Literature Review

A panel of 10 lipid metabolites can predict the development of either amnestic mild cognitive impairment (aMCI) or Alzheimer’s disease within two to three years with 90% sensitivity and 90% specificity, according to an article published online ahead of print March 9 in Nature Medicine.

“The defined 10-metabolite profile features PCs [phosphatidylcholines] and ACs [acylcarnitines], phospholipids that have essential structural and functional roles in the integrity and functionality of cell membranes,” said Mark Mapstone, PhD, Associate Professor of Neurology at the University of Rochester Medical Center in New York.

Of the 525 healthy, community-dwelling individuals ages 70 and older enrolled in the observational study, 74 met the criteria for aMCI or mild Alzheimer’s disease during the five-year follow-up. Of these participants, 46 had incidental findings at study entry, and 28 developed cognitive problems during a mean period of 2.1 years.

In the third year of the study, the investigators conducted untargeted metabolomic and lipidomic analysis on blood samples from 53 participants with either aMCI or Alzheimer’s disease, including 18 converters, and 53 cognitively normal controls. Blood samples from the converters were taken before and after conversion.

Analysis revealed that several amino acids and phospholipids were present in significantly different quantities between the two groups, and a further targeted analysis showed that the converter group had significantly lower plasma levels of serotonin, phenylalanine, proline, lysine, PC, taurine, and AC.

Dr. Mapstone and his colleagues identified a set of 10 metabolites that comprised PCs, lysophosphatidylcholine, and ACs, which were each found at much lower levels in the plasma of the converter group before conversion than in the plasma of the cognitively normal group. APOE e4 allele status did not significantly affect the classification of converters to aMCI or Alzheimer’s disease or the normal controls.

“These metabolites remained depleted after phenoconversion to aMCI or Alzheimer’s disease ... and were similar to the levels in the aMCI or Alzheimer’s disease group,” reported the researchers.

“We posit that this 10-phospholipid biomarker panel, consisting of PC and AC species, reveals the breakdown of neural cell membranes in those individuals destined to phenoconvert from cognitive intactness to aMCI or Alzheimer’s disease and may mark the transition between preclinical states where synaptic dysfunction and early neurodegeneration give rise to subtle cognitive changes,” said Dr. Mapstone.

—Bianca Nogrady

A panel of 10 lipid metabolites can predict the development of either amnestic mild cognitive impairment (aMCI) or Alzheimer’s disease within two to three years with 90% sensitivity and 90% specificity, according to an article published online ahead of print March 9 in Nature Medicine.

“The defined 10-metabolite profile features PCs [phosphatidylcholines] and ACs [acylcarnitines], phospholipids that have essential structural and functional roles in the integrity and functionality of cell membranes,” said Mark Mapstone, PhD, Associate Professor of Neurology at the University of Rochester Medical Center in New York.

Of the 525 healthy, community-dwelling individuals ages 70 and older enrolled in the observational study, 74 met the criteria for aMCI or mild Alzheimer’s disease during the five-year follow-up. Of these participants, 46 had incidental findings at study entry, and 28 developed cognitive problems during a mean period of 2.1 years.

In the third year of the study, the investigators conducted untargeted metabolomic and lipidomic analysis on blood samples from 53 participants with either aMCI or Alzheimer’s disease, including 18 converters, and 53 cognitively normal controls. Blood samples from the converters were taken before and after conversion.

Analysis revealed that several amino acids and phospholipids were present in significantly different quantities between the two groups, and a further targeted analysis showed that the converter group had significantly lower plasma levels of serotonin, phenylalanine, proline, lysine, PC, taurine, and AC.

Dr. Mapstone and his colleagues identified a set of 10 metabolites that comprised PCs, lysophosphatidylcholine, and ACs, which were each found at much lower levels in the plasma of the converter group before conversion than in the plasma of the cognitively normal group. APOE e4 allele status did not significantly affect the classification of converters to aMCI or Alzheimer’s disease or the normal controls.

“These metabolites remained depleted after phenoconversion to aMCI or Alzheimer’s disease ... and were similar to the levels in the aMCI or Alzheimer’s disease group,” reported the researchers.

“We posit that this 10-phospholipid biomarker panel, consisting of PC and AC species, reveals the breakdown of neural cell membranes in those individuals destined to phenoconvert from cognitive intactness to aMCI or Alzheimer’s disease and may mark the transition between preclinical states where synaptic dysfunction and early neurodegeneration give rise to subtle cognitive changes,” said Dr. Mapstone.

—Bianca Nogrady

A panel of 10 lipid metabolites can predict the development of either amnestic mild cognitive impairment (aMCI) or Alzheimer’s disease within two to three years with 90% sensitivity and 90% specificity, according to an article published online ahead of print March 9 in Nature Medicine.

“The defined 10-metabolite profile features PCs [phosphatidylcholines] and ACs [acylcarnitines], phospholipids that have essential structural and functional roles in the integrity and functionality of cell membranes,” said Mark Mapstone, PhD, Associate Professor of Neurology at the University of Rochester Medical Center in New York.

Of the 525 healthy, community-dwelling individuals ages 70 and older enrolled in the observational study, 74 met the criteria for aMCI or mild Alzheimer’s disease during the five-year follow-up. Of these participants, 46 had incidental findings at study entry, and 28 developed cognitive problems during a mean period of 2.1 years.

In the third year of the study, the investigators conducted untargeted metabolomic and lipidomic analysis on blood samples from 53 participants with either aMCI or Alzheimer’s disease, including 18 converters, and 53 cognitively normal controls. Blood samples from the converters were taken before and after conversion.

Analysis revealed that several amino acids and phospholipids were present in significantly different quantities between the two groups, and a further targeted analysis showed that the converter group had significantly lower plasma levels of serotonin, phenylalanine, proline, lysine, PC, taurine, and AC.

Dr. Mapstone and his colleagues identified a set of 10 metabolites that comprised PCs, lysophosphatidylcholine, and ACs, which were each found at much lower levels in the plasma of the converter group before conversion than in the plasma of the cognitively normal group. APOE e4 allele status did not significantly affect the classification of converters to aMCI or Alzheimer’s disease or the normal controls.

“These metabolites remained depleted after phenoconversion to aMCI or Alzheimer’s disease ... and were similar to the levels in the aMCI or Alzheimer’s disease group,” reported the researchers.

“We posit that this 10-phospholipid biomarker panel, consisting of PC and AC species, reveals the breakdown of neural cell membranes in those individuals destined to phenoconvert from cognitive intactness to aMCI or Alzheimer’s disease and may mark the transition between preclinical states where synaptic dysfunction and early neurodegeneration give rise to subtle cognitive changes,” said Dr. Mapstone.

—Bianca Nogrady

Neuroimaging still is “substantially overused” for the outpatient treatment of headache, and its use is increasing despite the publication of numerous guidelines recommending against it in this patient population, according to a data analysis published online ahead of print March 17 in JAMA Internal Medicine.

Brian C. Callaghan, MD, Assistant Professor of Neurology at the University of Michigan in Ann Arbor, and his associates analyzed data from the National Ambulatory Medical Care Survey to characterize recent trends in the use of CT or MRI for routine headache visits to primary care physicians, neurologists, other specialists, and nonprimary care generalists from 2007 through 2010. The researchers identified 51.1 million headache visits, including 25.4 million for migraine.

Of all visits, 88% were by patients younger than 65. Approximately 78% of patients were female. Most visits were to primary care physicians (54.8%), followed by neurologists (20%), other specialists (12.9%), and nonprimary care generalists (12.4%).

Rate of Neuroimaging Has Nearly Tripled Since 1995
Clinicians ordered neuroimaging for 12.4% of outpatient headache visits and 9.8% of migraine visits annually. Headache neuroimaging use was higher if the headache or migraine diagnosis was listed as the primary diagnosis for the visit. The total cost of this imaging was approximately $1 billion each year. “Total neuroimaging expenditures were estimated at $3.9 billion over four years, including $1.5 billion from migraine visits,” said Dr. Callaghan.

The researchers found that the rate of neuroimaging increased from 5.1% of all annual headache visits in 1995 to 14.7% in 2010. This increase occurred despite the fact that since 2000, “multiple guidelines have recommended against routine neuroimaging in patients with headache because a serious intracranial pathologic condition is an uncommon cause.” Moreover, the yield of significant abnormalities on neuroimaging of headache patients ranges from 1% to 3%—a rate that is comparable to that in patients without headaches. As part of the American Board of Internal Medicine’s Choose Wisely campaign, the American College of Radiology listed imaging for uncomplicated headache as one of the top five things that physicians and patients should question.

“Perhaps guidelines have not curbed utilization because patients, as opposed to health care providers, may be the primary drivers of utilization,” said Dr. Callaghan. If so, efforts to better inform patients about unwarranted testing or to shift the costs of expensive, low-yield tests to patients may be more effective, he added.

“Given that headache neuroimaging is common, costly, and likely substantially overused, interventions to curb utilization of these tests have the potential to substantially reduce health care expenditures while improving guideline concordance. Therefore, optimizing headache neuroimaging practices should be a major national priority,” Dr. Callaghan concluded.

Physicians May Discuss With Patients the Dangers of Neuroimaging
The financial costs of unwarranted neuroimaging are substantial, “but the costs we should care most about as physicians are the unnecessary radiation ... and incidental findings that lead to unnecessary medical procedures and great anxiety on the part of our patients,” said Mitchell H. Katz, MD, Director of the Los Angeles County Department of Health Services and deputy editor of JAMA Internal Medicine, in an accompanying editorial.

Because professional guidelines appear to have a limited effect on the use of neuroimaging, “we need to focus more on educating our patients about headaches and the dangers of neuroimaging,” said Dr. Katz. “Signs to us that the headache does not require further evaluation (ie, no change in the nature of headache for multiple years) may mean to the patient that the headache is serious (ie, it must be serious because I have had these pains for many years). If a physician simply says, ‘You don’t need a scan,’ patients may think that the physician does not understand how great the pain is, or worse yet, that the physician is saving money for an insurance company.”

The clinician first should acknowledge that headaches are frightening, can be disabling, and can afflict patients for their entire lives, he explained. This reassures patients that their symptoms are taken seriously and makes them less fearful when the symptoms recur. The clinician also should explain that he or she does not want patients to have neuroimaging because of the dangers of radiation and incidental findings. “Most patients are reassured when they feel that their physician understands their condition and is working with them to develop a strategy for coping with the problem,” said Dr. Katz.

—Mary Ann Moon

Neuroimaging still is “substantially overused” for the outpatient treatment of headache, and its use is increasing despite the publication of numerous guidelines recommending against it in this patient population, according to a data analysis published online ahead of print March 17 in JAMA Internal Medicine.

Brian C. Callaghan, MD, Assistant Professor of Neurology at the University of Michigan in Ann Arbor, and his associates analyzed data from the National Ambulatory Medical Care Survey to characterize recent trends in the use of CT or MRI for routine headache visits to primary care physicians, neurologists, other specialists, and nonprimary care generalists from 2007 through 2010. The researchers identified 51.1 million headache visits, including 25.4 million for migraine.

Of all visits, 88% were by patients younger than 65. Approximately 78% of patients were female. Most visits were to primary care physicians (54.8%), followed by neurologists (20%), other specialists (12.9%), and nonprimary care generalists (12.4%).

Rate of Neuroimaging Has Nearly Tripled Since 1995
Clinicians ordered neuroimaging for 12.4% of outpatient headache visits and 9.8% of migraine visits annually. Headache neuroimaging use was higher if the headache or migraine diagnosis was listed as the primary diagnosis for the visit. The total cost of this imaging was approximately $1 billion each year. “Total neuroimaging expenditures were estimated at $3.9 billion over four years, including $1.5 billion from migraine visits,” said Dr. Callaghan.

The researchers found that the rate of neuroimaging increased from 5.1% of all annual headache visits in 1995 to 14.7% in 2010. This increase occurred despite the fact that since 2000, “multiple guidelines have recommended against routine neuroimaging in patients with headache because a serious intracranial pathologic condition is an uncommon cause.” Moreover, the yield of significant abnormalities on neuroimaging of headache patients ranges from 1% to 3%—a rate that is comparable to that in patients without headaches. As part of the American Board of Internal Medicine’s Choose Wisely campaign, the American College of Radiology listed imaging for uncomplicated headache as one of the top five things that physicians and patients should question.

“Perhaps guidelines have not curbed utilization because patients, as opposed to health care providers, may be the primary drivers of utilization,” said Dr. Callaghan. If so, efforts to better inform patients about unwarranted testing or to shift the costs of expensive, low-yield tests to patients may be more effective, he added.

“Given that headache neuroimaging is common, costly, and likely substantially overused, interventions to curb utilization of these tests have the potential to substantially reduce health care expenditures while improving guideline concordance. Therefore, optimizing headache neuroimaging practices should be a major national priority,” Dr. Callaghan concluded.

Physicians May Discuss With Patients the Dangers of Neuroimaging
The financial costs of unwarranted neuroimaging are substantial, “but the costs we should care most about as physicians are the unnecessary radiation ... and incidental findings that lead to unnecessary medical procedures and great anxiety on the part of our patients,” said Mitchell H. Katz, MD, Director of the Los Angeles County Department of Health Services and deputy editor of JAMA Internal Medicine, in an accompanying editorial.

Because professional guidelines appear to have a limited effect on the use of neuroimaging, “we need to focus more on educating our patients about headaches and the dangers of neuroimaging,” said Dr. Katz. “Signs to us that the headache does not require further evaluation (ie, no change in the nature of headache for multiple years) may mean to the patient that the headache is serious (ie, it must be serious because I have had these pains for many years). If a physician simply says, ‘You don’t need a scan,’ patients may think that the physician does not understand how great the pain is, or worse yet, that the physician is saving money for an insurance company.”

The clinician first should acknowledge that headaches are frightening, can be disabling, and can afflict patients for their entire lives, he explained. This reassures patients that their symptoms are taken seriously and makes them less fearful when the symptoms recur. The clinician also should explain that he or she does not want patients to have neuroimaging because of the dangers of radiation and incidental findings. “Most patients are reassured when they feel that their physician understands their condition and is working with them to develop a strategy for coping with the problem,” said Dr. Katz.

—Mary Ann Moon

Neuroimaging still is “substantially overused” for the outpatient treatment of headache, and its use is increasing despite the publication of numerous guidelines recommending against it in this patient population, according to a data analysis published online ahead of print March 17 in JAMA Internal Medicine.

Brian C. Callaghan, MD, Assistant Professor of Neurology at the University of Michigan in Ann Arbor, and his associates analyzed data from the National Ambulatory Medical Care Survey to characterize recent trends in the use of CT or MRI for routine headache visits to primary care physicians, neurologists, other specialists, and nonprimary care generalists from 2007 through 2010. The researchers identified 51.1 million headache visits, including 25.4 million for migraine.

Of all visits, 88% were by patients younger than 65. Approximately 78% of patients were female. Most visits were to primary care physicians (54.8%), followed by neurologists (20%), other specialists (12.9%), and nonprimary care generalists (12.4%).

Rate of Neuroimaging Has Nearly Tripled Since 1995
Clinicians ordered neuroimaging for 12.4% of outpatient headache visits and 9.8% of migraine visits annually. Headache neuroimaging use was higher if the headache or migraine diagnosis was listed as the primary diagnosis for the visit. The total cost of this imaging was approximately $1 billion each year. “Total neuroimaging expenditures were estimated at $3.9 billion over four years, including $1.5 billion from migraine visits,” said Dr. Callaghan.

The researchers found that the rate of neuroimaging increased from 5.1% of all annual headache visits in 1995 to 14.7% in 2010. This increase occurred despite the fact that since 2000, “multiple guidelines have recommended against routine neuroimaging in patients with headache because a serious intracranial pathologic condition is an uncommon cause.” Moreover, the yield of significant abnormalities on neuroimaging of headache patients ranges from 1% to 3%—a rate that is comparable to that in patients without headaches. As part of the American Board of Internal Medicine’s Choose Wisely campaign, the American College of Radiology listed imaging for uncomplicated headache as one of the top five things that physicians and patients should question.

“Perhaps guidelines have not curbed utilization because patients, as opposed to health care providers, may be the primary drivers of utilization,” said Dr. Callaghan. If so, efforts to better inform patients about unwarranted testing or to shift the costs of expensive, low-yield tests to patients may be more effective, he added.

“Given that headache neuroimaging is common, costly, and likely substantially overused, interventions to curb utilization of these tests have the potential to substantially reduce health care expenditures while improving guideline concordance. Therefore, optimizing headache neuroimaging practices should be a major national priority,” Dr. Callaghan concluded.

Physicians May Discuss With Patients the Dangers of Neuroimaging
The financial costs of unwarranted neuroimaging are substantial, “but the costs we should care most about as physicians are the unnecessary radiation ... and incidental findings that lead to unnecessary medical procedures and great anxiety on the part of our patients,” said Mitchell H. Katz, MD, Director of the Los Angeles County Department of Health Services and deputy editor of JAMA Internal Medicine, in an accompanying editorial.

Because professional guidelines appear to have a limited effect on the use of neuroimaging, “we need to focus more on educating our patients about headaches and the dangers of neuroimaging,” said Dr. Katz. “Signs to us that the headache does not require further evaluation (ie, no change in the nature of headache for multiple years) may mean to the patient that the headache is serious (ie, it must be serious because I have had these pains for many years). If a physician simply says, ‘You don’t need a scan,’ patients may think that the physician does not understand how great the pain is, or worse yet, that the physician is saving money for an insurance company.”

The clinician first should acknowledge that headaches are frightening, can be disabling, and can afflict patients for their entire lives, he explained. This reassures patients that their symptoms are taken seriously and makes them less fearful when the symptoms recur. The clinician also should explain that he or she does not want patients to have neuroimaging because of the dangers of radiation and incidental findings. “Most patients are reassured when they feel that their physician understands their condition and is working with them to develop a strategy for coping with the problem,” said Dr. Katz.

—Mary Ann Moon

Prehypertension is associated with an increased risk for stroke, researchers reported online ahead of print March 12 in Neurology. The risk was observed even in persons with low-range prehypertension, although it was largely influenced by high-range prehypertension, according to Yuli Huang, MD, and colleagues.

“The results were consistent across stroke type, stroke end point, age, study characteristics, follow-up duration, and ethnicity,” said Dr. Huang, a researcher in the Department of Cardiology, Nanfang Hospital, Southern Medical University in Guangzhou, China.

The findings are based on a meta-analysis of 19 prospective cohort studies that included 762,393 patients. All eligible studies that were analyzed had reported multivariate-adjusted relative risks (RRs) with 95% confidence intervals for the associations between stroke and prehypertension or its two subranges—low-range prehypertension (120–129/80–84 mm Hg) and high-range prehypertension (130–139/85–89 mm Hg). Subgroup analyses were conducted according to blood pressure ranges, stroke type, end point, age, sex, ethnicity, and study characteristics.

Six of the reviewed studies were from the United States or Europe, and 13 were from Asia. The prevalence of prehypertension among participants ranged from 25.2% to 54.2%, and the duration of follow-up ranged from four to 36 years. Three studies included only women.

The researchers found that prehypertension increased the risk of stroke (RR, 1.66), compared with the optimal blood pressure of less than 120/80 mm Hg. Secondary outcome analyses revealed that low-range prehypertension increased the risk of stroke (RR, 1.44), and the risk was greater for high-range prehypertension (RR, 1.95).

“Our results are supported by a meta-analysis recently published by our group, showing that even low-range prehypertension increased the risk of cardiovascular disease compared with optimal blood pressure, and the risk was higher in individuals with high-range prehypertension,” stated the investigators.

The researchers also noted that their findings “reaffirm the importance of the definition of ‘prehypertension’ rather than being ‘normal’ for individuals with blood pressure of 120–139/80–89 mm Hg.” Hypertension is defined as a blood pressure greater than or equal to 140/90 mm Hg.

“Considering the high incidence of prehypertension, up to 30%–50%, successful intervention in this large population could have a major public health impact,” stated Dr. Huang’s group. “Many placebo-controlled trials have been performed in cohorts with prehypertensive average blood pressure levels for the treatment of other conditions (eg, treatment of atherosclerosis and prevention of diabetes), and a meta-analysis of these studies showed that the risk of stroke was significantly decreased by antihypertensive therapy in individuals with prehypertension.”

The researchers advised health care professionals to recommend lifestyle changes to their patients who have prehypertension. “High-risk subpopulations with prehypertension, especially individuals with high-range prehypertension combined with other cardiovascular risk factors, should be considered for future controlled trials of pharmacologic treatment to prevent stroke,” concluded Dr. Huang.

—Colby Stong

Prehypertension is associated with an increased risk for stroke, researchers reported online ahead of print March 12 in Neurology. The risk was observed even in persons with low-range prehypertension, although it was largely influenced by high-range prehypertension, according to Yuli Huang, MD, and colleagues.

“The results were consistent across stroke type, stroke end point, age, study characteristics, follow-up duration, and ethnicity,” said Dr. Huang, a researcher in the Department of Cardiology, Nanfang Hospital, Southern Medical University in Guangzhou, China.

The findings are based on a meta-analysis of 19 prospective cohort studies that included 762,393 patients. All eligible studies that were analyzed had reported multivariate-adjusted relative risks (RRs) with 95% confidence intervals for the associations between stroke and prehypertension or its two subranges—low-range prehypertension (120–129/80–84 mm Hg) and high-range prehypertension (130–139/85–89 mm Hg). Subgroup analyses were conducted according to blood pressure ranges, stroke type, end point, age, sex, ethnicity, and study characteristics.

Six of the reviewed studies were from the United States or Europe, and 13 were from Asia. The prevalence of prehypertension among participants ranged from 25.2% to 54.2%, and the duration of follow-up ranged from four to 36 years. Three studies included only women.

The researchers found that prehypertension increased the risk of stroke (RR, 1.66), compared with the optimal blood pressure of less than 120/80 mm Hg. Secondary outcome analyses revealed that low-range prehypertension increased the risk of stroke (RR, 1.44), and the risk was greater for high-range prehypertension (RR, 1.95).

“Our results are supported by a meta-analysis recently published by our group, showing that even low-range prehypertension increased the risk of cardiovascular disease compared with optimal blood pressure, and the risk was higher in individuals with high-range prehypertension,” stated the investigators.

The researchers also noted that their findings “reaffirm the importance of the definition of ‘prehypertension’ rather than being ‘normal’ for individuals with blood pressure of 120–139/80–89 mm Hg.” Hypertension is defined as a blood pressure greater than or equal to 140/90 mm Hg.

“Considering the high incidence of prehypertension, up to 30%–50%, successful intervention in this large population could have a major public health impact,” stated Dr. Huang’s group. “Many placebo-controlled trials have been performed in cohorts with prehypertensive average blood pressure levels for the treatment of other conditions (eg, treatment of atherosclerosis and prevention of diabetes), and a meta-analysis of these studies showed that the risk of stroke was significantly decreased by antihypertensive therapy in individuals with prehypertension.”

The researchers advised health care professionals to recommend lifestyle changes to their patients who have prehypertension. “High-risk subpopulations with prehypertension, especially individuals with high-range prehypertension combined with other cardiovascular risk factors, should be considered for future controlled trials of pharmacologic treatment to prevent stroke,” concluded Dr. Huang.

—Colby Stong

Prehypertension is associated with an increased risk for stroke, researchers reported online ahead of print March 12 in Neurology. The risk was observed even in persons with low-range prehypertension, although it was largely influenced by high-range prehypertension, according to Yuli Huang, MD, and colleagues.

“The results were consistent across stroke type, stroke end point, age, study characteristics, follow-up duration, and ethnicity,” said Dr. Huang, a researcher in the Department of Cardiology, Nanfang Hospital, Southern Medical University in Guangzhou, China.

The findings are based on a meta-analysis of 19 prospective cohort studies that included 762,393 patients. All eligible studies that were analyzed had reported multivariate-adjusted relative risks (RRs) with 95% confidence intervals for the associations between stroke and prehypertension or its two subranges—low-range prehypertension (120–129/80–84 mm Hg) and high-range prehypertension (130–139/85–89 mm Hg). Subgroup analyses were conducted according to blood pressure ranges, stroke type, end point, age, sex, ethnicity, and study characteristics.

Six of the reviewed studies were from the United States or Europe, and 13 were from Asia. The prevalence of prehypertension among participants ranged from 25.2% to 54.2%, and the duration of follow-up ranged from four to 36 years. Three studies included only women.

The researchers found that prehypertension increased the risk of stroke (RR, 1.66), compared with the optimal blood pressure of less than 120/80 mm Hg. Secondary outcome analyses revealed that low-range prehypertension increased the risk of stroke (RR, 1.44), and the risk was greater for high-range prehypertension (RR, 1.95).

“Our results are supported by a meta-analysis recently published by our group, showing that even low-range prehypertension increased the risk of cardiovascular disease compared with optimal blood pressure, and the risk was higher in individuals with high-range prehypertension,” stated the investigators.

The researchers also noted that their findings “reaffirm the importance of the definition of ‘prehypertension’ rather than being ‘normal’ for individuals with blood pressure of 120–139/80–89 mm Hg.” Hypertension is defined as a blood pressure greater than or equal to 140/90 mm Hg.

“Considering the high incidence of prehypertension, up to 30%–50%, successful intervention in this large population could have a major public health impact,” stated Dr. Huang’s group. “Many placebo-controlled trials have been performed in cohorts with prehypertensive average blood pressure levels for the treatment of other conditions (eg, treatment of atherosclerosis and prevention of diabetes), and a meta-analysis of these studies showed that the risk of stroke was significantly decreased by antihypertensive therapy in individuals with prehypertension.”

The researchers advised health care professionals to recommend lifestyle changes to their patients who have prehypertension. “High-risk subpopulations with prehypertension, especially individuals with high-range prehypertension combined with other cardiovascular risk factors, should be considered for future controlled trials of pharmacologic treatment to prevent stroke,” concluded Dr. Huang.

—Colby Stong

Neither intensive blood pressure control nor intensive lipid management may slow cognitive decline in adults with long-standing type 2 diabetes, according to research published online ahead of print February 3 in JAMA Internal Medicine. Intensive blood pressure control, however, may be associated with a greater decrease in total brain volume, compared with standard therapy.

After 40 months, patients on intensive blood pressure treatment in the Memory in Diabetes (MIND) trial had significantly more decline in total brain volume than patients on a standard blood pressure control program. Interpreting this result will require much more study, said Jeff Williamson, MD, Chief of Gerontology and Geriatric Medicine at Wake Forest University in Winston-Salem, North Carolina, and his colleagues.

“Although a greater decline in total brain volume is associated with early cognitive impairment, a precursor to dementia, the long-term implications are unknown and remain a focus of ongoing investigation and analyses,” said Dr. Williamson. “Our finding suggests that total brain volume and white matter lesion burden cannot, to date, be used as surrogate markers for cognitive outcomes.”

A Substudy of the ACCORD Trial
The MIND trial was a substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study and encompassed 2,977 participants who were randomly assigned to receive either intensive glycemic treatment (with the goal of reducing hemoglobin A1c to less than 6.0%) or standard treatment (with the goal of reducing HbA1c to between 7.0% and 7.9%). Participants also were assigned to either intensive or standard lipid-lowering and blood pressure–lowering treatment arms.

In 2011, the investigators concluded that intensive glycemic management did not alter the trajectory of cognitive decline. They observed, however, that total brain volume had declined significantly less in the intensive therapy group. Therefore, the investigators suggested that structural changes were preceding cognitive decline and that a treatment difference might have emerged if the therapy had been extended. The point was moot, however; ACCORD was halted early because patients in the intensive-therapy group had increased overall mortality, increased hypoglycemic events, weight gain, and no evidence of cardiovascular benefit.

Focus on Prevention, Not Treatment
The newly published data focus on the blood pressure and lipid treatment arms of the MIND study. The two-by-two design randomized patients to intensive or standard blood pressure control (120 vs 140 mmHg), or to a statin plus fibrate or statin plus placebo treatment.

Cognition was assessed at baseline, at 20 months, and at 40 months. The main outcome measure was the Digit Symbol Substitution Test (DSST), which gauges psychomotor speed and working memory. Secondary measures included the Stoop Test, the Rey Auditory Verbal Learning Test, and the Mini-Mental State Exam.

By 40 months, the DSST scores had declined to similar extents in the standard and intensive treatment groups of the blood pressure and lipid cohorts. The investigators found no significant between-group differences in any of the other three cognitive measures.

A subset of patients (378 from the blood pressure arm and 236 from the lipid arm) also underwent MRI of the brain at baseline and at 40 months. Participants in the intensive blood pressure therapy group had a significantly lower total brain volume than did those in the standard therapy group. The mean difference between the groups was approximately 4.4 cm³. The researchers found no significant differences in brain volume in the lipid management cohort.

The investigators compared this finding with the MRI results of the glycemic control study, which had shown preserved brain volume to be associated with intensive management in the blood pressure and lipid therapy groups. “Participants receiving the combination of standard antihypertensive therapy and intensive glycemic control experienced approximately 50% of the decline in total brain volume observed in the other blood pressure trial groups,” noted the authors. The results seem to reinforce the idea that earlier is better when it comes to controlling the cognitive effects of diabetes, they added.

“During the past two decades, the belief that more intensive treatment strategies for controlling type 2 diabetes-related comorbidities, such as hyperglycemia, hyperlipidemia, and hypertension, would reduce clinical complications has driven large investment in new medications for this disease syndrome,” stated the researchers. “However, these results from the ACCORD MIND substudy, along with the other recent ACCORD results, make clear the decreasing returns of intensive medication-based therapy for advanced type 2 diabetes and add further evidence to the need for increased investment in disease prevention and early intervention.”

—Michele G. Sullivan

Neither intensive blood pressure control nor intensive lipid management may slow cognitive decline in adults with long-standing type 2 diabetes, according to research published online ahead of print February 3 in JAMA Internal Medicine. Intensive blood pressure control, however, may be associated with a greater decrease in total brain volume, compared with standard therapy.

After 40 months, patients on intensive blood pressure treatment in the Memory in Diabetes (MIND) trial had significantly more decline in total brain volume than patients on a standard blood pressure control program. Interpreting this result will require much more study, said Jeff Williamson, MD, Chief of Gerontology and Geriatric Medicine at Wake Forest University in Winston-Salem, North Carolina, and his colleagues.

“Although a greater decline in total brain volume is associated with early cognitive impairment, a precursor to dementia, the long-term implications are unknown and remain a focus of ongoing investigation and analyses,” said Dr. Williamson. “Our finding suggests that total brain volume and white matter lesion burden cannot, to date, be used as surrogate markers for cognitive outcomes.”

A Substudy of the ACCORD Trial
The MIND trial was a substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study and encompassed 2,977 participants who were randomly assigned to receive either intensive glycemic treatment (with the goal of reducing hemoglobin A1c to less than 6.0%) or standard treatment (with the goal of reducing HbA1c to between 7.0% and 7.9%). Participants also were assigned to either intensive or standard lipid-lowering and blood pressure–lowering treatment arms.

In 2011, the investigators concluded that intensive glycemic management did not alter the trajectory of cognitive decline. They observed, however, that total brain volume had declined significantly less in the intensive therapy group. Therefore, the investigators suggested that structural changes were preceding cognitive decline and that a treatment difference might have emerged if the therapy had been extended. The point was moot, however; ACCORD was halted early because patients in the intensive-therapy group had increased overall mortality, increased hypoglycemic events, weight gain, and no evidence of cardiovascular benefit.

Focus on Prevention, Not Treatment
The newly published data focus on the blood pressure and lipid treatment arms of the MIND study. The two-by-two design randomized patients to intensive or standard blood pressure control (120 vs 140 mmHg), or to a statin plus fibrate or statin plus placebo treatment.

Cognition was assessed at baseline, at 20 months, and at 40 months. The main outcome measure was the Digit Symbol Substitution Test (DSST), which gauges psychomotor speed and working memory. Secondary measures included the Stoop Test, the Rey Auditory Verbal Learning Test, and the Mini-Mental State Exam.

By 40 months, the DSST scores had declined to similar extents in the standard and intensive treatment groups of the blood pressure and lipid cohorts. The investigators found no significant between-group differences in any of the other three cognitive measures.

A subset of patients (378 from the blood pressure arm and 236 from the lipid arm) also underwent MRI of the brain at baseline and at 40 months. Participants in the intensive blood pressure therapy group had a significantly lower total brain volume than did those in the standard therapy group. The mean difference between the groups was approximately 4.4 cm³. The researchers found no significant differences in brain volume in the lipid management cohort.

The investigators compared this finding with the MRI results of the glycemic control study, which had shown preserved brain volume to be associated with intensive management in the blood pressure and lipid therapy groups. “Participants receiving the combination of standard antihypertensive therapy and intensive glycemic control experienced approximately 50% of the decline in total brain volume observed in the other blood pressure trial groups,” noted the authors. The results seem to reinforce the idea that earlier is better when it comes to controlling the cognitive effects of diabetes, they added.

“During the past two decades, the belief that more intensive treatment strategies for controlling type 2 diabetes-related comorbidities, such as hyperglycemia, hyperlipidemia, and hypertension, would reduce clinical complications has driven large investment in new medications for this disease syndrome,” stated the researchers. “However, these results from the ACCORD MIND substudy, along with the other recent ACCORD results, make clear the decreasing returns of intensive medication-based therapy for advanced type 2 diabetes and add further evidence to the need for increased investment in disease prevention and early intervention.”

—Michele G. Sullivan

Neither intensive blood pressure control nor intensive lipid management may slow cognitive decline in adults with long-standing type 2 diabetes, according to research published online ahead of print February 3 in JAMA Internal Medicine. Intensive blood pressure control, however, may be associated with a greater decrease in total brain volume, compared with standard therapy.

After 40 months, patients on intensive blood pressure treatment in the Memory in Diabetes (MIND) trial had significantly more decline in total brain volume than patients on a standard blood pressure control program. Interpreting this result will require much more study, said Jeff Williamson, MD, Chief of Gerontology and Geriatric Medicine at Wake Forest University in Winston-Salem, North Carolina, and his colleagues.

“Although a greater decline in total brain volume is associated with early cognitive impairment, a precursor to dementia, the long-term implications are unknown and remain a focus of ongoing investigation and analyses,” said Dr. Williamson. “Our finding suggests that total brain volume and white matter lesion burden cannot, to date, be used as surrogate markers for cognitive outcomes.”

A Substudy of the ACCORD Trial
The MIND trial was a substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study and encompassed 2,977 participants who were randomly assigned to receive either intensive glycemic treatment (with the goal of reducing hemoglobin A1c to less than 6.0%) or standard treatment (with the goal of reducing HbA1c to between 7.0% and 7.9%). Participants also were assigned to either intensive or standard lipid-lowering and blood pressure–lowering treatment arms.

In 2011, the investigators concluded that intensive glycemic management did not alter the trajectory of cognitive decline. They observed, however, that total brain volume had declined significantly less in the intensive therapy group. Therefore, the investigators suggested that structural changes were preceding cognitive decline and that a treatment difference might have emerged if the therapy had been extended. The point was moot, however; ACCORD was halted early because patients in the intensive-therapy group had increased overall mortality, increased hypoglycemic events, weight gain, and no evidence of cardiovascular benefit.

Focus on Prevention, Not Treatment
The newly published data focus on the blood pressure and lipid treatment arms of the MIND study. The two-by-two design randomized patients to intensive or standard blood pressure control (120 vs 140 mmHg), or to a statin plus fibrate or statin plus placebo treatment.

Cognition was assessed at baseline, at 20 months, and at 40 months. The main outcome measure was the Digit Symbol Substitution Test (DSST), which gauges psychomotor speed and working memory. Secondary measures included the Stoop Test, the Rey Auditory Verbal Learning Test, and the Mini-Mental State Exam.

By 40 months, the DSST scores had declined to similar extents in the standard and intensive treatment groups of the blood pressure and lipid cohorts. The investigators found no significant between-group differences in any of the other three cognitive measures.

A subset of patients (378 from the blood pressure arm and 236 from the lipid arm) also underwent MRI of the brain at baseline and at 40 months. Participants in the intensive blood pressure therapy group had a significantly lower total brain volume than did those in the standard therapy group. The mean difference between the groups was approximately 4.4 cm³. The researchers found no significant differences in brain volume in the lipid management cohort.

The investigators compared this finding with the MRI results of the glycemic control study, which had shown preserved brain volume to be associated with intensive management in the blood pressure and lipid therapy groups. “Participants receiving the combination of standard antihypertensive therapy and intensive glycemic control experienced approximately 50% of the decline in total brain volume observed in the other blood pressure trial groups,” noted the authors. The results seem to reinforce the idea that earlier is better when it comes to controlling the cognitive effects of diabetes, they added.

“During the past two decades, the belief that more intensive treatment strategies for controlling type 2 diabetes-related comorbidities, such as hyperglycemia, hyperlipidemia, and hypertension, would reduce clinical complications has driven large investment in new medications for this disease syndrome,” stated the researchers. “However, these results from the ACCORD MIND substudy, along with the other recent ACCORD results, make clear the decreasing returns of intensive medication-based therapy for advanced type 2 diabetes and add further evidence to the need for increased investment in disease prevention and early intervention.”

—Michele G. Sullivan

Teriflunomide significantly reduced the annualized relapse rate in patients with relapsing-remitting multiple sclerosis (MS) by more than one-third, compared with placebo, in the second of two large, randomized, phase III trials that have been conducted with the drug.

The latest study—Teriflunomide Oral in People With Relapsing Multiple Sclerosis (TOWER)—demonstrated that the 14-mg dose of teriflunomide produced a 36% relative risk reduction in the annualized relapse rate, compared with placebo. A 7-mg dose of the oral MS agent yielded a 22% relative risk reduction. Teriflunomide 14 mg, but not 7 mg, was also associated with a significantly lower sustained disability accumulation than placebo.

“These data support the use of teriflunomide as an initial therapy for patients with relapsing-remitting MS and as an option for patients who are unable to tolerate other disease-modifying therapies,” Christian Confavreux, MD, of the Université Claude Bernard Lyon 1 in France, and associates wrote online ahead of print January 22 in Lancet Neurology.

The TOWER trial involved 1,169 patients with relapsing-remitting MS who were randomized to treatment—408 were assigned to teriflunomide 14 mg, 372 to teriflunomide 7 mg, and 389 to placebo. The mean age of patients at study entry was approximately 38—slightly more than 80% were white, 15% were Asian, and 2% were black.

The annualized relapse rates were 0.50 for patients treated with placebo, 0.32 for patients treated with teriflunomide 14 mg, and 0.39 for those treated with teriflunomide 7 mg. Absolute risk reductions for teriflunomide 14 mg and 7 mg versus placebo were –0.11 and –0.18, respectively.

A key secondary end point was sustained accumulation of disability. This outcome was defined as an increase of at least 1 point on the Expanded Disability Status Scale from baseline that persisted for at least 12 weeks. The hazard ratios for the time to sustained accumulation of disability were 0.68 for the 14-mg dose of teriflunomide and 0.95 for the 7-mg dose versus placebo.

“The safety and tolerability profile of teriflunomide ... was similar for both the 7-mg and 14-mg doses, including long-term treatment observations,” the investigators wrote. Common side effects in patients treated with teriflunomide were hair thinning and headache.

—Sara Freeman

Teriflunomide significantly reduced the annualized relapse rate in patients with relapsing-remitting multiple sclerosis (MS) by more than one-third, compared with placebo, in the second of two large, randomized, phase III trials that have been conducted with the drug.

The latest study—Teriflunomide Oral in People With Relapsing Multiple Sclerosis (TOWER)—demonstrated that the 14-mg dose of teriflunomide produced a 36% relative risk reduction in the annualized relapse rate, compared with placebo. A 7-mg dose of the oral MS agent yielded a 22% relative risk reduction. Teriflunomide 14 mg, but not 7 mg, was also associated with a significantly lower sustained disability accumulation than placebo.

“These data support the use of teriflunomide as an initial therapy for patients with relapsing-remitting MS and as an option for patients who are unable to tolerate other disease-modifying therapies,” Christian Confavreux, MD, of the Université Claude Bernard Lyon 1 in France, and associates wrote online ahead of print January 22 in Lancet Neurology.

The TOWER trial involved 1,169 patients with relapsing-remitting MS who were randomized to treatment—408 were assigned to teriflunomide 14 mg, 372 to teriflunomide 7 mg, and 389 to placebo. The mean age of patients at study entry was approximately 38—slightly more than 80% were white, 15% were Asian, and 2% were black.

The annualized relapse rates were 0.50 for patients treated with placebo, 0.32 for patients treated with teriflunomide 14 mg, and 0.39 for those treated with teriflunomide 7 mg. Absolute risk reductions for teriflunomide 14 mg and 7 mg versus placebo were –0.11 and –0.18, respectively.

A key secondary end point was sustained accumulation of disability. This outcome was defined as an increase of at least 1 point on the Expanded Disability Status Scale from baseline that persisted for at least 12 weeks. The hazard ratios for the time to sustained accumulation of disability were 0.68 for the 14-mg dose of teriflunomide and 0.95 for the 7-mg dose versus placebo.

“The safety and tolerability profile of teriflunomide ... was similar for both the 7-mg and 14-mg doses, including long-term treatment observations,” the investigators wrote. Common side effects in patients treated with teriflunomide were hair thinning and headache.

—Sara Freeman

Teriflunomide significantly reduced the annualized relapse rate in patients with relapsing-remitting multiple sclerosis (MS) by more than one-third, compared with placebo, in the second of two large, randomized, phase III trials that have been conducted with the drug.

The latest study—Teriflunomide Oral in People With Relapsing Multiple Sclerosis (TOWER)—demonstrated that the 14-mg dose of teriflunomide produced a 36% relative risk reduction in the annualized relapse rate, compared with placebo. A 7-mg dose of the oral MS agent yielded a 22% relative risk reduction. Teriflunomide 14 mg, but not 7 mg, was also associated with a significantly lower sustained disability accumulation than placebo.

“These data support the use of teriflunomide as an initial therapy for patients with relapsing-remitting MS and as an option for patients who are unable to tolerate other disease-modifying therapies,” Christian Confavreux, MD, of the Université Claude Bernard Lyon 1 in France, and associates wrote online ahead of print January 22 in Lancet Neurology.

The TOWER trial involved 1,169 patients with relapsing-remitting MS who were randomized to treatment—408 were assigned to teriflunomide 14 mg, 372 to teriflunomide 7 mg, and 389 to placebo. The mean age of patients at study entry was approximately 38—slightly more than 80% were white, 15% were Asian, and 2% were black.

The annualized relapse rates were 0.50 for patients treated with placebo, 0.32 for patients treated with teriflunomide 14 mg, and 0.39 for those treated with teriflunomide 7 mg. Absolute risk reductions for teriflunomide 14 mg and 7 mg versus placebo were –0.11 and –0.18, respectively.

A key secondary end point was sustained accumulation of disability. This outcome was defined as an increase of at least 1 point on the Expanded Disability Status Scale from baseline that persisted for at least 12 weeks. The hazard ratios for the time to sustained accumulation of disability were 0.68 for the 14-mg dose of teriflunomide and 0.95 for the 7-mg dose versus placebo.

“The safety and tolerability profile of teriflunomide ... was similar for both the 7-mg and 14-mg doses, including long-term treatment observations,” the investigators wrote. Common side effects in patients treated with teriflunomide were hair thinning and headache.

—Sara Freeman

Two investigational immunotherapies for Alzheimer’s disease failed to show any benefit in a series of phase III trials involving more than 4,000 patients, according to data published in the January 23 issue of the New England Journal of Medicine. Neither bapineuzumab, which targets soluble and aggregated amyloid-beta, nor solanezumab, which targets soluble amyloid-beta, achieved the primary end points in their overall cohorts.

No clinical gains were detected with either drug on the primary end points of change in the 11- or 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale and the Disability Assessment for Dementia. In addition, no gains were detected on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale.

Bapineuzumab May Reduce Amyloid Plaque Burden
The two bapineuzumab studies were 78 weeks long and were completed in 2012. Pfizer, which was developing the drug in collaboration with Janssen Alzheimer Immunotherapy, released top-line results in July 2012. A few weeks later, the company canceled the entire bapineuzumab development program.

The newly published bapineuzumab studies contain all of the final data, including several a priori subanalyses that were designed to identify possible treatment effects. Although bapineuzumab did not show any clinical benefits, it did apparently act on its main target: brain plaques composed of aggregated amyloid-beta. In one trial involving patients who carried the high-risk APOE ε4 allele, PET brain scans with Pittsburgh compound B showed no increase in amyloid-beta plaque burden in bapineuzumab-treated patients. In contrast, participants who had placebo infusions had increases in amyloid-beta plaque burden.

APOE ε4 carriers also showed significant changes in two biomarkers of plaque dissolution. In one trial, phosphorylated tau, a marker of neuronal damage, decreased in serum and CSF among patients treated with bapineuzumab. Amyloid-beta in CSF increased among these patients, suggesting that the protein bound in plaques was being freed. In the other trial, noncarriers did not show these changes.

Amyloid-related imaging abnormalities with edema occurred in as much as 27% of APOE ε4 carriers, depending on their zygosity. It also appeared in as much as 14% of noncarriers; the relationship was dose-dependent.

Solanezumab May Benefit Patients With Mild Disease
The findings were similar in the two studies of solanezumab. EXPEDITION 1 and EXPEDITION 2 each lasted 18 months and included approximately 2,000 patients. Results initially were reported at the 2013 Alzheimer’s Association International Conference.

More detail is available in the new study, including numerous biomarker findings. Solanezumab increased amyloid-beta in plasma and CSF, which indicates that the protein was no longer accumulating in the brain. These findings, however, were not consistently significant in either of the two studies.

Solanezumab did not have any significant effect on plaque burden or brain pathophysiology. Because it is designed to prevent plaques from forming, investigators did not expect that it would attack existing plaques.

In addition, the drug provided no cognitive or functional gains. In contrast with bapineuzumab, a signal of benefit with solanezumab in patients with mild disease prompted the launch of the EXPEDITION 3 trial. The study is now recruiting patients who have cognitive changes consistent with Alzheimer’s disease and brain plaques detected with 18F-florbetapir amyloid-beta imaging.

These more stringent entry requirements should ensure the enrollment of an appropriate cohort. Investigators who conducted previous EXPEDITION studies said that as many as 25% of patients enrolled with mild Alzheimer’s disease did not actually have Alzheimer’s disease. This factor could have diluted or negated any treatment effect, according to the investigators.

Potential Regulatory Pathways for Solanezumab
If EXPEDITION 3 can complement the potentially positive biomarker data for solanezumab with a positive clinical benefit, the drug might have a future as a preventive agent, said Samuel E. Gandy, MD, PhD, Professor of Neurology at Mount Sinai Hospital in New York City. “Perhaps the most discouraging bottom line here is the absence of an obvious relationship between biomarker trends and hints at benefit,” he added. Dr. Gandy was not involved in the four studies.

“There are currently two pathways to FDA registration of a new Alzheimer’s drug,” he continued. The first pathway is proof of cognitive and functional benefit. “Since solanezumab has failed to meet that bar in multiple studies, that avenue is extremely unlikely.”

The second pathway is approval as a preventive agent, which means providing biomarker and neuropsychologic benefit. “This seems the more attractive pathway until we consider the dissociation between biomarker benefit and clinical benefit. If the two do not go hand in hand, it is hard to imagine that the FDA would be supportive,” concluded Dr. Gandy.

—Michele G. Sullivan

Two investigational immunotherapies for Alzheimer’s disease failed to show any benefit in a series of phase III trials involving more than 4,000 patients, according to data published in the January 23 issue of the New England Journal of Medicine. Neither bapineuzumab, which targets soluble and aggregated amyloid-beta, nor solanezumab, which targets soluble amyloid-beta, achieved the primary end points in their overall cohorts.

No clinical gains were detected with either drug on the primary end points of change in the 11- or 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale and the Disability Assessment for Dementia. In addition, no gains were detected on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale.

Bapineuzumab May Reduce Amyloid Plaque Burden
The two bapineuzumab studies were 78 weeks long and were completed in 2012. Pfizer, which was developing the drug in collaboration with Janssen Alzheimer Immunotherapy, released top-line results in July 2012. A few weeks later, the company canceled the entire bapineuzumab development program.

The newly published bapineuzumab studies contain all of the final data, including several a priori subanalyses that were designed to identify possible treatment effects. Although bapineuzumab did not show any clinical benefits, it did apparently act on its main target: brain plaques composed of aggregated amyloid-beta. In one trial involving patients who carried the high-risk APOE ε4 allele, PET brain scans with Pittsburgh compound B showed no increase in amyloid-beta plaque burden in bapineuzumab-treated patients. In contrast, participants who had placebo infusions had increases in amyloid-beta plaque burden.

APOE ε4 carriers also showed significant changes in two biomarkers of plaque dissolution. In one trial, phosphorylated tau, a marker of neuronal damage, decreased in serum and CSF among patients treated with bapineuzumab. Amyloid-beta in CSF increased among these patients, suggesting that the protein bound in plaques was being freed. In the other trial, noncarriers did not show these changes.

Amyloid-related imaging abnormalities with edema occurred in as much as 27% of APOE ε4 carriers, depending on their zygosity. It also appeared in as much as 14% of noncarriers; the relationship was dose-dependent.

Solanezumab May Benefit Patients With Mild Disease
The findings were similar in the two studies of solanezumab. EXPEDITION 1 and EXPEDITION 2 each lasted 18 months and included approximately 2,000 patients. Results initially were reported at the 2013 Alzheimer’s Association International Conference.

More detail is available in the new study, including numerous biomarker findings. Solanezumab increased amyloid-beta in plasma and CSF, which indicates that the protein was no longer accumulating in the brain. These findings, however, were not consistently significant in either of the two studies.

Solanezumab did not have any significant effect on plaque burden or brain pathophysiology. Because it is designed to prevent plaques from forming, investigators did not expect that it would attack existing plaques.

In addition, the drug provided no cognitive or functional gains. In contrast with bapineuzumab, a signal of benefit with solanezumab in patients with mild disease prompted the launch of the EXPEDITION 3 trial. The study is now recruiting patients who have cognitive changes consistent with Alzheimer’s disease and brain plaques detected with 18F-florbetapir amyloid-beta imaging.

These more stringent entry requirements should ensure the enrollment of an appropriate cohort. Investigators who conducted previous EXPEDITION studies said that as many as 25% of patients enrolled with mild Alzheimer’s disease did not actually have Alzheimer’s disease. This factor could have diluted or negated any treatment effect, according to the investigators.

Potential Regulatory Pathways for Solanezumab
If EXPEDITION 3 can complement the potentially positive biomarker data for solanezumab with a positive clinical benefit, the drug might have a future as a preventive agent, said Samuel E. Gandy, MD, PhD, Professor of Neurology at Mount Sinai Hospital in New York City. “Perhaps the most discouraging bottom line here is the absence of an obvious relationship between biomarker trends and hints at benefit,” he added. Dr. Gandy was not involved in the four studies.

“There are currently two pathways to FDA registration of a new Alzheimer’s drug,” he continued. The first pathway is proof of cognitive and functional benefit. “Since solanezumab has failed to meet that bar in multiple studies, that avenue is extremely unlikely.”

The second pathway is approval as a preventive agent, which means providing biomarker and neuropsychologic benefit. “This seems the more attractive pathway until we consider the dissociation between biomarker benefit and clinical benefit. If the two do not go hand in hand, it is hard to imagine that the FDA would be supportive,” concluded Dr. Gandy.

—Michele G. Sullivan

Two investigational immunotherapies for Alzheimer’s disease failed to show any benefit in a series of phase III trials involving more than 4,000 patients, according to data published in the January 23 issue of the New England Journal of Medicine. Neither bapineuzumab, which targets soluble and aggregated amyloid-beta, nor solanezumab, which targets soluble amyloid-beta, achieved the primary end points in their overall cohorts.

No clinical gains were detected with either drug on the primary end points of change in the 11- or 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale and the Disability Assessment for Dementia. In addition, no gains were detected on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale.

Bapineuzumab May Reduce Amyloid Plaque Burden
The two bapineuzumab studies were 78 weeks long and were completed in 2012. Pfizer, which was developing the drug in collaboration with Janssen Alzheimer Immunotherapy, released top-line results in July 2012. A few weeks later, the company canceled the entire bapineuzumab development program.

The newly published bapineuzumab studies contain all of the final data, including several a priori subanalyses that were designed to identify possible treatment effects. Although bapineuzumab did not show any clinical benefits, it did apparently act on its main target: brain plaques composed of aggregated amyloid-beta. In one trial involving patients who carried the high-risk APOE ε4 allele, PET brain scans with Pittsburgh compound B showed no increase in amyloid-beta plaque burden in bapineuzumab-treated patients. In contrast, participants who had placebo infusions had increases in amyloid-beta plaque burden.

APOE ε4 carriers also showed significant changes in two biomarkers of plaque dissolution. In one trial, phosphorylated tau, a marker of neuronal damage, decreased in serum and CSF among patients treated with bapineuzumab. Amyloid-beta in CSF increased among these patients, suggesting that the protein bound in plaques was being freed. In the other trial, noncarriers did not show these changes.

Amyloid-related imaging abnormalities with edema occurred in as much as 27% of APOE ε4 carriers, depending on their zygosity. It also appeared in as much as 14% of noncarriers; the relationship was dose-dependent.

Solanezumab May Benefit Patients With Mild Disease
The findings were similar in the two studies of solanezumab. EXPEDITION 1 and EXPEDITION 2 each lasted 18 months and included approximately 2,000 patients. Results initially were reported at the 2013 Alzheimer’s Association International Conference.

More detail is available in the new study, including numerous biomarker findings. Solanezumab increased amyloid-beta in plasma and CSF, which indicates that the protein was no longer accumulating in the brain. These findings, however, were not consistently significant in either of the two studies.

Solanezumab did not have any significant effect on plaque burden or brain pathophysiology. Because it is designed to prevent plaques from forming, investigators did not expect that it would attack existing plaques.

In addition, the drug provided no cognitive or functional gains. In contrast with bapineuzumab, a signal of benefit with solanezumab in patients with mild disease prompted the launch of the EXPEDITION 3 trial. The study is now recruiting patients who have cognitive changes consistent with Alzheimer’s disease and brain plaques detected with 18F-florbetapir amyloid-beta imaging.

These more stringent entry requirements should ensure the enrollment of an appropriate cohort. Investigators who conducted previous EXPEDITION studies said that as many as 25% of patients enrolled with mild Alzheimer’s disease did not actually have Alzheimer’s disease. This factor could have diluted or negated any treatment effect, according to the investigators.

Potential Regulatory Pathways for Solanezumab
If EXPEDITION 3 can complement the potentially positive biomarker data for solanezumab with a positive clinical benefit, the drug might have a future as a preventive agent, said Samuel E. Gandy, MD, PhD, Professor of Neurology at Mount Sinai Hospital in New York City. “Perhaps the most discouraging bottom line here is the absence of an obvious relationship between biomarker trends and hints at benefit,” he added. Dr. Gandy was not involved in the four studies.

“There are currently two pathways to FDA registration of a new Alzheimer’s drug,” he continued. The first pathway is proof of cognitive and functional benefit. “Since solanezumab has failed to meet that bar in multiple studies, that avenue is extremely unlikely.”

The second pathway is approval as a preventive agent, which means providing biomarker and neuropsychologic benefit. “This seems the more attractive pathway until we consider the dissociation between biomarker benefit and clinical benefit. If the two do not go hand in hand, it is hard to imagine that the FDA would be supportive,” concluded Dr. Gandy.

—Michele G. Sullivan

Video EEG may be more likely to capture an event of interest if a patient has had frequent past events, if the last event was within 24 hours of admission, and if the patient has an intellectual disability, according to a retrospective study published online ahead of print January 27 in Pediatric Neurology. Video EEG probably would not be as informative for developmentally normal children or for children who have less frequent events with more time between them, said Elaine C. Wirrell, MD, Professor of Neurology at Mayo Medical School in Rochester, Minnesota.

The study examined 213 children who underwent prolonged inpatient monitoring at one institution during a recent three-year period. Its findings can help neurologists counsel families about the likelihood of having a successful admission. The research also could prompt neurologists to suggest that patients and their caregivers try to capture an event on their own, said Dr. Wirrell.

“The utility of [video EEG] monitoring for events that do not occur at least on a weekly basis is limited, even in the context of identifiable provocative factors,” she explained. “With the ubiquity of cellular phone video cameras, asking parents to make a recording of a rare event when it occurs in vivo so that a child neurologist may review it in conjunction with the remainder of the clinical history and a routine EEG may be higher yield than video EEG monitoring, at least as an initial step.”

High-Frequency Events Were More Likely to Be Recorded
The children’s (ages 2 to 13) inpatient stays were intended to capture physical events related to EEG changes. The median recording duration was 25 hours, and the length of recordings ranged from 22 to 48 hours.

The monitoring captured at least one event in 66% of the children at a median monitoring duration of 4.5 hours. The median time to capturing an EEG-related event was directly related to how often the events occurred before admission. For children who had daily events, the median time to capture an event was approximately four hours. For children who had events at least three times per week, the median time to capture an event was 24 hours. For children who had events once or twice per week, the median time to capture an event was 23 hours. The median time to capture an event was approximately eight hours for children whose events occurred less than once per week.

The events that occurred most frequently (ie, at least three times per week) were recorded during admission 72% of the time. The recording rate was 41% for events that occurred at frequencies ranging from less than three times per week to once monthly. The recording rate was 26% for events that occurred less than once monthly.

In general, the sooner a child was brought in for monitoring, the more successful the procedure. The median time to capture an event was almost four hours if the previous event had happened less than 24 hours before admission, compared with 22.4 hours if the previous event had happened between 24 and 72 hours before admission, and 22.7 hours if it had occurred between 72 hours and one week before admission. But the median time to capture an event was approximately 15 hours if the previous event had occurred more than one week before admission.

Events were captured 71% of the time when the previous event had occurred less than 24 hours before admission. The capture rate was 52% when the previous event had occurred between 24 and 72 hours before admission and 32% when it had occurred more than 72 hours before admission. The highest preadmission event frequency significantly increased the chance of capturing an event (odds ratio [OR], 3.77), as did the shortest event latency (OR, 2.31).

Dosing Changes May Decrease the Likelihood of Successful Monitoring
Intellectual disability in the patient significantly increased the likelihood of capturing an EEG-related event (OR, 3.26). But the common practices of sleep deprivation and antiepileptic medication withdrawal did not increase the likelihood of capturing one, said Dr. Wirrell. Medication withdrawal or dose change decreased the chance of an event capture (OR, 0.46).

That finding “came as a surprise,” the investigators noted. Its significance is uncertain, however, because it was not a prespecified outcome, and not many patients were in these subgroups. “It typically takes five half-lives to reach a new steady state of each medication adjustment,” said Dr. Wirrell. “Therefore, depending on the half-life duration of the medications, levels may not become subtherapeutic for several days after discontinuation or dose reduction.”

A family history of epilepsy, a prior interictal discharge on routine EEG, and a prior diagnosis of possible epilepsy also significantly increased the chance that a captured event would be EEG related. This result suggests a need for greater urgency in arranging video EEG monitoring for patients with these characteristics “to make the diagnosis and promptly initiate antiepileptic treatment,” Dr. Wirrell concluded.

—Michele G. Sullivan

Video EEG may be more likely to capture an event of interest if a patient has had frequent past events, if the last event was within 24 hours of admission, and if the patient has an intellectual disability, according to a retrospective study published online ahead of print January 27 in Pediatric Neurology. Video EEG probably would not be as informative for developmentally normal children or for children who have less frequent events with more time between them, said Elaine C. Wirrell, MD, Professor of Neurology at Mayo Medical School in Rochester, Minnesota.

The study examined 213 children who underwent prolonged inpatient monitoring at one institution during a recent three-year period. Its findings can help neurologists counsel families about the likelihood of having a successful admission. The research also could prompt neurologists to suggest that patients and their caregivers try to capture an event on their own, said Dr. Wirrell.

“The utility of [video EEG] monitoring for events that do not occur at least on a weekly basis is limited, even in the context of identifiable provocative factors,” she explained. “With the ubiquity of cellular phone video cameras, asking parents to make a recording of a rare event when it occurs in vivo so that a child neurologist may review it in conjunction with the remainder of the clinical history and a routine EEG may be higher yield than video EEG monitoring, at least as an initial step.”

High-Frequency Events Were More Likely to Be Recorded
The children’s (ages 2 to 13) inpatient stays were intended to capture physical events related to EEG changes. The median recording duration was 25 hours, and the length of recordings ranged from 22 to 48 hours.

The monitoring captured at least one event in 66% of the children at a median monitoring duration of 4.5 hours. The median time to capturing an EEG-related event was directly related to how often the events occurred before admission. For children who had daily events, the median time to capture an event was approximately four hours. For children who had events at least three times per week, the median time to capture an event was 24 hours. For children who had events once or twice per week, the median time to capture an event was 23 hours. The median time to capture an event was approximately eight hours for children whose events occurred less than once per week.

The events that occurred most frequently (ie, at least three times per week) were recorded during admission 72% of the time. The recording rate was 41% for events that occurred at frequencies ranging from less than three times per week to once monthly. The recording rate was 26% for events that occurred less than once monthly.

In general, the sooner a child was brought in for monitoring, the more successful the procedure. The median time to capture an event was almost four hours if the previous event had happened less than 24 hours before admission, compared with 22.4 hours if the previous event had happened between 24 and 72 hours before admission, and 22.7 hours if it had occurred between 72 hours and one week before admission. But the median time to capture an event was approximately 15 hours if the previous event had occurred more than one week before admission.

Events were captured 71% of the time when the previous event had occurred less than 24 hours before admission. The capture rate was 52% when the previous event had occurred between 24 and 72 hours before admission and 32% when it had occurred more than 72 hours before admission. The highest preadmission event frequency significantly increased the chance of capturing an event (odds ratio [OR], 3.77), as did the shortest event latency (OR, 2.31).

Dosing Changes May Decrease the Likelihood of Successful Monitoring
Intellectual disability in the patient significantly increased the likelihood of capturing an EEG-related event (OR, 3.26). But the common practices of sleep deprivation and antiepileptic medication withdrawal did not increase the likelihood of capturing one, said Dr. Wirrell. Medication withdrawal or dose change decreased the chance of an event capture (OR, 0.46).

That finding “came as a surprise,” the investigators noted. Its significance is uncertain, however, because it was not a prespecified outcome, and not many patients were in these subgroups. “It typically takes five half-lives to reach a new steady state of each medication adjustment,” said Dr. Wirrell. “Therefore, depending on the half-life duration of the medications, levels may not become subtherapeutic for several days after discontinuation or dose reduction.”

A family history of epilepsy, a prior interictal discharge on routine EEG, and a prior diagnosis of possible epilepsy also significantly increased the chance that a captured event would be EEG related. This result suggests a need for greater urgency in arranging video EEG monitoring for patients with these characteristics “to make the diagnosis and promptly initiate antiepileptic treatment,” Dr. Wirrell concluded.

—Michele G. Sullivan

Video EEG may be more likely to capture an event of interest if a patient has had frequent past events, if the last event was within 24 hours of admission, and if the patient has an intellectual disability, according to a retrospective study published online ahead of print January 27 in Pediatric Neurology. Video EEG probably would not be as informative for developmentally normal children or for children who have less frequent events with more time between them, said Elaine C. Wirrell, MD, Professor of Neurology at Mayo Medical School in Rochester, Minnesota.

The study examined 213 children who underwent prolonged inpatient monitoring at one institution during a recent three-year period. Its findings can help neurologists counsel families about the likelihood of having a successful admission. The research also could prompt neurologists to suggest that patients and their caregivers try to capture an event on their own, said Dr. Wirrell.

“The utility of [video EEG] monitoring for events that do not occur at least on a weekly basis is limited, even in the context of identifiable provocative factors,” she explained. “With the ubiquity of cellular phone video cameras, asking parents to make a recording of a rare event when it occurs in vivo so that a child neurologist may review it in conjunction with the remainder of the clinical history and a routine EEG may be higher yield than video EEG monitoring, at least as an initial step.”

High-Frequency Events Were More Likely to Be Recorded
The children’s (ages 2 to 13) inpatient stays were intended to capture physical events related to EEG changes. The median recording duration was 25 hours, and the length of recordings ranged from 22 to 48 hours.

The monitoring captured at least one event in 66% of the children at a median monitoring duration of 4.5 hours. The median time to capturing an EEG-related event was directly related to how often the events occurred before admission. For children who had daily events, the median time to capture an event was approximately four hours. For children who had events at least three times per week, the median time to capture an event was 24 hours. For children who had events once or twice per week, the median time to capture an event was 23 hours. The median time to capture an event was approximately eight hours for children whose events occurred less than once per week.

The events that occurred most frequently (ie, at least three times per week) were recorded during admission 72% of the time. The recording rate was 41% for events that occurred at frequencies ranging from less than three times per week to once monthly. The recording rate was 26% for events that occurred less than once monthly.

In general, the sooner a child was brought in for monitoring, the more successful the procedure. The median time to capture an event was almost four hours if the previous event had happened less than 24 hours before admission, compared with 22.4 hours if the previous event had happened between 24 and 72 hours before admission, and 22.7 hours if it had occurred between 72 hours and one week before admission. But the median time to capture an event was approximately 15 hours if the previous event had occurred more than one week before admission.

Events were captured 71% of the time when the previous event had occurred less than 24 hours before admission. The capture rate was 52% when the previous event had occurred between 24 and 72 hours before admission and 32% when it had occurred more than 72 hours before admission. The highest preadmission event frequency significantly increased the chance of capturing an event (odds ratio [OR], 3.77), as did the shortest event latency (OR, 2.31).

Dosing Changes May Decrease the Likelihood of Successful Monitoring
Intellectual disability in the patient significantly increased the likelihood of capturing an EEG-related event (OR, 3.26). But the common practices of sleep deprivation and antiepileptic medication withdrawal did not increase the likelihood of capturing one, said Dr. Wirrell. Medication withdrawal or dose change decreased the chance of an event capture (OR, 0.46).

That finding “came as a surprise,” the investigators noted. Its significance is uncertain, however, because it was not a prespecified outcome, and not many patients were in these subgroups. “It typically takes five half-lives to reach a new steady state of each medication adjustment,” said Dr. Wirrell. “Therefore, depending on the half-life duration of the medications, levels may not become subtherapeutic for several days after discontinuation or dose reduction.”

A family history of epilepsy, a prior interictal discharge on routine EEG, and a prior diagnosis of possible epilepsy also significantly increased the chance that a captured event would be EEG related. This result suggests a need for greater urgency in arranging video EEG monitoring for patients with these characteristics “to make the diagnosis and promptly initiate antiepileptic treatment,” Dr. Wirrell concluded.

—Michele G. Sullivan

Multiple sclerosis (MS) has a “striking” association with obesity at age 20 that strongly interacts with genetic susceptibility, according to an analysis of data from two case–control studies that examined environmental and genetic risk factors for MS and was published online ahead of print February 5 in Neurology.

This relationship between adolescent obesity and MS is of the same magnitude as the separate associations between MS and carriage of the high-risk HLA-DRB1*15 allele, absence of the protective HLA-A*02 allele, and smoking, according to Anna Karin Hedström, MD, of the Institute of Environmental Medicine, Karolinska Institutet, Stockholm, and colleagues.

“The biologic explanations for these interactions are far from clear, but the data open [the way] for mechanistically oriented studies,” the study authors stated.

Three previous studies have suggested that obesity in early life may be linked to an increased risk of developing MS later. Dr. Hedström and her colleagues examined this association using data from a Swedish population-based, case–control study and from a separate American case–control study.

In the Swedish study, 1,510 adults with incident MS who were treated at 40 clinics across the country during a seven-year period and 2,017 control subjects completed detailed questionnaires concerning environmental exposures and other factors. The controls were matched for age, sex, and area of residence, and all the participants gave blood samples for HLA typing.

The American study involved 937 white adults with prevalent MS who were members of a single large health maintenance organization covering northern California and 609 white control subjects matched for age, sex, and area of residence. All the participants completed computer-assisted telephone interviews regarding environmental exposures and lifestyle factors.

All the subjects in both studies reported what their height and weight had been at age 20, from which the investigators calculated BMI.

In both studies, participants whose BMI at age 20 was 27 kg/m² or greater showed an increased risk of developing MS later in life, compared with those whose BMI was 18.5 to 21 kg/m². The odds ratios (ORs) were 2.2 for subjects in the Swedish study and 1.8 for those in the American study, Dr. Hedström and her associates said.

Similarly, participants with a slightly lower but still above-normal BMI of 25 to 27 kg/m² had a modestly increased risk of developing MS later in life. The ORs were 1.4 in the Swedish study and 1.3 in the American study.

These ORs were unchanged when a sensitivity analysis was performed, including only the study subjects who had been genotyped.

Participants who carried the high-risk HLA-DRB1*15 gene, did not carry the protective HLA-A*02 gene, and had a BMI of 27 kg/m² or greater at age 20 had an OR of 16.2 for developing later MS, compared with those who had none of those risk factors. In contrast, subjects who had the same HLA profile but had not been obese at age 20 had an OR of 5.1.

The investigators proposed that the low-grade chronic inflammation associated with obesity, together with obesity’s adverse effects on autoimmunity, may increase the risk of HLA-related activation of T cells that attack the CNS.

Both studies were limited in that they were retrospective and relied on participants’ self-reports. In addition, Dr. Hedström and her associates modified the usual definition of obesity for the purposes of their study. The typical standard for obesity is a BMI of greater than 30 kg/m², not greater than 27 kg/m². However, the number of subjects at this level of BMI was too small in the Swedish cohort to allow accurate analysis, so the researchers combined the top two categories of BMI into one designation of obese.

—Mary Ann Moon

Multiple sclerosis (MS) has a “striking” association with obesity at age 20 that strongly interacts with genetic susceptibility, according to an analysis of data from two case–control studies that examined environmental and genetic risk factors for MS and was published online ahead of print February 5 in Neurology.

This relationship between adolescent obesity and MS is of the same magnitude as the separate associations between MS and carriage of the high-risk HLA-DRB1*15 allele, absence of the protective HLA-A*02 allele, and smoking, according to Anna Karin Hedström, MD, of the Institute of Environmental Medicine, Karolinska Institutet, Stockholm, and colleagues.

“The biologic explanations for these interactions are far from clear, but the data open [the way] for mechanistically oriented studies,” the study authors stated.

Three previous studies have suggested that obesity in early life may be linked to an increased risk of developing MS later. Dr. Hedström and her colleagues examined this association using data from a Swedish population-based, case–control study and from a separate American case–control study.

In the Swedish study, 1,510 adults with incident MS who were treated at 40 clinics across the country during a seven-year period and 2,017 control subjects completed detailed questionnaires concerning environmental exposures and other factors. The controls were matched for age, sex, and area of residence, and all the participants gave blood samples for HLA typing.

The American study involved 937 white adults with prevalent MS who were members of a single large health maintenance organization covering northern California and 609 white control subjects matched for age, sex, and area of residence. All the participants completed computer-assisted telephone interviews regarding environmental exposures and lifestyle factors.

All the subjects in both studies reported what their height and weight had been at age 20, from which the investigators calculated BMI.

In both studies, participants whose BMI at age 20 was 27 kg/m² or greater showed an increased risk of developing MS later in life, compared with those whose BMI was 18.5 to 21 kg/m². The odds ratios (ORs) were 2.2 for subjects in the Swedish study and 1.8 for those in the American study, Dr. Hedström and her associates said.

Similarly, participants with a slightly lower but still above-normal BMI of 25 to 27 kg/m² had a modestly increased risk of developing MS later in life. The ORs were 1.4 in the Swedish study and 1.3 in the American study.

These ORs were unchanged when a sensitivity analysis was performed, including only the study subjects who had been genotyped.

Participants who carried the high-risk HLA-DRB1*15 gene, did not carry the protective HLA-A*02 gene, and had a BMI of 27 kg/m² or greater at age 20 had an OR of 16.2 for developing later MS, compared with those who had none of those risk factors. In contrast, subjects who had the same HLA profile but had not been obese at age 20 had an OR of 5.1.

The investigators proposed that the low-grade chronic inflammation associated with obesity, together with obesity’s adverse effects on autoimmunity, may increase the risk of HLA-related activation of T cells that attack the CNS.

Both studies were limited in that they were retrospective and relied on participants’ self-reports. In addition, Dr. Hedström and her associates modified the usual definition of obesity for the purposes of their study. The typical standard for obesity is a BMI of greater than 30 kg/m², not greater than 27 kg/m². However, the number of subjects at this level of BMI was too small in the Swedish cohort to allow accurate analysis, so the researchers combined the top two categories of BMI into one designation of obese.

—Mary Ann Moon

Multiple sclerosis (MS) has a “striking” association with obesity at age 20 that strongly interacts with genetic susceptibility, according to an analysis of data from two case–control studies that examined environmental and genetic risk factors for MS and was published online ahead of print February 5 in Neurology.

This relationship between adolescent obesity and MS is of the same magnitude as the separate associations between MS and carriage of the high-risk HLA-DRB1*15 allele, absence of the protective HLA-A*02 allele, and smoking, according to Anna Karin Hedström, MD, of the Institute of Environmental Medicine, Karolinska Institutet, Stockholm, and colleagues.

“The biologic explanations for these interactions are far from clear, but the data open [the way] for mechanistically oriented studies,” the study authors stated.

Three previous studies have suggested that obesity in early life may be linked to an increased risk of developing MS later. Dr. Hedström and her colleagues examined this association using data from a Swedish population-based, case–control study and from a separate American case–control study.

In the Swedish study, 1,510 adults with incident MS who were treated at 40 clinics across the country during a seven-year period and 2,017 control subjects completed detailed questionnaires concerning environmental exposures and other factors. The controls were matched for age, sex, and area of residence, and all the participants gave blood samples for HLA typing.

The American study involved 937 white adults with prevalent MS who were members of a single large health maintenance organization covering northern California and 609 white control subjects matched for age, sex, and area of residence. All the participants completed computer-assisted telephone interviews regarding environmental exposures and lifestyle factors.

All the subjects in both studies reported what their height and weight had been at age 20, from which the investigators calculated BMI.

In both studies, participants whose BMI at age 20 was 27 kg/m² or greater showed an increased risk of developing MS later in life, compared with those whose BMI was 18.5 to 21 kg/m². The odds ratios (ORs) were 2.2 for subjects in the Swedish study and 1.8 for those in the American study, Dr. Hedström and her associates said.

Similarly, participants with a slightly lower but still above-normal BMI of 25 to 27 kg/m² had a modestly increased risk of developing MS later in life. The ORs were 1.4 in the Swedish study and 1.3 in the American study.

These ORs were unchanged when a sensitivity analysis was performed, including only the study subjects who had been genotyped.

Participants who carried the high-risk HLA-DRB1*15 gene, did not carry the protective HLA-A*02 gene, and had a BMI of 27 kg/m² or greater at age 20 had an OR of 16.2 for developing later MS, compared with those who had none of those risk factors. In contrast, subjects who had the same HLA profile but had not been obese at age 20 had an OR of 5.1.

The investigators proposed that the low-grade chronic inflammation associated with obesity, together with obesity’s adverse effects on autoimmunity, may increase the risk of HLA-related activation of T cells that attack the CNS.

Both studies were limited in that they were retrospective and relied on participants’ self-reports. In addition, Dr. Hedström and her associates modified the usual definition of obesity for the purposes of their study. The typical standard for obesity is a BMI of greater than 30 kg/m², not greater than 27 kg/m². However, the number of subjects at this level of BMI was too small in the Swedish cohort to allow accurate analysis, so the researchers combined the top two categories of BMI into one designation of obese.

—Mary Ann Moon

Researchers have identified a new form of autoimmune encephalitis characterized by high serum and CSF titers of antibodies against the gamma-aminobutyric acid A receptor (GABA_AR) and a rapid onset of severe, refractory seizures or status epilepticus. The findings were published online ahead of print January 21 in Lancet Neurology.

In affected patients, these antibodies may cause a selective reduction of clusters of GABA_AR at the synapses. Unlike the GABA_B receptor, the GABA_AR has never been recognized as a target of autoimmunity. Identifying this novel form of autoimmune epileptic disorder, which affected children and adults in this series, is important because, although it is not responsive to antiseizure measures, it is potentially treatable with other approaches, said Mar Petit-Pedrol of the August Pi i Sunyer Biomedical Research Institute, Barcelona, and associates.

The investigators first noted the disorder in two patients seen at their medical center within four months of each other. Both patients presented with encephalitis and severe, refractory seizures and showed serum and CSF cell-surface antibodies with a similar but unrecognized pattern of reactivity against the neuropil of rat brain. “The severity of the symptoms and unknown identity of the antigen prompted us to immunoprecipitate the antigen and to retrospectively review clinical and immunologic information from patients with similar symptoms,” the researchers wrote.

Serum and CSF Analysis
The study authors collected and examined serum and CSF samples from 1,134 patients around the world whose encephalitis and seizures were suspected to be autoimmune in origin and found 140 who had antibodies against the same unknown rat brain neuropil antigen. The investigators also examined samples from 75 healthy blood donors and 416 patients with a range of neurologic disorders.

Four of the 140 patients, in addition to the two index patients, showed high titers of antibodies to the GABA_AR, but none of the control patients did. Among these six patients, three were children (ages 3, 4, and 16) and three were adults (ages 28, 51, and 63). All had a rapidly progressive encephalopathy preceded by or associated with a change in behavior or level of cognition. All patients developed refractory seizures, and five had status epilepticus. Five of the six patients had at least one CSF abnormality.

MRI Reveals Abnormal Findings
All six patients had abnormal findings on brain MRI, with extensive multifocal or diffuse cortical and subcortical involvement. It is not yet known if these anomalies were caused by the immune response or resulted from the lengthy seizures. However, they were different from the abnormalities seen in other forms of autoimmune encephalitis, the researchers noted. All six patients had abnormal EEG findings and multifocal seizures. Two also showed generalized periodic discharges.

This new form of encephalitis was not associated with any underlying tumor. In contrast, as much as 60% of patients with GABA_BR antibodies are found to have underlying small-cell lung cancer.

In addition to the GABA_AR antibodies, three of these six patients had thyroid peroxidase antibodies, one had glutamic acid decarboxylase 65 (GAD65) antibodies, and two had GABA_BR antibodies. This result indicates that patients with this new form of encephalitis have a propensity for autoimmunity or immune dysregulation, according to the researchers. Further supporting that connection, one patient had a history of idiopathic thrombocytopenic purpura, and another had a history of Hodgkin’s lymphoma, the investigators said.

Regarding treatment, one of the affected children received levetiracetam but no immunotherapy and showed “substantial recovery,” but three years later still requires antiseizure medication to prevent a recurrence of epilepsy. The other five patients received immunotherapy and multiple antiepileptic drugs; three had a partial or total recovery, while two died from sepsis that developed during status epilepticus. In addition to these six patients who had high titers of GABA_AR antibodies, 12 patients from the 140 global cases had low but detectable levels of GABA_AR antibodies. Most of the 12 also had low titers of other antibodies, which “could explain the broader range of symptoms in this group,” noted the authors.

Of these 12 patients, six presented with encephalitis with refractory seizures, including a 2-year-old boy with status epilepticus and a 41-year-old man with epilepsia partialis continua. Of the remaining six patients, four presented with stiff-person syndrome and two with opsoclonus-myoclonus.

Testing for GABA_AR Antibodies
These findings indicate that patients who have encephalitis or severe, refractory seizures thought to be autoimmune in origin with MRI and CSF abnormalities suggestive of an inflammatory process should be tested for GABA_AR antibodies, the researchers advised. In addition, “future studies should establish, in a prospective manner, the incidence of serum and CSF GABA_AR antibodies in patients with seizures or status epilepticus, opsoclonus-myo-clonus, and stiff-person syndrome,” the authors said.

“Whether these antibodies might also have a role in milder syndromes, or perhaps in cryptogenic epilepsy, warrants further study,” Lawrence J. Hirsch, MD, wrote in an accompanying editorial.

This preliminary study could not determine which, if any, antiepileptic drugs might be effective, nor which immunotherapies might be helpful. Future research should address those issues as well, said Dr. Hirsch, Professor of Neurology at Yale University in New Haven, Connecticut.

—Mary Ann Moon

Researchers have identified a new form of autoimmune encephalitis characterized by high serum and CSF titers of antibodies against the gamma-aminobutyric acid A receptor (GABA_AR) and a rapid onset of severe, refractory seizures or status epilepticus. The findings were published online ahead of print January 21 in Lancet Neurology.

In affected patients, these antibodies may cause a selective reduction of clusters of GABA_AR at the synapses. Unlike the GABA_B receptor, the GABA_AR has never been recognized as a target of autoimmunity. Identifying this novel form of autoimmune epileptic disorder, which affected children and adults in this series, is important because, although it is not responsive to antiseizure measures, it is potentially treatable with other approaches, said Mar Petit-Pedrol of the August Pi i Sunyer Biomedical Research Institute, Barcelona, and associates.

The investigators first noted the disorder in two patients seen at their medical center within four months of each other. Both patients presented with encephalitis and severe, refractory seizures and showed serum and CSF cell-surface antibodies with a similar but unrecognized pattern of reactivity against the neuropil of rat brain. “The severity of the symptoms and unknown identity of the antigen prompted us to immunoprecipitate the antigen and to retrospectively review clinical and immunologic information from patients with similar symptoms,” the researchers wrote.

Serum and CSF Analysis
The study authors collected and examined serum and CSF samples from 1,134 patients around the world whose encephalitis and seizures were suspected to be autoimmune in origin and found 140 who had antibodies against the same unknown rat brain neuropil antigen. The investigators also examined samples from 75 healthy blood donors and 416 patients with a range of neurologic disorders.

Four of the 140 patients, in addition to the two index patients, showed high titers of antibodies to the GABA_AR, but none of the control patients did. Among these six patients, three were children (ages 3, 4, and 16) and three were adults (ages 28, 51, and 63). All had a rapidly progressive encephalopathy preceded by or associated with a change in behavior or level of cognition. All patients developed refractory seizures, and five had status epilepticus. Five of the six patients had at least one CSF abnormality.

MRI Reveals Abnormal Findings
All six patients had abnormal findings on brain MRI, with extensive multifocal or diffuse cortical and subcortical involvement. It is not yet known if these anomalies were caused by the immune response or resulted from the lengthy seizures. However, they were different from the abnormalities seen in other forms of autoimmune encephalitis, the researchers noted. All six patients had abnormal EEG findings and multifocal seizures. Two also showed generalized periodic discharges.

This new form of encephalitis was not associated with any underlying tumor. In contrast, as much as 60% of patients with GABA_BR antibodies are found to have underlying small-cell lung cancer.

In addition to the GABA_AR antibodies, three of these six patients had thyroid peroxidase antibodies, one had glutamic acid decarboxylase 65 (GAD65) antibodies, and two had GABA_BR antibodies. This result indicates that patients with this new form of encephalitis have a propensity for autoimmunity or immune dysregulation, according to the researchers. Further supporting that connection, one patient had a history of idiopathic thrombocytopenic purpura, and another had a history of Hodgkin’s lymphoma, the investigators said.

Regarding treatment, one of the affected children received levetiracetam but no immunotherapy and showed “substantial recovery,” but three years later still requires antiseizure medication to prevent a recurrence of epilepsy. The other five patients received immunotherapy and multiple antiepileptic drugs; three had a partial or total recovery, while two died from sepsis that developed during status epilepticus. In addition to these six patients who had high titers of GABA_AR antibodies, 12 patients from the 140 global cases had low but detectable levels of GABA_AR antibodies. Most of the 12 also had low titers of other antibodies, which “could explain the broader range of symptoms in this group,” noted the authors.

Of these 12 patients, six presented with encephalitis with refractory seizures, including a 2-year-old boy with status epilepticus and a 41-year-old man with epilepsia partialis continua. Of the remaining six patients, four presented with stiff-person syndrome and two with opsoclonus-myoclonus.

Testing for GABA_AR Antibodies
These findings indicate that patients who have encephalitis or severe, refractory seizures thought to be autoimmune in origin with MRI and CSF abnormalities suggestive of an inflammatory process should be tested for GABA_AR antibodies, the researchers advised. In addition, “future studies should establish, in a prospective manner, the incidence of serum and CSF GABA_AR antibodies in patients with seizures or status epilepticus, opsoclonus-myo-clonus, and stiff-person syndrome,” the authors said.

“Whether these antibodies might also have a role in milder syndromes, or perhaps in cryptogenic epilepsy, warrants further study,” Lawrence J. Hirsch, MD, wrote in an accompanying editorial.

This preliminary study could not determine which, if any, antiepileptic drugs might be effective, nor which immunotherapies might be helpful. Future research should address those issues as well, said Dr. Hirsch, Professor of Neurology at Yale University in New Haven, Connecticut.

—Mary Ann Moon

Researchers have identified a new form of autoimmune encephalitis characterized by high serum and CSF titers of antibodies against the gamma-aminobutyric acid A receptor (GABA_AR) and a rapid onset of severe, refractory seizures or status epilepticus. The findings were published online ahead of print January 21 in Lancet Neurology.

In affected patients, these antibodies may cause a selective reduction of clusters of GABA_AR at the synapses. Unlike the GABA_B receptor, the GABA_AR has never been recognized as a target of autoimmunity. Identifying this novel form of autoimmune epileptic disorder, which affected children and adults in this series, is important because, although it is not responsive to antiseizure measures, it is potentially treatable with other approaches, said Mar Petit-Pedrol of the August Pi i Sunyer Biomedical Research Institute, Barcelona, and associates.

The investigators first noted the disorder in two patients seen at their medical center within four months of each other. Both patients presented with encephalitis and severe, refractory seizures and showed serum and CSF cell-surface antibodies with a similar but unrecognized pattern of reactivity against the neuropil of rat brain. “The severity of the symptoms and unknown identity of the antigen prompted us to immunoprecipitate the antigen and to retrospectively review clinical and immunologic information from patients with similar symptoms,” the researchers wrote.

Serum and CSF Analysis
The study authors collected and examined serum and CSF samples from 1,134 patients around the world whose encephalitis and seizures were suspected to be autoimmune in origin and found 140 who had antibodies against the same unknown rat brain neuropil antigen. The investigators also examined samples from 75 healthy blood donors and 416 patients with a range of neurologic disorders.

Four of the 140 patients, in addition to the two index patients, showed high titers of antibodies to the GABA_AR, but none of the control patients did. Among these six patients, three were children (ages 3, 4, and 16) and three were adults (ages 28, 51, and 63). All had a rapidly progressive encephalopathy preceded by or associated with a change in behavior or level of cognition. All patients developed refractory seizures, and five had status epilepticus. Five of the six patients had at least one CSF abnormality.

MRI Reveals Abnormal Findings
All six patients had abnormal findings on brain MRI, with extensive multifocal or diffuse cortical and subcortical involvement. It is not yet known if these anomalies were caused by the immune response or resulted from the lengthy seizures. However, they were different from the abnormalities seen in other forms of autoimmune encephalitis, the researchers noted. All six patients had abnormal EEG findings and multifocal seizures. Two also showed generalized periodic discharges.

This new form of encephalitis was not associated with any underlying tumor. In contrast, as much as 60% of patients with GABA_BR antibodies are found to have underlying small-cell lung cancer.

In addition to the GABA_AR antibodies, three of these six patients had thyroid peroxidase antibodies, one had glutamic acid decarboxylase 65 (GAD65) antibodies, and two had GABA_BR antibodies. This result indicates that patients with this new form of encephalitis have a propensity for autoimmunity or immune dysregulation, according to the researchers. Further supporting that connection, one patient had a history of idiopathic thrombocytopenic purpura, and another had a history of Hodgkin’s lymphoma, the investigators said.

Regarding treatment, one of the affected children received levetiracetam but no immunotherapy and showed “substantial recovery,” but three years later still requires antiseizure medication to prevent a recurrence of epilepsy. The other five patients received immunotherapy and multiple antiepileptic drugs; three had a partial or total recovery, while two died from sepsis that developed during status epilepticus. In addition to these six patients who had high titers of GABA_AR antibodies, 12 patients from the 140 global cases had low but detectable levels of GABA_AR antibodies. Most of the 12 also had low titers of other antibodies, which “could explain the broader range of symptoms in this group,” noted the authors.

Of these 12 patients, six presented with encephalitis with refractory seizures, including a 2-year-old boy with status epilepticus and a 41-year-old man with epilepsia partialis continua. Of the remaining six patients, four presented with stiff-person syndrome and two with opsoclonus-myoclonus.

Testing for GABA_AR Antibodies
These findings indicate that patients who have encephalitis or severe, refractory seizures thought to be autoimmune in origin with MRI and CSF abnormalities suggestive of an inflammatory process should be tested for GABA_AR antibodies, the researchers advised. In addition, “future studies should establish, in a prospective manner, the incidence of serum and CSF GABA_AR antibodies in patients with seizures or status epilepticus, opsoclonus-myo-clonus, and stiff-person syndrome,” the authors said.

“Whether these antibodies might also have a role in milder syndromes, or perhaps in cryptogenic epilepsy, warrants further study,” Lawrence J. Hirsch, MD, wrote in an accompanying editorial.

This preliminary study could not determine which, if any, antiepileptic drugs might be effective, nor which immunotherapies might be helpful. Future research should address those issues as well, said Dr. Hirsch, Professor of Neurology at Yale University in New Haven, Connecticut.

—Mary Ann Moon