including not only NMO, but also isolated or recurrent longitudinally extensive transverse myelitis, or optic neuritis, encephalopathy, intractable nausea and vomiting, a posterior reversible leukoencephalopathy (PRES)-like syndrome, endocrinopathies, and even narcolepsy,” she said.
Aquaporin-4
Subsequent studies led by Dr. Lennon identified AQP4 as the target auto-antigen in NMO. AQP4 is the dominant CNS water channel, which regulates bidirectional water flux between the blood and brain, and the brain and spinal fluid, and is concentrated at the astrocytic end-feet. It is expressed in two isoforms, M1 and M23, and consists of six membranes that determine the channel’s selectivity for water molecules, Dr. Lucchinetti said.
AQP4 is found on the surfaces of astrocytes, concentrated in periventricular regions, circumventricular organs, and spinal cord gray matter in healthy controls. Normal AQP4 expression parallels the classic ring and rosette staining pattern of immune complex deposition observed in active NMO lesions. In contrast to active MS lesions, which show an increase in AQP4 immunoreactivity, NMO lesions show a striking loss of AQP4, she explained. “Interestingly, myelin may be relatively preserved in some of these lesions, despite the profound loss of AQP4,” said Dr. Lucchinetti.
Brain Lesions in NMO
MRI detects brain lesions in 60% of NMO patients, which include NMO-specific brain lesions in regions of high AQP4 expression (eg, area postrema, hypothalamus), as well as supratentorial lesions that are either nonspecific or MS-like in appearance. The presence of these supratentorial brain lesions has suggested a possible pathologic overlap of NMO and MS. However, comparison of supratentorial (ST) NMO lesions with opticospinal (OS) NMO lesions, as well as supratentorial MS lesions, confirmed that the pathology of NMO ST lesions is similar to NMO OS lesions with respect to type of inflammation, presence of perivascular immune complex deposits and AQP4 loss. Dr. Lucchinetti suggests these findings indicate that NMO ST and OS lesions have a shared pathogenesis.
Clinical reports have also described intractable hiccups, nausea, and vomiting in NMO. NMO specific medullary lesions have been observed in the area postrema, which are characterized by a selective and targeted loss of AQP4, and likely reflect the pathologic substrate of intractable nausea and vomiting reported in some NMO patients. A study in press by members of the Mayo Clinic NMO consortium suggests that the area postrema may even be the first point of attack in NMO in at least 12% of NMO cases, Dr. Lucchinetti reported.
The Role of NMO IgG
In vitro studies demonstrate that NMO-IgG binds selectively to the surface of living target cell membranes expressing AQP4, a prerequisite for IgG to affect organ-specific pathogenicity. This binding initiates two potentially competing outcomes: 1) rapid downregulation of AQP4 via endocytosis/degradation; and 2) activation of the lytic complement cascade. The relative predominance of antigenic modulation and complement activation that represent competing sequelae of IgG binding to the surface AQP4 may determine an individual’s clinical presentation, response to therapy, and disease course. The rapid endocytosis and degradation of surface AQP4 initiated by IgG binding coupled with the rapid replenishment of newly synthesized AQP4 also supports a potentially reversible insult, at least during early disease stages.
A recent study further demonstrated that exposure to NMO patient serum and active complement compromised the membrane integrity of CNS-derived astrocytes. Without complement, astrocyte membranes remained intact, but AQP4 was endocytosed with concomitant loss of sodium-dependent glutamate transport and loss of the excitatory transporter, EAAT2. These findings suggest that EAAT2 and AQP4 exist in astrocytic membranes as a macromolecular complex. Furthermore, Dr. Lucchinetti reported that NMO lesions demonstrated marked reduction in EAAT2 in regions of AQP4 loss. In summary, binding of NMO-IgG to astrocytic AQP4 initiates not only complement activation, but AQP4 and EAAT2 downregulation, which would be expected to disrupt glutamate homeostasis. This could lead to injury of oligodendrocytes that express calcium-permeable glutamate receptors.
Dr. Lucchinetti discussed several possible mechanisms that might initiate demyelination in NMO. First, oligodendrocyte are more susceptible than astrocytes to lethal injury by noxious stimuli, and would be expected to be injured at the paranode where they directly contact AQP4 containing astrocytic foot processes. Second, demyelination could be secondary as a result of axonal injury due to alterations in the ionic microenvironment at the internode. Third, glutamate toxicity may contribute to demyelination.
“NMO IgG can produce three potentially pathogenic outcomes—AQP4 and EAAT2 modulation, complement activation, and reduced glutamate uptake,” she said. “Treatment strategies targeting complement activation and glutamate excitotoxicity may prove effective."

Suggested Reading
Hinson SR, Roemer SF, Lucchinetti CF, et al. Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2. J Exp Med. 2008;205(11):2473-2481.
Lennon VA, Kryzer TJ, Pittock SJ, et al. IgG marker of optic-spinal MS binds to the aquaporin-4 water channel. J Exp Med. 2005;202(4):473-477.
Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: Distinction from multiple sclerosis. Lancet. 2004;364(9451):2106-2112.
McKeon A, Fryer JP, Apiwattanakul M, et al. Diagnosis of neuromyelitis spectrum disorders: comparative sensitivities and specificities of immunohistochemical and immunoprecipitation assays. Arch Neurol. 2009;66(9):1134-1138.
Pittock SJ, Lennon VA, Krecke K, et al. Brain abnormalities in neuromyelitis optica. Arch Neurol. 2006;63(3):390-396.
Pittock SJ, Weinshenker BG, Lucchinetti CF, et al. Neuromyelitis optica brain lesions localized to sites of high aquaporin 4 expression. Arch Neurol. 2006;63(7):964-968.
Roemer SF, Parisi JE, Lennon VA, et al. Pattern specific loss of aquaporin 4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Brain. 2007;130(Pt 5):1194-1205.
Wingerchuk Dean M, Lennon V, et al. The spectrum of neuromyelitis optica. Lancet Neurol. 2007;6(9):805-815.

Paroxysmal Dystonia Is Associated With Neuromyelitis Optica

SAN FRANCISCO—Paroxysmal dystonia occurs in 14% of patients with neuromyelitis optica, according to research presented at the 135th Annual Meeting of the American Neurological Association. The rate is similar to its association with multiple sclerosis (MS) and may be a presenting sign in both neuromyelitis optica and MS, reported Nida Usmani, MD, and colleagues.

“The pathogenesis of paroxysmal dystonia in neuromyelitis optica is unknown,” stated Dr. Usmani, of the Department of Neurology at the University of Miami. “In MS, it has been hypothesized to be due to ephaptic transmission in demyelinated axons.”

The researchers conducted a retrospective, longitudinal study of 57 patients with neuromyelitis optica. Eight patients had paroxysmal dystonia, which was defined as spontaneous brief, frequent, stereotyped episodes of abnormal posturing of an extremity, face, or neck. The mean age of onset was 37.4 (range, 13.8 to 54.2), with a seven-to-one ratio of females to males. Neuromyelitis optica antibody was found in one of five patients.

Paroxysmal dystonia appeared after a mean of 24.6 months of diagnosis of neuromyelitis optica. In two patients, paroxysmal dystonia was their initial presentation, and the average interval between onset of paroxysmal dystonia and development of other neurologic deficit was 2.5 months. Five patients had single limbs affected, two patients had ipsilateral arm and leg involvement, and one patient had tonic spasms. Two patients had cervical spine lesions on MRI. Seven patients responded to carbamazepine within one week.

“The incidence of paroxysmal dystonia in our neuromyelitis optica case series was 14%, which is similar to reports of its association with MS—3.8% to 17%,” stated Dr. Usmani. “Heretofore, only one well characterized case of neuromyelitis optica with paroxysmal dystonia has been reported. Unfamiliarity with this association can lead to a diagnostic dilemma, especially in cases of paroxysmal dystonia as a presenting symptom.”

Onabotulinum toxin A may have a role in treating lower extremity spasticity and aiding walking in patients with MS, researchers report.

SAN ANTONIO—Onabotulinum toxin A (Botox) may help improve ambulation in patients with multiple sclerosis (MS), according to research presented at the 24th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

“We observed improvements in ambulation speed, endurance, ambulation on uneven surfaces, and in the ability to ascend and descend inclines and stairs,” reported Christine Short, MD. “Overall improvements in total ambulation capability occurred. Subjectively, individuals also reported improved clonus, decreased tone, decreased pain, decreased muscle spasm, and greater ease of ambulation.” Dr. Short is an Assistant Professor, Division of Physical Medicine, Rehabilitation, and Neurosurgery, Dalhousie University in Halifax, Nova Scotia, Canada.

The findings are based on a case series of five patients with MS whose walking abilities had been compromised by spasticity in the lower extremities. Each participant had problems with extensor and inversion spasticity in one or both lower extremities at the time of treatment. The patients also complained of catching their toes during ambulation, which led to tripping and falling, painful muscle spasms, clonus, and spasticity that interfered with sleep.

All patients participated in physical therapy and were treated with oral antispasticity agents. “In each case, focal neurolysis with Botox was considered when, clinically, there was a suboptimal response to oral and physical therapies or if the therapies were not tolerated due to side effects,” Dr. Short noted.

The total dosage of Botox for each patient ranged from 200 units to 400 units. The investigators measured ambulation speed and endurance before Botox therapy and six weeks after the therapy, “when Botox would be having a maximal effect,” Dr. Short stated. Speed and endurance were determined with use of the six-minute walk test.

“All the individuals treated showed improvements in ambulation speed,” reported Dr. Short. “All subjects also showed improvements in ambulation endurance. Some of the improvements were greater than twofold above baseline. Subjectively, individuals also described improvements in other areas, including decreased pain and decreased clonus, decreased muscle spasms, and greater ease of ambulation in all five cases. Clinically, we observed decreased spasticity in the treated muscles and improved gait."

Dr. Short pointed out that the small sample size of patients did not allow for a more rigorous statistical analysis. “However,” she concluded, “our very interesting observations suggest that further research would be valuable to assess the usefulness of Botox as a treatment for improving ambulation in persons with MS and lower extremity spasticity.

—Rebecca K. Abma

Onabotulinum toxin A may have a role in treating lower extremity spasticity and aiding walking in patients with MS, researchers report.

SAN ANTONIO—Onabotulinum toxin A (Botox) may help improve ambulation in patients with multiple sclerosis (MS), according to research presented at the 24th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

“We observed improvements in ambulation speed, endurance, ambulation on uneven surfaces, and in the ability to ascend and descend inclines and stairs,” reported Christine Short, MD. “Overall improvements in total ambulation capability occurred. Subjectively, individuals also reported improved clonus, decreased tone, decreased pain, decreased muscle spasm, and greater ease of ambulation.” Dr. Short is an Assistant Professor, Division of Physical Medicine, Rehabilitation, and Neurosurgery, Dalhousie University in Halifax, Nova Scotia, Canada.

The findings are based on a case series of five patients with MS whose walking abilities had been compromised by spasticity in the lower extremities. Each participant had problems with extensor and inversion spasticity in one or both lower extremities at the time of treatment. The patients also complained of catching their toes during ambulation, which led to tripping and falling, painful muscle spasms, clonus, and spasticity that interfered with sleep.

All patients participated in physical therapy and were treated with oral antispasticity agents. “In each case, focal neurolysis with Botox was considered when, clinically, there was a suboptimal response to oral and physical therapies or if the therapies were not tolerated due to side effects,” Dr. Short noted.

The total dosage of Botox for each patient ranged from 200 units to 400 units. The investigators measured ambulation speed and endurance before Botox therapy and six weeks after the therapy, “when Botox would be having a maximal effect,” Dr. Short stated. Speed and endurance were determined with use of the six-minute walk test.

“All the individuals treated showed improvements in ambulation speed,” reported Dr. Short. “All subjects also showed improvements in ambulation endurance. Some of the improvements were greater than twofold above baseline. Subjectively, individuals also described improvements in other areas, including decreased pain and decreased clonus, decreased muscle spasms, and greater ease of ambulation in all five cases. Clinically, we observed decreased spasticity in the treated muscles and improved gait."

Dr. Short pointed out that the small sample size of patients did not allow for a more rigorous statistical analysis. “However,” she concluded, “our very interesting observations suggest that further research would be valuable to assess the usefulness of Botox as a treatment for improving ambulation in persons with MS and lower extremity spasticity.

—Rebecca K. Abma

Onabotulinum toxin A may have a role in treating lower extremity spasticity and aiding walking in patients with MS, researchers report.

SAN ANTONIO—Onabotulinum toxin A (Botox) may help improve ambulation in patients with multiple sclerosis (MS), according to research presented at the 24th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

“We observed improvements in ambulation speed, endurance, ambulation on uneven surfaces, and in the ability to ascend and descend inclines and stairs,” reported Christine Short, MD. “Overall improvements in total ambulation capability occurred. Subjectively, individuals also reported improved clonus, decreased tone, decreased pain, decreased muscle spasm, and greater ease of ambulation.” Dr. Short is an Assistant Professor, Division of Physical Medicine, Rehabilitation, and Neurosurgery, Dalhousie University in Halifax, Nova Scotia, Canada.

The findings are based on a case series of five patients with MS whose walking abilities had been compromised by spasticity in the lower extremities. Each participant had problems with extensor and inversion spasticity in one or both lower extremities at the time of treatment. The patients also complained of catching their toes during ambulation, which led to tripping and falling, painful muscle spasms, clonus, and spasticity that interfered with sleep.

All patients participated in physical therapy and were treated with oral antispasticity agents. “In each case, focal neurolysis with Botox was considered when, clinically, there was a suboptimal response to oral and physical therapies or if the therapies were not tolerated due to side effects,” Dr. Short noted.

The total dosage of Botox for each patient ranged from 200 units to 400 units. The investigators measured ambulation speed and endurance before Botox therapy and six weeks after the therapy, “when Botox would be having a maximal effect,” Dr. Short stated. Speed and endurance were determined with use of the six-minute walk test.

“All the individuals treated showed improvements in ambulation speed,” reported Dr. Short. “All subjects also showed improvements in ambulation endurance. Some of the improvements were greater than twofold above baseline. Subjectively, individuals also described improvements in other areas, including decreased pain and decreased clonus, decreased muscle spasms, and greater ease of ambulation in all five cases. Clinically, we observed decreased spasticity in the treated muscles and improved gait."

Dr. Short pointed out that the small sample size of patients did not allow for a more rigorous statistical analysis. “However,” she concluded, “our very interesting observations suggest that further research would be valuable to assess the usefulness of Botox as a treatment for improving ambulation in persons with MS and lower extremity spasticity.

—Rebecca K. Abma

Hyperinsulinemia and hyperglycemia due to insulin resistance may accelerate the formation of neuritic plaques in combination with the effects of apolipoprotein (APOE) e4, as reported in the August 25 online Neurology. This is the conclusion from autopsy studies of 135 residents of Hisayama, Japan, who died between 1998 and 2003. In 1988, the subjects underwent a 75-g oral glucose tolerance test in which measurements of diabetes-related factors, including fasting glucose, two-hour postload plasma glucose, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were taken. The investigators found that higher levels of postload glucose, fasting insulin, and HOMA-IR were associated with an increased risk for neuritic plaques. In addition, “the coexistence of hyperglycemia and APOE e4 increased the risk for neuritic plaque formation,” the researchers reported. “A similar enhancement was observed for hyperinsulinemia and high HOMA-IR.”

A novel gamma-secretase activating protein (GSAP) that “drastically and selectively increases beta-amyloid production” without impairing Notch cleavage was reported in the September 1 online Nature. According to the paper, GSAP stimulates beta-amyloid production in vitro, while mouse models have shown that reducing GSAP decreases beta-amyloid concentrations. The researchers demonstrated that the anti-cancer drug imatinib prevents GSAP interaction with the gamma-secretase substrate amyloid precursor protein carboxy-terminal fragment, without affecting Notch cleavage, and thereby may provide a new therapeutic target for the treatment and prevention of Alzheimer’s disease.
Brain games aimed at stimulating mental acuity appear to slow cognitive decline prior to the onset of dementia, but accelerate it afterward, according to a study in the September 1 online Neurology. Researchers assessed cognitive performance of older subjects at three-year intervals as a composite measure of global cognition, while a subset was sampled for clinical evaluation. Subjects were dementia-free at baseline, at which point they rated the frequency at which they engaged in cognitively stimulating activity. “During follow-up, the annual rate of global cognitive decline in persons without cognitive impairment was reduced by 52% for each additional point on the cognitive activity scale,” the investigators reported. “In the mild cognitive impairment group, cognitive decline rate was unrelated to cognitive activity. In Alzheimer’s disease, the mean rate of decline per year increased by 42% for each point on the cognitive activity scale.”
Researchers have found a new genetic risk factor for amyotrophic lateral sclerosis (ALS), as reported in the August 26 Nature. The study authors showed that ataxin 2 (ATXN2) is a potent modifier of TDP-43 toxicity in animal and cellular models and analyzed the length of the polyQ repeat in the ATXN2 gene in 915 patients with ALS. “We found that intermediate-length polyQ expansions (27 to 33 glutamines) in ATXN2 were significantly associated with ALS,” the investigators stated. “These data establish ATXN2 as a relatively common ALS susceptibility gene. Furthermore, these findings indicate that the TDP-43 ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.”
Two studies in the August 27 online Lancet Neurology have identified genetic variations on chromosome 9 as having a role in the development of amyotrophic lateral sclerosis (ALS). In one study of 442 Finnish patients with ALS, researchers found data suggesting the presence of a founder mutation for chromosome 9p21-linked ALS. “The overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases.” A second study of 599 patients with ALS from the UK found “strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent genome-wide association studies of ALS and linkage studies of ALS-frontotemporal dementia.”
Infants born at 37 or 38 weeks gestation or at 42 weeks or later have an increased risk for cerebral palsy, compared with those born at 40 weeks, researchers reported in the September 1 JAMA. Among 1,938 children with cerebral palsy, infants born at 40 weeks had the lowest risk of the disease, with a prevalence of 0.99/1,000. At 37 weeks, the prevalence was 1.91 (relative risk [RR], 1.9), at 38 weeks the prevalence was 1.25 (RR, 1.3), at 42 weeks the prevalence was 1.36 (RR, 1.4), and after 42 weeks the prevalence was 1.44 (RR, 1.4). “These associations were even stronger in a subset with gestational age based on ultrasound measurements: at 37 weeks the prevalence was 1.17/1,000 and the RR was 3.7,” the investigators reported. “At 42 weeks the prevalence was 0.85/1,000 and the RR was 2.4.”
Use of anticholinergic medications may increase the risk of cognitive impairment, according to a study in the July 13 Neurology. In a six-year longitudinal, observational study of 1,652 community-dwelling African American subjects older than 70, investigators found the number of definite anticholinergics used was associated with a 1.46-fold increased risk of cognitive impairment. Possible anticholinergics were not associated with an increased risk of cognitive impairment. Medications were rated as possible or definite based on the Anticholinergic Cognitive Burden scale. In addition, the investigators found that the increased risk of cognitive impairment was evident among definite anticholinergic users regardless of their apolipoprotein (APOE) e4 allele status. “Limiting the clinical use of definite anticholinergics may reduce the incidence of cognitive impairment among African Americans,” the study authors wrote.
Veterans who experienced post-traumatic stress disorder (PTSD) have a higher incidence and prevalence of dementia, researchers reported in the September Journal of the American Geriatrics Society. In an administrative database study of veterans enrolled in the South Central VA Healthcare Network, which comprises Arkansas, Louisiana, Mississippi, Oklahoma, and parts of Alabama, Florida, Missouri, and Texas, the investigators identified subjects 65 and older who had a diagnosis of PTSD or received a Purple Heart to compare with a group of contemporaries without PTSD or a Purple Heart. After controlling for confounding factors in a multivariate logistic regression, those with PTSD who had not received a Purple Heart had the highest rates of dementia. “It is unclear whether this is due to a common risk factor underlying PTSD and dementia or to PTSD being a risk factor for dementia,” the investigators wrote. “Regardless, this study suggests that veterans with PTSD should be screened more closely for dementia. Because PTSD is so common in veterans, this association has important implications for veteran care.”
The FDA has approved Silenor (doxepin) for the treatment of insomnia characterized by difficulty with sleep maintenance. The first and only prescription sleep medicine approved for treating patients who have episodes of frequent waking during the night or waking too early and being unable to return to sleep, the oral tablet formulation is now commercially available by prescription in 3-mg and 6-mg doses. According to a representative for Somaxon Pharmaceuticals, Inc, in San Diego, “clinical studies demonstrate that Silenor supports seven to eight hours of sleep with no next-day residual effects in most patients and no evidence of abuse potential or physical dependence.”
Subclinical multiple sclerosis (MS) activity may have a strong seasonal pattern, peaking during the spring and summer months, according to a study published in the August 31 issue of Neurology. Basing their findings on noncontrast brain MRI, researchers reported that “the observed activity pattern is suggestive of a modulating role of seasonally changing environmental factors or season-dependent metabolic activity.” New T2 activity showed a likelihood of occurring two to three times higher from March to August than during the rest of the year, which “correlated strongly with regional climate data, in particular solar radiation,” the investigators wrote. In addition, disease intensity was elevated during the summer season. “The elevated risk season appears to lessen for progressive MS and occur about two months earlier,” the authors wrote.
An association between Parkinson’s disease and a gene in the human leukocyte antigen (HLA) region was found in a genome-wide association study (GWAS), researchers reported in the September issue of Nature Genetics. The finding links the involvement of the immune system in Parkinson’s disease and offers new targets for drug development, the investigators stated. The GWAS of 2,000 subjects and 1,986 controls, all of whom were Americans of European ancestry, found an association peak at rs3129882. The findings lend “strong and independent support to the involvement of neuroinflammation and humoral immunity in Parkinson’s disease pathogenesis,” the researchers wrote. The study also confirmed associations with SNCA2,6-8 and MAPT3,7-9 genes, and replicated an association with GAK9.
Drinking alcohol temporarily increases the risk of acute ischemic stroke, per a study that was published in the September Stroke. In a multicenter study of 209 men and 181 women who recently had a stroke, investigators questioned subjects regarding alcohol consumption in relation to stroke onset. “We found the risk of ischemic stroke was transiently elevated for two hours after drinking as little as one serving of alcohol,” they wrote. Fourteen patients reported alcohol consumption within one hour of stroke onset, for a 2.3-fold increased risk of stroke compared to periods of nonuse. The relative risk of stroke onset was 1.6 within two hours of alcohol consumption, and by three hours, the risk returned to baseline. By 24 hours, there was a 30% lower stroke risk. “Although speculative, it is possible that the transiently increased stroke risk from moderate alcohol consumption may be outweighed by the health benefits for the next 24 hours, but consuming multiple drinks at once may result in a sharp increase in acute risk with potential increased long-term risk as well,” the researchers stated.

Hyperinsulinemia and hyperglycemia due to insulin resistance may accelerate the formation of neuritic plaques in combination with the effects of apolipoprotein (APOE) e4, as reported in the August 25 online Neurology. This is the conclusion from autopsy studies of 135 residents of Hisayama, Japan, who died between 1998 and 2003. In 1988, the subjects underwent a 75-g oral glucose tolerance test in which measurements of diabetes-related factors, including fasting glucose, two-hour postload plasma glucose, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were taken. The investigators found that higher levels of postload glucose, fasting insulin, and HOMA-IR were associated with an increased risk for neuritic plaques. In addition, “the coexistence of hyperglycemia and APOE e4 increased the risk for neuritic plaque formation,” the researchers reported. “A similar enhancement was observed for hyperinsulinemia and high HOMA-IR.”

A novel gamma-secretase activating protein (GSAP) that “drastically and selectively increases beta-amyloid production” without impairing Notch cleavage was reported in the September 1 online Nature. According to the paper, GSAP stimulates beta-amyloid production in vitro, while mouse models have shown that reducing GSAP decreases beta-amyloid concentrations. The researchers demonstrated that the anti-cancer drug imatinib prevents GSAP interaction with the gamma-secretase substrate amyloid precursor protein carboxy-terminal fragment, without affecting Notch cleavage, and thereby may provide a new therapeutic target for the treatment and prevention of Alzheimer’s disease.
Brain games aimed at stimulating mental acuity appear to slow cognitive decline prior to the onset of dementia, but accelerate it afterward, according to a study in the September 1 online Neurology. Researchers assessed cognitive performance of older subjects at three-year intervals as a composite measure of global cognition, while a subset was sampled for clinical evaluation. Subjects were dementia-free at baseline, at which point they rated the frequency at which they engaged in cognitively stimulating activity. “During follow-up, the annual rate of global cognitive decline in persons without cognitive impairment was reduced by 52% for each additional point on the cognitive activity scale,” the investigators reported. “In the mild cognitive impairment group, cognitive decline rate was unrelated to cognitive activity. In Alzheimer’s disease, the mean rate of decline per year increased by 42% for each point on the cognitive activity scale.”
Researchers have found a new genetic risk factor for amyotrophic lateral sclerosis (ALS), as reported in the August 26 Nature. The study authors showed that ataxin 2 (ATXN2) is a potent modifier of TDP-43 toxicity in animal and cellular models and analyzed the length of the polyQ repeat in the ATXN2 gene in 915 patients with ALS. “We found that intermediate-length polyQ expansions (27 to 33 glutamines) in ATXN2 were significantly associated with ALS,” the investigators stated. “These data establish ATXN2 as a relatively common ALS susceptibility gene. Furthermore, these findings indicate that the TDP-43 ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.”
Two studies in the August 27 online Lancet Neurology have identified genetic variations on chromosome 9 as having a role in the development of amyotrophic lateral sclerosis (ALS). In one study of 442 Finnish patients with ALS, researchers found data suggesting the presence of a founder mutation for chromosome 9p21-linked ALS. “The overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases.” A second study of 599 patients with ALS from the UK found “strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent genome-wide association studies of ALS and linkage studies of ALS-frontotemporal dementia.”
Infants born at 37 or 38 weeks gestation or at 42 weeks or later have an increased risk for cerebral palsy, compared with those born at 40 weeks, researchers reported in the September 1 JAMA. Among 1,938 children with cerebral palsy, infants born at 40 weeks had the lowest risk of the disease, with a prevalence of 0.99/1,000. At 37 weeks, the prevalence was 1.91 (relative risk [RR], 1.9), at 38 weeks the prevalence was 1.25 (RR, 1.3), at 42 weeks the prevalence was 1.36 (RR, 1.4), and after 42 weeks the prevalence was 1.44 (RR, 1.4). “These associations were even stronger in a subset with gestational age based on ultrasound measurements: at 37 weeks the prevalence was 1.17/1,000 and the RR was 3.7,” the investigators reported. “At 42 weeks the prevalence was 0.85/1,000 and the RR was 2.4.”
Use of anticholinergic medications may increase the risk of cognitive impairment, according to a study in the July 13 Neurology. In a six-year longitudinal, observational study of 1,652 community-dwelling African American subjects older than 70, investigators found the number of definite anticholinergics used was associated with a 1.46-fold increased risk of cognitive impairment. Possible anticholinergics were not associated with an increased risk of cognitive impairment. Medications were rated as possible or definite based on the Anticholinergic Cognitive Burden scale. In addition, the investigators found that the increased risk of cognitive impairment was evident among definite anticholinergic users regardless of their apolipoprotein (APOE) e4 allele status. “Limiting the clinical use of definite anticholinergics may reduce the incidence of cognitive impairment among African Americans,” the study authors wrote.
Veterans who experienced post-traumatic stress disorder (PTSD) have a higher incidence and prevalence of dementia, researchers reported in the September Journal of the American Geriatrics Society. In an administrative database study of veterans enrolled in the South Central VA Healthcare Network, which comprises Arkansas, Louisiana, Mississippi, Oklahoma, and parts of Alabama, Florida, Missouri, and Texas, the investigators identified subjects 65 and older who had a diagnosis of PTSD or received a Purple Heart to compare with a group of contemporaries without PTSD or a Purple Heart. After controlling for confounding factors in a multivariate logistic regression, those with PTSD who had not received a Purple Heart had the highest rates of dementia. “It is unclear whether this is due to a common risk factor underlying PTSD and dementia or to PTSD being a risk factor for dementia,” the investigators wrote. “Regardless, this study suggests that veterans with PTSD should be screened more closely for dementia. Because PTSD is so common in veterans, this association has important implications for veteran care.”
The FDA has approved Silenor (doxepin) for the treatment of insomnia characterized by difficulty with sleep maintenance. The first and only prescription sleep medicine approved for treating patients who have episodes of frequent waking during the night or waking too early and being unable to return to sleep, the oral tablet formulation is now commercially available by prescription in 3-mg and 6-mg doses. According to a representative for Somaxon Pharmaceuticals, Inc, in San Diego, “clinical studies demonstrate that Silenor supports seven to eight hours of sleep with no next-day residual effects in most patients and no evidence of abuse potential or physical dependence.”
Subclinical multiple sclerosis (MS) activity may have a strong seasonal pattern, peaking during the spring and summer months, according to a study published in the August 31 issue of Neurology. Basing their findings on noncontrast brain MRI, researchers reported that “the observed activity pattern is suggestive of a modulating role of seasonally changing environmental factors or season-dependent metabolic activity.” New T2 activity showed a likelihood of occurring two to three times higher from March to August than during the rest of the year, which “correlated strongly with regional climate data, in particular solar radiation,” the investigators wrote. In addition, disease intensity was elevated during the summer season. “The elevated risk season appears to lessen for progressive MS and occur about two months earlier,” the authors wrote.
An association between Parkinson’s disease and a gene in the human leukocyte antigen (HLA) region was found in a genome-wide association study (GWAS), researchers reported in the September issue of Nature Genetics. The finding links the involvement of the immune system in Parkinson’s disease and offers new targets for drug development, the investigators stated. The GWAS of 2,000 subjects and 1,986 controls, all of whom were Americans of European ancestry, found an association peak at rs3129882. The findings lend “strong and independent support to the involvement of neuroinflammation and humoral immunity in Parkinson’s disease pathogenesis,” the researchers wrote. The study also confirmed associations with SNCA2,6-8 and MAPT3,7-9 genes, and replicated an association with GAK9.
Drinking alcohol temporarily increases the risk of acute ischemic stroke, per a study that was published in the September Stroke. In a multicenter study of 209 men and 181 women who recently had a stroke, investigators questioned subjects regarding alcohol consumption in relation to stroke onset. “We found the risk of ischemic stroke was transiently elevated for two hours after drinking as little as one serving of alcohol,” they wrote. Fourteen patients reported alcohol consumption within one hour of stroke onset, for a 2.3-fold increased risk of stroke compared to periods of nonuse. The relative risk of stroke onset was 1.6 within two hours of alcohol consumption, and by three hours, the risk returned to baseline. By 24 hours, there was a 30% lower stroke risk. “Although speculative, it is possible that the transiently increased stroke risk from moderate alcohol consumption may be outweighed by the health benefits for the next 24 hours, but consuming multiple drinks at once may result in a sharp increase in acute risk with potential increased long-term risk as well,” the researchers stated.

Hyperinsulinemia and hyperglycemia due to insulin resistance may accelerate the formation of neuritic plaques in combination with the effects of apolipoprotein (APOE) e4, as reported in the August 25 online Neurology. This is the conclusion from autopsy studies of 135 residents of Hisayama, Japan, who died between 1998 and 2003. In 1988, the subjects underwent a 75-g oral glucose tolerance test in which measurements of diabetes-related factors, including fasting glucose, two-hour postload plasma glucose, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were taken. The investigators found that higher levels of postload glucose, fasting insulin, and HOMA-IR were associated with an increased risk for neuritic plaques. In addition, “the coexistence of hyperglycemia and APOE e4 increased the risk for neuritic plaque formation,” the researchers reported. “A similar enhancement was observed for hyperinsulinemia and high HOMA-IR.”

A novel gamma-secretase activating protein (GSAP) that “drastically and selectively increases beta-amyloid production” without impairing Notch cleavage was reported in the September 1 online Nature. According to the paper, GSAP stimulates beta-amyloid production in vitro, while mouse models have shown that reducing GSAP decreases beta-amyloid concentrations. The researchers demonstrated that the anti-cancer drug imatinib prevents GSAP interaction with the gamma-secretase substrate amyloid precursor protein carboxy-terminal fragment, without affecting Notch cleavage, and thereby may provide a new therapeutic target for the treatment and prevention of Alzheimer’s disease.
Brain games aimed at stimulating mental acuity appear to slow cognitive decline prior to the onset of dementia, but accelerate it afterward, according to a study in the September 1 online Neurology. Researchers assessed cognitive performance of older subjects at three-year intervals as a composite measure of global cognition, while a subset was sampled for clinical evaluation. Subjects were dementia-free at baseline, at which point they rated the frequency at which they engaged in cognitively stimulating activity. “During follow-up, the annual rate of global cognitive decline in persons without cognitive impairment was reduced by 52% for each additional point on the cognitive activity scale,” the investigators reported. “In the mild cognitive impairment group, cognitive decline rate was unrelated to cognitive activity. In Alzheimer’s disease, the mean rate of decline per year increased by 42% for each point on the cognitive activity scale.”
Researchers have found a new genetic risk factor for amyotrophic lateral sclerosis (ALS), as reported in the August 26 Nature. The study authors showed that ataxin 2 (ATXN2) is a potent modifier of TDP-43 toxicity in animal and cellular models and analyzed the length of the polyQ repeat in the ATXN2 gene in 915 patients with ALS. “We found that intermediate-length polyQ expansions (27 to 33 glutamines) in ATXN2 were significantly associated with ALS,” the investigators stated. “These data establish ATXN2 as a relatively common ALS susceptibility gene. Furthermore, these findings indicate that the TDP-43 ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.”
Two studies in the August 27 online Lancet Neurology have identified genetic variations on chromosome 9 as having a role in the development of amyotrophic lateral sclerosis (ALS). In one study of 442 Finnish patients with ALS, researchers found data suggesting the presence of a founder mutation for chromosome 9p21-linked ALS. “The overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases.” A second study of 599 patients with ALS from the UK found “strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent genome-wide association studies of ALS and linkage studies of ALS-frontotemporal dementia.”
Infants born at 37 or 38 weeks gestation or at 42 weeks or later have an increased risk for cerebral palsy, compared with those born at 40 weeks, researchers reported in the September 1 JAMA. Among 1,938 children with cerebral palsy, infants born at 40 weeks had the lowest risk of the disease, with a prevalence of 0.99/1,000. At 37 weeks, the prevalence was 1.91 (relative risk [RR], 1.9), at 38 weeks the prevalence was 1.25 (RR, 1.3), at 42 weeks the prevalence was 1.36 (RR, 1.4), and after 42 weeks the prevalence was 1.44 (RR, 1.4). “These associations were even stronger in a subset with gestational age based on ultrasound measurements: at 37 weeks the prevalence was 1.17/1,000 and the RR was 3.7,” the investigators reported. “At 42 weeks the prevalence was 0.85/1,000 and the RR was 2.4.”
Use of anticholinergic medications may increase the risk of cognitive impairment, according to a study in the July 13 Neurology. In a six-year longitudinal, observational study of 1,652 community-dwelling African American subjects older than 70, investigators found the number of definite anticholinergics used was associated with a 1.46-fold increased risk of cognitive impairment. Possible anticholinergics were not associated with an increased risk of cognitive impairment. Medications were rated as possible or definite based on the Anticholinergic Cognitive Burden scale. In addition, the investigators found that the increased risk of cognitive impairment was evident among definite anticholinergic users regardless of their apolipoprotein (APOE) e4 allele status. “Limiting the clinical use of definite anticholinergics may reduce the incidence of cognitive impairment among African Americans,” the study authors wrote.
Veterans who experienced post-traumatic stress disorder (PTSD) have a higher incidence and prevalence of dementia, researchers reported in the September Journal of the American Geriatrics Society. In an administrative database study of veterans enrolled in the South Central VA Healthcare Network, which comprises Arkansas, Louisiana, Mississippi, Oklahoma, and parts of Alabama, Florida, Missouri, and Texas, the investigators identified subjects 65 and older who had a diagnosis of PTSD or received a Purple Heart to compare with a group of contemporaries without PTSD or a Purple Heart. After controlling for confounding factors in a multivariate logistic regression, those with PTSD who had not received a Purple Heart had the highest rates of dementia. “It is unclear whether this is due to a common risk factor underlying PTSD and dementia or to PTSD being a risk factor for dementia,” the investigators wrote. “Regardless, this study suggests that veterans with PTSD should be screened more closely for dementia. Because PTSD is so common in veterans, this association has important implications for veteran care.”
The FDA has approved Silenor (doxepin) for the treatment of insomnia characterized by difficulty with sleep maintenance. The first and only prescription sleep medicine approved for treating patients who have episodes of frequent waking during the night or waking too early and being unable to return to sleep, the oral tablet formulation is now commercially available by prescription in 3-mg and 6-mg doses. According to a representative for Somaxon Pharmaceuticals, Inc, in San Diego, “clinical studies demonstrate that Silenor supports seven to eight hours of sleep with no next-day residual effects in most patients and no evidence of abuse potential or physical dependence.”
Subclinical multiple sclerosis (MS) activity may have a strong seasonal pattern, peaking during the spring and summer months, according to a study published in the August 31 issue of Neurology. Basing their findings on noncontrast brain MRI, researchers reported that “the observed activity pattern is suggestive of a modulating role of seasonally changing environmental factors or season-dependent metabolic activity.” New T2 activity showed a likelihood of occurring two to three times higher from March to August than during the rest of the year, which “correlated strongly with regional climate data, in particular solar radiation,” the investigators wrote. In addition, disease intensity was elevated during the summer season. “The elevated risk season appears to lessen for progressive MS and occur about two months earlier,” the authors wrote.
An association between Parkinson’s disease and a gene in the human leukocyte antigen (HLA) region was found in a genome-wide association study (GWAS), researchers reported in the September issue of Nature Genetics. The finding links the involvement of the immune system in Parkinson’s disease and offers new targets for drug development, the investigators stated. The GWAS of 2,000 subjects and 1,986 controls, all of whom were Americans of European ancestry, found an association peak at rs3129882. The findings lend “strong and independent support to the involvement of neuroinflammation and humoral immunity in Parkinson’s disease pathogenesis,” the researchers wrote. The study also confirmed associations with SNCA2,6-8 and MAPT3,7-9 genes, and replicated an association with GAK9.
Drinking alcohol temporarily increases the risk of acute ischemic stroke, per a study that was published in the September Stroke. In a multicenter study of 209 men and 181 women who recently had a stroke, investigators questioned subjects regarding alcohol consumption in relation to stroke onset. “We found the risk of ischemic stroke was transiently elevated for two hours after drinking as little as one serving of alcohol,” they wrote. Fourteen patients reported alcohol consumption within one hour of stroke onset, for a 2.3-fold increased risk of stroke compared to periods of nonuse. The relative risk of stroke onset was 1.6 within two hours of alcohol consumption, and by three hours, the risk returned to baseline. By 24 hours, there was a 30% lower stroke risk. “Although speculative, it is possible that the transiently increased stroke risk from moderate alcohol consumption may be outweighed by the health benefits for the next 24 hours, but consuming multiple drinks at once may result in a sharp increase in acute risk with potential increased long-term risk as well,” the researchers stated.

Fatigue is one of the most common symptoms of MS. It is characterized by the sudden loss of energy and the inability to continue an activity that is out of proportion to the activity undertaken. Patients with MS often experience a particular type of fatigue, or lassitude, that occurs daily, worsens as the day goes on, is aggravated by heat, and comes on more easily than normal fatigue. This “invisible” symptom can have a major impact on people’s lives. The following tips may help lessen fatigue’s impact on your daily life.

Fatigue is one of the most common symptoms of MS. It is characterized by the sudden loss of energy and the inability to continue an activity that is out of proportion to the activity undertaken. Patients with MS often experience a particular type of fatigue, or lassitude, that occurs daily, worsens as the day goes on, is aggravated by heat, and comes on more easily than normal fatigue. This “invisible” symptom can have a major impact on people’s lives. The following tips may help lessen fatigue’s impact on your daily life.

Fatigue is one of the most common symptoms of MS. It is characterized by the sudden loss of energy and the inability to continue an activity that is out of proportion to the activity undertaken. Patients with MS often experience a particular type of fatigue, or lassitude, that occurs daily, worsens as the day goes on, is aggravated by heat, and comes on more easily than normal fatigue. This “invisible” symptom can have a major impact on people’s lives. The following tips may help lessen fatigue’s impact on your daily life.

In patients with multiple sclerosis, cognitive reserve is associated with greater cerebral efficiency and appears to protect against cognitive decline.

SAN ANTONIO—A life filled with intellectual enrichment can help to shield patients with multiple sclerosis (MS) from cognitive impairment, according to research presented at the 24th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

“Environmental enrichment can protect against disease severity,” said John DeLuca, PhD, Professor of Physical Medicine and Rehabilitation, University of Medicine and Dentistry of New Jersey–New Jersey Medical School, in Newark. “We think this is very critical and very important in even thinking about MS rehabilitation.”

The Cognitive Reserve Hypothesis

Dr. DeLuca and colleagues conducted four studies (all led by James F. Sumowski, PhD) on cognitive function in MS. Although 50% to 70% of patients with MS have cognitive impairment—most commonly, problems with processing speed and episodic memory—the exact mechanisms behind such impairment are unclear.

“Studies of MRIs that look at brain atrophy in MS provide very little and limited validity in terms of predicting who will have cognitive impairment,” Dr. DeLuca said. “If you look at brain atrophy and at cognitive impairment, the correlation is not really high. Well, why not?”

To answer this question, the researchers looked to the cognitive reserve hypothesis, which postulates that intellectual enrichment is associated with greater cerebral efficiency and provides a bulwark against cognitive impairment. In Alzheimer’s disease, this hypothesis is supported by multiple studies finding that lower educational attainment is a risk factor for dementia.

“Greater enrichment in life somehow creates this reserve that protects against the expression of cognitive impairment, even with the same degree of pathology,” Dr. DeLuca explained. “So when disease challenges cerebral functioning, patients with greater premorbid cerebral efficiency or cognitive reserve can withstand more advanced disease before suffering cognitive impairment.”

Cerebral Efficiency

The researchers began their investigation of cognitive reserve in MS by studying 58 patients with MS and 43 healthy controls. They estimated the participants’ cognitive reserve based on a word-reading proxy of premorbid intelligence (the Wide Range Achievement Test–3). In addition, they administered tests of simple processing efficiency, complex processing efficiency, and verbal learning and memory to all participants.

Patients with MS and lower cognitive reserve showed very significant cognitive deficits relative to controls with regard to complex processing efficiency and verbal learning and memory, the researchers found. In contrast, patients with MS and higher cognitive reserve showed no impairments relative to controls.

“So this first study showed us that the cognitive reserve hypothesis existed in persons with MS—there’s a protective factor,” Dr. DeLuca concluded.

Atrophy and Information Processing

In their second study, the researchers focused on whether cognitive reserve moderates brain atrophy’s effects on information processing efficiency in MS.

They recruited 38 patients with MS and used the Wechsler Abbreviated Scale of Intelligence (WASI) vocabulary subtest to estimate patients’ premorbid intelligence. In addition, they used a composite score of the Symbol Digit Modalities Test and the Paced Auditory Serial Addition Task to determine the patients’ information processing efficiency. Subjects underwent higher resolution brain MRI, and third ventricle width was used as a measure of their brain atrophy.

Brain atrophy predicted worse information processing efficiency, cognitive reserve predicted better information processing efficiency, and these effects were moderated by an interaction between atrophy and cognitive reserve, the researchers found.

“Among persons with higher reserve, even as you increase to a high level of brain atrophy, there is a protective effect against the expression of cognitive impairment,” Dr. DeLuca noted. “Well, compare that to persons with lower reserve. As you increase brain atrophy, you’re showing a very significant drop in cognitive function—almost three standard deviations lower, and that’s huge. I think cognitive reserve is demonstrating a protective effect against the expression of these disease pathologies.”

Atrophy, Learning, and Memory 

Next, the researchers looked at the relationship between cognitive reserve, learning, and memory in MS. They used the WASI vocabulary test to estimate lifetime intellectual enrichment in 44 patients with MS. The patients’ degrees of learning were estimated with total learning across trials of the selective reminding test (SRT), their degrees of memory were estimated with SRT 30-Minute Delayed Recall, and their brain atrophy was determined by third ventricle width.

Although brain atrophy was associated with worse learning and memory, these effects were moderated by cognitive reserve, with greater reserve lessening atrophy’s negative effects. “Among patients with higher reserve, there’s essentially no change, even with the increase in pathology,” Dr. DeLuca noted. “Patients with lower reserve, however, are showing a decline in performance. We find the same thing in processing speed and in immediate recall.”

Brain Activity During Cognitive Tasks

The researchers also investigated the associations between cognitive reserve and brain activity during cognitive tasks in patients with MS. They used the WASI vocabulary test to estimate cognitive reserve among 18 such patients and administered the N-Back Working Memory Task to these patients during fMRI.

Cognitive reserve was positively associated with cerebral activity within the default network and negatively associated with prefrontal recruitment. These results indicate that patients with greater cognitive reserve were better able to maintain a resting state during cognitive processing, while patients with less cognitive reserve required more cerebral resources for cognitive tasks.

The Next Step

The evidence for cognitive reserve’s protective effects has implications for the treatment of MS, Dr. DeLuca emphasized. “The next step is, ‘What are we going to have to do to have environmental enrichment?’” he said. “In persons diagnosed with MS, how do we maintain and build up the cognitive reserve so that, perhaps, they don’t show cognitive dysfunction?”

Virtual reality, video games, cognitive behavioral therapy, and physical activity all may contribute to cognitive reserve and protect against cognitive decline in MS, according to Dr. Deluca. He noted that research on these topics is ongoing.

–Jack Baney

In patients with multiple sclerosis, cognitive reserve is associated with greater cerebral efficiency and appears to protect against cognitive decline.

SAN ANTONIO—A life filled with intellectual enrichment can help to shield patients with multiple sclerosis (MS) from cognitive impairment, according to research presented at the 24th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

“Environmental enrichment can protect against disease severity,” said John DeLuca, PhD, Professor of Physical Medicine and Rehabilitation, University of Medicine and Dentistry of New Jersey–New Jersey Medical School, in Newark. “We think this is very critical and very important in even thinking about MS rehabilitation.”

The Cognitive Reserve Hypothesis

Dr. DeLuca and colleagues conducted four studies (all led by James F. Sumowski, PhD) on cognitive function in MS. Although 50% to 70% of patients with MS have cognitive impairment—most commonly, problems with processing speed and episodic memory—the exact mechanisms behind such impairment are unclear.

“Studies of MRIs that look at brain atrophy in MS provide very little and limited validity in terms of predicting who will have cognitive impairment,” Dr. DeLuca said. “If you look at brain atrophy and at cognitive impairment, the correlation is not really high. Well, why not?”

To answer this question, the researchers looked to the cognitive reserve hypothesis, which postulates that intellectual enrichment is associated with greater cerebral efficiency and provides a bulwark against cognitive impairment. In Alzheimer’s disease, this hypothesis is supported by multiple studies finding that lower educational attainment is a risk factor for dementia.

“Greater enrichment in life somehow creates this reserve that protects against the expression of cognitive impairment, even with the same degree of pathology,” Dr. DeLuca explained. “So when disease challenges cerebral functioning, patients with greater premorbid cerebral efficiency or cognitive reserve can withstand more advanced disease before suffering cognitive impairment.”

Cerebral Efficiency

The researchers began their investigation of cognitive reserve in MS by studying 58 patients with MS and 43 healthy controls. They estimated the participants’ cognitive reserve based on a word-reading proxy of premorbid intelligence (the Wide Range Achievement Test–3). In addition, they administered tests of simple processing efficiency, complex processing efficiency, and verbal learning and memory to all participants.

Patients with MS and lower cognitive reserve showed very significant cognitive deficits relative to controls with regard to complex processing efficiency and verbal learning and memory, the researchers found. In contrast, patients with MS and higher cognitive reserve showed no impairments relative to controls.

“So this first study showed us that the cognitive reserve hypothesis existed in persons with MS—there’s a protective factor,” Dr. DeLuca concluded.

Atrophy and Information Processing

In their second study, the researchers focused on whether cognitive reserve moderates brain atrophy’s effects on information processing efficiency in MS.

They recruited 38 patients with MS and used the Wechsler Abbreviated Scale of Intelligence (WASI) vocabulary subtest to estimate patients’ premorbid intelligence. In addition, they used a composite score of the Symbol Digit Modalities Test and the Paced Auditory Serial Addition Task to determine the patients’ information processing efficiency. Subjects underwent higher resolution brain MRI, and third ventricle width was used as a measure of their brain atrophy.

Brain atrophy predicted worse information processing efficiency, cognitive reserve predicted better information processing efficiency, and these effects were moderated by an interaction between atrophy and cognitive reserve, the researchers found.

“Among persons with higher reserve, even as you increase to a high level of brain atrophy, there is a protective effect against the expression of cognitive impairment,” Dr. DeLuca noted. “Well, compare that to persons with lower reserve. As you increase brain atrophy, you’re showing a very significant drop in cognitive function—almost three standard deviations lower, and that’s huge. I think cognitive reserve is demonstrating a protective effect against the expression of these disease pathologies.”

Atrophy, Learning, and Memory 

Next, the researchers looked at the relationship between cognitive reserve, learning, and memory in MS. They used the WASI vocabulary test to estimate lifetime intellectual enrichment in 44 patients with MS. The patients’ degrees of learning were estimated with total learning across trials of the selective reminding test (SRT), their degrees of memory were estimated with SRT 30-Minute Delayed Recall, and their brain atrophy was determined by third ventricle width.

Although brain atrophy was associated with worse learning and memory, these effects were moderated by cognitive reserve, with greater reserve lessening atrophy’s negative effects. “Among patients with higher reserve, there’s essentially no change, even with the increase in pathology,” Dr. DeLuca noted. “Patients with lower reserve, however, are showing a decline in performance. We find the same thing in processing speed and in immediate recall.”

Brain Activity During Cognitive Tasks

The researchers also investigated the associations between cognitive reserve and brain activity during cognitive tasks in patients with MS. They used the WASI vocabulary test to estimate cognitive reserve among 18 such patients and administered the N-Back Working Memory Task to these patients during fMRI.

Cognitive reserve was positively associated with cerebral activity within the default network and negatively associated with prefrontal recruitment. These results indicate that patients with greater cognitive reserve were better able to maintain a resting state during cognitive processing, while patients with less cognitive reserve required more cerebral resources for cognitive tasks.

The Next Step

The evidence for cognitive reserve’s protective effects has implications for the treatment of MS, Dr. DeLuca emphasized. “The next step is, ‘What are we going to have to do to have environmental enrichment?’” he said. “In persons diagnosed with MS, how do we maintain and build up the cognitive reserve so that, perhaps, they don’t show cognitive dysfunction?”

Virtual reality, video games, cognitive behavioral therapy, and physical activity all may contribute to cognitive reserve and protect against cognitive decline in MS, according to Dr. Deluca. He noted that research on these topics is ongoing.

–Jack Baney

In patients with multiple sclerosis, cognitive reserve is associated with greater cerebral efficiency and appears to protect against cognitive decline.

SAN ANTONIO—A life filled with intellectual enrichment can help to shield patients with multiple sclerosis (MS) from cognitive impairment, according to research presented at the 24th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

“Environmental enrichment can protect against disease severity,” said John DeLuca, PhD, Professor of Physical Medicine and Rehabilitation, University of Medicine and Dentistry of New Jersey–New Jersey Medical School, in Newark. “We think this is very critical and very important in even thinking about MS rehabilitation.”

The Cognitive Reserve Hypothesis

Dr. DeLuca and colleagues conducted four studies (all led by James F. Sumowski, PhD) on cognitive function in MS. Although 50% to 70% of patients with MS have cognitive impairment—most commonly, problems with processing speed and episodic memory—the exact mechanisms behind such impairment are unclear.

“Studies of MRIs that look at brain atrophy in MS provide very little and limited validity in terms of predicting who will have cognitive impairment,” Dr. DeLuca said. “If you look at brain atrophy and at cognitive impairment, the correlation is not really high. Well, why not?”

To answer this question, the researchers looked to the cognitive reserve hypothesis, which postulates that intellectual enrichment is associated with greater cerebral efficiency and provides a bulwark against cognitive impairment. In Alzheimer’s disease, this hypothesis is supported by multiple studies finding that lower educational attainment is a risk factor for dementia.

“Greater enrichment in life somehow creates this reserve that protects against the expression of cognitive impairment, even with the same degree of pathology,” Dr. DeLuca explained. “So when disease challenges cerebral functioning, patients with greater premorbid cerebral efficiency or cognitive reserve can withstand more advanced disease before suffering cognitive impairment.”

Cerebral Efficiency

The researchers began their investigation of cognitive reserve in MS by studying 58 patients with MS and 43 healthy controls. They estimated the participants’ cognitive reserve based on a word-reading proxy of premorbid intelligence (the Wide Range Achievement Test–3). In addition, they administered tests of simple processing efficiency, complex processing efficiency, and verbal learning and memory to all participants.

Patients with MS and lower cognitive reserve showed very significant cognitive deficits relative to controls with regard to complex processing efficiency and verbal learning and memory, the researchers found. In contrast, patients with MS and higher cognitive reserve showed no impairments relative to controls.

“So this first study showed us that the cognitive reserve hypothesis existed in persons with MS—there’s a protective factor,” Dr. DeLuca concluded.

Atrophy and Information Processing

In their second study, the researchers focused on whether cognitive reserve moderates brain atrophy’s effects on information processing efficiency in MS.

They recruited 38 patients with MS and used the Wechsler Abbreviated Scale of Intelligence (WASI) vocabulary subtest to estimate patients’ premorbid intelligence. In addition, they used a composite score of the Symbol Digit Modalities Test and the Paced Auditory Serial Addition Task to determine the patients’ information processing efficiency. Subjects underwent higher resolution brain MRI, and third ventricle width was used as a measure of their brain atrophy.

Brain atrophy predicted worse information processing efficiency, cognitive reserve predicted better information processing efficiency, and these effects were moderated by an interaction between atrophy and cognitive reserve, the researchers found.

“Among persons with higher reserve, even as you increase to a high level of brain atrophy, there is a protective effect against the expression of cognitive impairment,” Dr. DeLuca noted. “Well, compare that to persons with lower reserve. As you increase brain atrophy, you’re showing a very significant drop in cognitive function—almost three standard deviations lower, and that’s huge. I think cognitive reserve is demonstrating a protective effect against the expression of these disease pathologies.”

Atrophy, Learning, and Memory 

Next, the researchers looked at the relationship between cognitive reserve, learning, and memory in MS. They used the WASI vocabulary test to estimate lifetime intellectual enrichment in 44 patients with MS. The patients’ degrees of learning were estimated with total learning across trials of the selective reminding test (SRT), their degrees of memory were estimated with SRT 30-Minute Delayed Recall, and their brain atrophy was determined by third ventricle width.

Although brain atrophy was associated with worse learning and memory, these effects were moderated by cognitive reserve, with greater reserve lessening atrophy’s negative effects. “Among patients with higher reserve, there’s essentially no change, even with the increase in pathology,” Dr. DeLuca noted. “Patients with lower reserve, however, are showing a decline in performance. We find the same thing in processing speed and in immediate recall.”

Brain Activity During Cognitive Tasks

The researchers also investigated the associations between cognitive reserve and brain activity during cognitive tasks in patients with MS. They used the WASI vocabulary test to estimate cognitive reserve among 18 such patients and administered the N-Back Working Memory Task to these patients during fMRI.

Cognitive reserve was positively associated with cerebral activity within the default network and negatively associated with prefrontal recruitment. These results indicate that patients with greater cognitive reserve were better able to maintain a resting state during cognitive processing, while patients with less cognitive reserve required more cerebral resources for cognitive tasks.

The Next Step

The evidence for cognitive reserve’s protective effects has implications for the treatment of MS, Dr. DeLuca emphasized. “The next step is, ‘What are we going to have to do to have environmental enrichment?’” he said. “In persons diagnosed with MS, how do we maintain and build up the cognitive reserve so that, perhaps, they don’t show cognitive dysfunction?”

Virtual reality, video games, cognitive behavioral therapy, and physical activity all may contribute to cognitive reserve and protect against cognitive decline in MS, according to Dr. Deluca. He noted that research on these topics is ongoing.

–Jack Baney

Memory problems in patients with depression increase the risk for medication noncompliance, a pilot study has found.

SAN ANTONIO—Depression and fatigue have a negative impact on memory function in patients with multiple sclerosis (MS), researchers reported at the 24th Annual Meeting of the Consortium of Multiple Sclerosis Centers. Although the study found that patients with depression had impairments in recall and recognition, patients who experienced fatigue along with depression showed even greater impairments.

“Depression, a common comorbid diagnosis in MS, is often debilitating and can result in a diminished quality of life, increased social stress, and cognitive deficits, such as reduced information processing speed and working memory,” Megan Ensley, Cognitive Coordinator at the Neurology Center of Fairfax, Virginia, told Neurology Reviews. “Additionally, a significant portion of MS patients report fatigue, a subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual or desired activities, as either their worst symptom or the symptom that has the greatest effect on their quality of life.”

In a study of 29 patients with MS, Ms. Ensley and colleagues assessed subjects using a standardized cognitive screening battery to evaluate simple attention, verbal learning, verbal recall, verbal recognition memory, information processing speed, executive function, mental status, and mood. The researchers also administered the 36-item Short Form Health Status Survey (SF-36), using its vitality scale to evaluate subjects’ quality of life.

Almost half of all subjects (48%) reported significant fatigue, 79% reported clinical depression, and 41% reported both fatigue and depression. Of the subjects who were both depressed and fatigued, 83% scored below expectations on one or more cognitive screening elements, while 73% of those reporting depression without fatigue (38% of subjects) scored below expectations.

For information processing speed, 78% of depressed and fatigued subjects and 75% of depressed-only subjects were impaired. In verbal learning, 67% of the depressed-fatigued group and 50% of the depressed group were impaired. Recall was impaired in 67% of depression-fatigue subjects and 50% of depressed subjects. Recognition was impaired in 67% of the depression-fatigue group and 13% of the depression-only group. Executive function was hindered in 33% of depressed and fatigued subjects and in 63% of depressed-only subjects. Language skills were impaired in 78% of depressed and fatigued subjects and 50% of the depressed-only group. Simple attention was impaired in 22% of the depressed and fatigued subjects and 38% of the depressed-only group.

“The patients reporting clinically significant depression and fatigue appear to have had more difficulty with verbal learning, delayed recall, and recognition than patients only reporting clinically significant depression,” Ms. Ensley said. “This information suggests that fatigue may be exacerbating the cognitive difficulties of patients already reporting depression. In the clinical setting, this may mean that patients do not have the cognitive energy to attend to their doctor’s instructions once they have left the office. This could be particularly detrimental if a patient is unable to recall important details, such as what prescriptions to take and when.

“Patients with MS are most likely to discuss their experience of memory loss, depression, and fatigue with their clinician, and as such it is important for clinicians to assess the potential impact of depression and/or fatigue on such memory difficulties, as this information could be diagnostically important for distinguishing between an organic versus functional etiology of the memory dysfunction,” she added. “This information could be significant for clinicians in determining the best course of treatment. It can be presumed that treating the patient’s depression and/or fatigue will greatly improve cognitive function … subsequently leading to an overall enhancement of quality of life.”

—Rebecca K. Abma

Memory problems in patients with depression increase the risk for medication noncompliance, a pilot study has found.

SAN ANTONIO—Depression and fatigue have a negative impact on memory function in patients with multiple sclerosis (MS), researchers reported at the 24th Annual Meeting of the Consortium of Multiple Sclerosis Centers. Although the study found that patients with depression had impairments in recall and recognition, patients who experienced fatigue along with depression showed even greater impairments.

“Depression, a common comorbid diagnosis in MS, is often debilitating and can result in a diminished quality of life, increased social stress, and cognitive deficits, such as reduced information processing speed and working memory,” Megan Ensley, Cognitive Coordinator at the Neurology Center of Fairfax, Virginia, told Neurology Reviews. “Additionally, a significant portion of MS patients report fatigue, a subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual or desired activities, as either their worst symptom or the symptom that has the greatest effect on their quality of life.”

In a study of 29 patients with MS, Ms. Ensley and colleagues assessed subjects using a standardized cognitive screening battery to evaluate simple attention, verbal learning, verbal recall, verbal recognition memory, information processing speed, executive function, mental status, and mood. The researchers also administered the 36-item Short Form Health Status Survey (SF-36), using its vitality scale to evaluate subjects’ quality of life.

Almost half of all subjects (48%) reported significant fatigue, 79% reported clinical depression, and 41% reported both fatigue and depression. Of the subjects who were both depressed and fatigued, 83% scored below expectations on one or more cognitive screening elements, while 73% of those reporting depression without fatigue (38% of subjects) scored below expectations.

For information processing speed, 78% of depressed and fatigued subjects and 75% of depressed-only subjects were impaired. In verbal learning, 67% of the depressed-fatigued group and 50% of the depressed group were impaired. Recall was impaired in 67% of depression-fatigue subjects and 50% of depressed subjects. Recognition was impaired in 67% of the depression-fatigue group and 13% of the depression-only group. Executive function was hindered in 33% of depressed and fatigued subjects and in 63% of depressed-only subjects. Language skills were impaired in 78% of depressed and fatigued subjects and 50% of the depressed-only group. Simple attention was impaired in 22% of the depressed and fatigued subjects and 38% of the depressed-only group.

“The patients reporting clinically significant depression and fatigue appear to have had more difficulty with verbal learning, delayed recall, and recognition than patients only reporting clinically significant depression,” Ms. Ensley said. “This information suggests that fatigue may be exacerbating the cognitive difficulties of patients already reporting depression. In the clinical setting, this may mean that patients do not have the cognitive energy to attend to their doctor’s instructions once they have left the office. This could be particularly detrimental if a patient is unable to recall important details, such as what prescriptions to take and when.

“Patients with MS are most likely to discuss their experience of memory loss, depression, and fatigue with their clinician, and as such it is important for clinicians to assess the potential impact of depression and/or fatigue on such memory difficulties, as this information could be diagnostically important for distinguishing between an organic versus functional etiology of the memory dysfunction,” she added. “This information could be significant for clinicians in determining the best course of treatment. It can be presumed that treating the patient’s depression and/or fatigue will greatly improve cognitive function … subsequently leading to an overall enhancement of quality of life.”

—Rebecca K. Abma

Memory problems in patients with depression increase the risk for medication noncompliance, a pilot study has found.

SAN ANTONIO—Depression and fatigue have a negative impact on memory function in patients with multiple sclerosis (MS), researchers reported at the 24th Annual Meeting of the Consortium of Multiple Sclerosis Centers. Although the study found that patients with depression had impairments in recall and recognition, patients who experienced fatigue along with depression showed even greater impairments.

“Depression, a common comorbid diagnosis in MS, is often debilitating and can result in a diminished quality of life, increased social stress, and cognitive deficits, such as reduced information processing speed and working memory,” Megan Ensley, Cognitive Coordinator at the Neurology Center of Fairfax, Virginia, told Neurology Reviews. “Additionally, a significant portion of MS patients report fatigue, a subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual or desired activities, as either their worst symptom or the symptom that has the greatest effect on their quality of life.”

In a study of 29 patients with MS, Ms. Ensley and colleagues assessed subjects using a standardized cognitive screening battery to evaluate simple attention, verbal learning, verbal recall, verbal recognition memory, information processing speed, executive function, mental status, and mood. The researchers also administered the 36-item Short Form Health Status Survey (SF-36), using its vitality scale to evaluate subjects’ quality of life.

Almost half of all subjects (48%) reported significant fatigue, 79% reported clinical depression, and 41% reported both fatigue and depression. Of the subjects who were both depressed and fatigued, 83% scored below expectations on one or more cognitive screening elements, while 73% of those reporting depression without fatigue (38% of subjects) scored below expectations.

For information processing speed, 78% of depressed and fatigued subjects and 75% of depressed-only subjects were impaired. In verbal learning, 67% of the depressed-fatigued group and 50% of the depressed group were impaired. Recall was impaired in 67% of depression-fatigue subjects and 50% of depressed subjects. Recognition was impaired in 67% of the depression-fatigue group and 13% of the depression-only group. Executive function was hindered in 33% of depressed and fatigued subjects and in 63% of depressed-only subjects. Language skills were impaired in 78% of depressed and fatigued subjects and 50% of the depressed-only group. Simple attention was impaired in 22% of the depressed and fatigued subjects and 38% of the depressed-only group.

“The patients reporting clinically significant depression and fatigue appear to have had more difficulty with verbal learning, delayed recall, and recognition than patients only reporting clinically significant depression,” Ms. Ensley said. “This information suggests that fatigue may be exacerbating the cognitive difficulties of patients already reporting depression. In the clinical setting, this may mean that patients do not have the cognitive energy to attend to their doctor’s instructions once they have left the office. This could be particularly detrimental if a patient is unable to recall important details, such as what prescriptions to take and when.

“Patients with MS are most likely to discuss their experience of memory loss, depression, and fatigue with their clinician, and as such it is important for clinicians to assess the potential impact of depression and/or fatigue on such memory difficulties, as this information could be diagnostically important for distinguishing between an organic versus functional etiology of the memory dysfunction,” she added. “This information could be significant for clinicians in determining the best course of treatment. It can be presumed that treating the patient’s depression and/or fatigue will greatly improve cognitive function … subsequently leading to an overall enhancement of quality of life.”

—Rebecca K. Abma

Investigators also found a high rate of misdiagnosis among patients with MS during emergency department visits.

TORONTO—The majority of emergency department visits for patients with multiple sclerosis (MS) are for medical comorbidities and complications indirectly related to MS, and not for neurologic problems, according to research presented at the 62nd Annual Meeting of the American Academy of Neurology (AAN). Investigators cautioned practitioners to avoid automatically ascribing symptoms of acutely ill patients to their underlying MS.

“MS is not simply a neurologic disease,” Megan Alcauskas, MD, and Stephen Krieger, MD, told Neurology Reviews. “It can have medical, urological, psychiatric, and other effects, and can touch almost all medical and surgical specialties.”

Drs. Krieger and Alcauskas and colleagues at the Corrine Goldsmith Dickinson Center for Multiple Sclerosis at the Mount Sinai School of Medicine, along with Svenja Oynhausen, MD, at University Hospital of Bonn, Germany, used a centralized, comprehensive database of patient visits to the emergency department of Mount Sinai Hospital in New York City between January 1, 2005, and December 31, 2007. The researchers identified 569 visits by 224 patients with MS as part of the Resource Utilization in MS (RESUMS) study. Slightly less than three-quarters of all emergency department visits (n = 424) were for nonneurologic complaints, while the remaining visits were for neurologic problems, including weakness, altered mental status, and sensory symptoms (see " Factors Affecting Frequent ER Use in MS Patients").

“Patients using the emergency department are more likely to be underinsured, have higher levels of disability, and are more likely to be undertreated with disease-modifying therapies [DMTs] than the general MS populations,” Dr. Oynhausen explained. “The acute care needs of patients change over the course of their disease, and as the disease progresses they are more likely to seek care for the comorbidities associated with MS than for relapses.”

Disability and DMTs

At each visit, a patient’s Expanded Disability Status Score (EDSS) was estimated to be either mild (less than 4), moderate (4 to 5.5), or severe (greater than 6) based on history, examination, and assistive device for ambulation. Although the majority of visits (63.8%) were made by patients with an EDSS in the severe range, the researchers noted that most emergency department visits “were attributable entirely to issues indirectly related to the MS diagnosis, such as urinary tract infections, falls, and indwelling hardware.” The majority of those with a mild or moderate EDSS also came to the emergency department for issues unrelated to MS, including abdominal pain, viral infections, respiratory problems, chest pain, or psychiatric issues.

“Our data show that the major proportion of MS patients seeking emergency department care suffer from nonneurologic, acute problems,” the investigators reported. “This validates the importance of interdisciplinary awareness of the medical needs within the MS population.”

Of the patients studied, 41.5% were taking DMTs, and slightly more than half of those with relapsing-remitting MS were taking DMTs. The majority of patients had either Medicaid or Medicare for insurance, 18.3% had private insurance, and 12.9% were uninsured. Half of all visits resulted in hospital admission, 54.7% of which were admissions to the medicine department and 25.6% were admissions to the neurology department.

Diagnostic Accuracy

A second part of the RESUMS study, also presented at the meeting, found that the accuracy of diagnoses made in the emergency department had room for improvement. In all, 42.1% of diagnoses were confirmed, 43.2% were modified, and 14.7% were altogether different.

“The emergency department is better at diagnosing nonneurologic problems than neurologic ones, even in a population of patients with a known diagnosis of relapsing neurologic illness,” Dr. Alcauskas and colleagues reported. “The emergency department was least accurate in diagnosing female patients presenting with neurologic complaints, a trend that has also been seen in the diagnosis of stroke patients.”

However, in men with neurologic complaints, the accuracy of diagnosis was similar to that of men presenting with nonneurologic complaints. The diagnostic accuracy was not significantly affected by patient age or EDSS scores.

As far as properly diagnosing an MS relapse, the emergency department diagnosed 55 relapses, 27 of which were false positives, and there were 10 false negatives, for a sensitivity of 76.7% and a specificity of 90.9%. The positive predictive value was 60%, and the negative predictive value was 95.6%.

Factors Affecting Frequent ER Use in MS Patients

SAN ANTONIO—One third of MS patient visits to the emergency department are by less than 10% of the patients, according to additional information from the RESUMS study presented at the 24th Annual Meeting of the Consortium for Multiple Sclerosis Centers. Using the same data set reported at AAN, Dr. Krieger and colleagues also reported that relapse accounted for only 13.2% of the visits and that one quarter of visits were for neurologic complaints.

“In the general population, it has been shown that frequent users of the emergency department strain the healthcare system, resulting in higher costs, overcrowding, and decreased quality of health care,” Drs. Krieger and Alcauskas reported.

During the three-year study period, 224 patients made 569 visits, with a mean of 2.5 visits among all patients. Twenty-one patients were defined as high-frequency users, with six or more visits each. The researchers found no significant difference in demographics between frequent and nonfrequent users; however, frequent users were more likely to have a longer disease duration and a history of psychiatric issues.

Frequent users were more likely than nonfrequent users to present with hardware malfunction, such as urinary catheters, urinary complaints, and fever.

“This study has identified several presentation-specific, and therefore, modifiable factors affecting high-frequency emergency department usage in the MS population,” the researchers wrote. “Unlike studies in other chronic medical conditions, no social or demographic factors were found to be significantly associated with high-frequency emergency department usage.”

Relapses constituted a small fraction of emergency department visits, representing just 13.2% of visits. Of the 75 visits in which patients presented with relapse, 43 were admissions to the hospital, with an average length of stay of 8.5 days. As noted in the study presented at AAN, emergency department doctors frequently misdiagnosed patients with MS as having a relapse or other neurologic event.

“Of patients thought to have MS relapses by the emergency department that turned out to be incorrectly diagnosed, 40% ended up having a urinary tract infection,” Dr. Krieger noted. “This is a diagnosis easily ruled out in the emergency department with a simple urinalysis and culture, and this finding underscores the need for a basic evaluation in the emergency department in all MS patients.”

Investigators also found a high rate of misdiagnosis among patients with MS during emergency department visits.

TORONTO—The majority of emergency department visits for patients with multiple sclerosis (MS) are for medical comorbidities and complications indirectly related to MS, and not for neurologic problems, according to research presented at the 62nd Annual Meeting of the American Academy of Neurology (AAN). Investigators cautioned practitioners to avoid automatically ascribing symptoms of acutely ill patients to their underlying MS.

“MS is not simply a neurologic disease,” Megan Alcauskas, MD, and Stephen Krieger, MD, told Neurology Reviews. “It can have medical, urological, psychiatric, and other effects, and can touch almost all medical and surgical specialties.”

Drs. Krieger and Alcauskas and colleagues at the Corrine Goldsmith Dickinson Center for Multiple Sclerosis at the Mount Sinai School of Medicine, along with Svenja Oynhausen, MD, at University Hospital of Bonn, Germany, used a centralized, comprehensive database of patient visits to the emergency department of Mount Sinai Hospital in New York City between January 1, 2005, and December 31, 2007. The researchers identified 569 visits by 224 patients with MS as part of the Resource Utilization in MS (RESUMS) study. Slightly less than three-quarters of all emergency department visits (n = 424) were for nonneurologic complaints, while the remaining visits were for neurologic problems, including weakness, altered mental status, and sensory symptoms (see " Factors Affecting Frequent ER Use in MS Patients").

“Patients using the emergency department are more likely to be underinsured, have higher levels of disability, and are more likely to be undertreated with disease-modifying therapies [DMTs] than the general MS populations,” Dr. Oynhausen explained. “The acute care needs of patients change over the course of their disease, and as the disease progresses they are more likely to seek care for the comorbidities associated with MS than for relapses.”

Disability and DMTs

At each visit, a patient’s Expanded Disability Status Score (EDSS) was estimated to be either mild (less than 4), moderate (4 to 5.5), or severe (greater than 6) based on history, examination, and assistive device for ambulation. Although the majority of visits (63.8%) were made by patients with an EDSS in the severe range, the researchers noted that most emergency department visits “were attributable entirely to issues indirectly related to the MS diagnosis, such as urinary tract infections, falls, and indwelling hardware.” The majority of those with a mild or moderate EDSS also came to the emergency department for issues unrelated to MS, including abdominal pain, viral infections, respiratory problems, chest pain, or psychiatric issues.

“Our data show that the major proportion of MS patients seeking emergency department care suffer from nonneurologic, acute problems,” the investigators reported. “This validates the importance of interdisciplinary awareness of the medical needs within the MS population.”

Of the patients studied, 41.5% were taking DMTs, and slightly more than half of those with relapsing-remitting MS were taking DMTs. The majority of patients had either Medicaid or Medicare for insurance, 18.3% had private insurance, and 12.9% were uninsured. Half of all visits resulted in hospital admission, 54.7% of which were admissions to the medicine department and 25.6% were admissions to the neurology department.

Diagnostic Accuracy

A second part of the RESUMS study, also presented at the meeting, found that the accuracy of diagnoses made in the emergency department had room for improvement. In all, 42.1% of diagnoses were confirmed, 43.2% were modified, and 14.7% were altogether different.

“The emergency department is better at diagnosing nonneurologic problems than neurologic ones, even in a population of patients with a known diagnosis of relapsing neurologic illness,” Dr. Alcauskas and colleagues reported. “The emergency department was least accurate in diagnosing female patients presenting with neurologic complaints, a trend that has also been seen in the diagnosis of stroke patients.”

However, in men with neurologic complaints, the accuracy of diagnosis was similar to that of men presenting with nonneurologic complaints. The diagnostic accuracy was not significantly affected by patient age or EDSS scores.

As far as properly diagnosing an MS relapse, the emergency department diagnosed 55 relapses, 27 of which were false positives, and there were 10 false negatives, for a sensitivity of 76.7% and a specificity of 90.9%. The positive predictive value was 60%, and the negative predictive value was 95.6%.

Factors Affecting Frequent ER Use in MS Patients

SAN ANTONIO—One third of MS patient visits to the emergency department are by less than 10% of the patients, according to additional information from the RESUMS study presented at the 24th Annual Meeting of the Consortium for Multiple Sclerosis Centers. Using the same data set reported at AAN, Dr. Krieger and colleagues also reported that relapse accounted for only 13.2% of the visits and that one quarter of visits were for neurologic complaints.

“In the general population, it has been shown that frequent users of the emergency department strain the healthcare system, resulting in higher costs, overcrowding, and decreased quality of health care,” Drs. Krieger and Alcauskas reported.

During the three-year study period, 224 patients made 569 visits, with a mean of 2.5 visits among all patients. Twenty-one patients were defined as high-frequency users, with six or more visits each. The researchers found no significant difference in demographics between frequent and nonfrequent users; however, frequent users were more likely to have a longer disease duration and a history of psychiatric issues.

Frequent users were more likely than nonfrequent users to present with hardware malfunction, such as urinary catheters, urinary complaints, and fever.

“This study has identified several presentation-specific, and therefore, modifiable factors affecting high-frequency emergency department usage in the MS population,” the researchers wrote. “Unlike studies in other chronic medical conditions, no social or demographic factors were found to be significantly associated with high-frequency emergency department usage.”

Relapses constituted a small fraction of emergency department visits, representing just 13.2% of visits. Of the 75 visits in which patients presented with relapse, 43 were admissions to the hospital, with an average length of stay of 8.5 days. As noted in the study presented at AAN, emergency department doctors frequently misdiagnosed patients with MS as having a relapse or other neurologic event.

“Of patients thought to have MS relapses by the emergency department that turned out to be incorrectly diagnosed, 40% ended up having a urinary tract infection,” Dr. Krieger noted. “This is a diagnosis easily ruled out in the emergency department with a simple urinalysis and culture, and this finding underscores the need for a basic evaluation in the emergency department in all MS patients.”

Investigators also found a high rate of misdiagnosis among patients with MS during emergency department visits.

TORONTO—The majority of emergency department visits for patients with multiple sclerosis (MS) are for medical comorbidities and complications indirectly related to MS, and not for neurologic problems, according to research presented at the 62nd Annual Meeting of the American Academy of Neurology (AAN). Investigators cautioned practitioners to avoid automatically ascribing symptoms of acutely ill patients to their underlying MS.

“MS is not simply a neurologic disease,” Megan Alcauskas, MD, and Stephen Krieger, MD, told Neurology Reviews. “It can have medical, urological, psychiatric, and other effects, and can touch almost all medical and surgical specialties.”

Drs. Krieger and Alcauskas and colleagues at the Corrine Goldsmith Dickinson Center for Multiple Sclerosis at the Mount Sinai School of Medicine, along with Svenja Oynhausen, MD, at University Hospital of Bonn, Germany, used a centralized, comprehensive database of patient visits to the emergency department of Mount Sinai Hospital in New York City between January 1, 2005, and December 31, 2007. The researchers identified 569 visits by 224 patients with MS as part of the Resource Utilization in MS (RESUMS) study. Slightly less than three-quarters of all emergency department visits (n = 424) were for nonneurologic complaints, while the remaining visits were for neurologic problems, including weakness, altered mental status, and sensory symptoms (see " Factors Affecting Frequent ER Use in MS Patients").

“Patients using the emergency department are more likely to be underinsured, have higher levels of disability, and are more likely to be undertreated with disease-modifying therapies [DMTs] than the general MS populations,” Dr. Oynhausen explained. “The acute care needs of patients change over the course of their disease, and as the disease progresses they are more likely to seek care for the comorbidities associated with MS than for relapses.”

Disability and DMTs

At each visit, a patient’s Expanded Disability Status Score (EDSS) was estimated to be either mild (less than 4), moderate (4 to 5.5), or severe (greater than 6) based on history, examination, and assistive device for ambulation. Although the majority of visits (63.8%) were made by patients with an EDSS in the severe range, the researchers noted that most emergency department visits “were attributable entirely to issues indirectly related to the MS diagnosis, such as urinary tract infections, falls, and indwelling hardware.” The majority of those with a mild or moderate EDSS also came to the emergency department for issues unrelated to MS, including abdominal pain, viral infections, respiratory problems, chest pain, or psychiatric issues.

“Our data show that the major proportion of MS patients seeking emergency department care suffer from nonneurologic, acute problems,” the investigators reported. “This validates the importance of interdisciplinary awareness of the medical needs within the MS population.”

Of the patients studied, 41.5% were taking DMTs, and slightly more than half of those with relapsing-remitting MS were taking DMTs. The majority of patients had either Medicaid or Medicare for insurance, 18.3% had private insurance, and 12.9% were uninsured. Half of all visits resulted in hospital admission, 54.7% of which were admissions to the medicine department and 25.6% were admissions to the neurology department.

Diagnostic Accuracy

A second part of the RESUMS study, also presented at the meeting, found that the accuracy of diagnoses made in the emergency department had room for improvement. In all, 42.1% of diagnoses were confirmed, 43.2% were modified, and 14.7% were altogether different.

“The emergency department is better at diagnosing nonneurologic problems than neurologic ones, even in a population of patients with a known diagnosis of relapsing neurologic illness,” Dr. Alcauskas and colleagues reported. “The emergency department was least accurate in diagnosing female patients presenting with neurologic complaints, a trend that has also been seen in the diagnosis of stroke patients.”

However, in men with neurologic complaints, the accuracy of diagnosis was similar to that of men presenting with nonneurologic complaints. The diagnostic accuracy was not significantly affected by patient age or EDSS scores.

As far as properly diagnosing an MS relapse, the emergency department diagnosed 55 relapses, 27 of which were false positives, and there were 10 false negatives, for a sensitivity of 76.7% and a specificity of 90.9%. The positive predictive value was 60%, and the negative predictive value was 95.6%.

Factors Affecting Frequent ER Use in MS Patients

SAN ANTONIO—One third of MS patient visits to the emergency department are by less than 10% of the patients, according to additional information from the RESUMS study presented at the 24th Annual Meeting of the Consortium for Multiple Sclerosis Centers. Using the same data set reported at AAN, Dr. Krieger and colleagues also reported that relapse accounted for only 13.2% of the visits and that one quarter of visits were for neurologic complaints.

“In the general population, it has been shown that frequent users of the emergency department strain the healthcare system, resulting in higher costs, overcrowding, and decreased quality of health care,” Drs. Krieger and Alcauskas reported.

During the three-year study period, 224 patients made 569 visits, with a mean of 2.5 visits among all patients. Twenty-one patients were defined as high-frequency users, with six or more visits each. The researchers found no significant difference in demographics between frequent and nonfrequent users; however, frequent users were more likely to have a longer disease duration and a history of psychiatric issues.

Frequent users were more likely than nonfrequent users to present with hardware malfunction, such as urinary catheters, urinary complaints, and fever.

“This study has identified several presentation-specific, and therefore, modifiable factors affecting high-frequency emergency department usage in the MS population,” the researchers wrote. “Unlike studies in other chronic medical conditions, no social or demographic factors were found to be significantly associated with high-frequency emergency department usage.”

Relapses constituted a small fraction of emergency department visits, representing just 13.2% of visits. Of the 75 visits in which patients presented with relapse, 43 were admissions to the hospital, with an average length of stay of 8.5 days. As noted in the study presented at AAN, emergency department doctors frequently misdiagnosed patients with MS as having a relapse or other neurologic event.

“Of patients thought to have MS relapses by the emergency department that turned out to be incorrectly diagnosed, 40% ended up having a urinary tract infection,” Dr. Krieger noted. “This is a diagnosis easily ruled out in the emergency department with a simple urinalysis and culture, and this finding underscores the need for a basic evaluation in the emergency department in all MS patients.”