ICYMI Multiple Sclerosis

MONTREAL—Macrophages and microglia represent rational targets in the treatment of patients with multiple sclerosis (MS), given that these cells are key effectors for tissue injury in inflammatory conditions in the CNS, said Samia J. Khoury, MD, at the 2008 World Congress on Treatment and Research in Multiple Sclerosis.
Therapies that inhibit microglial activation may be beneficial in chronic inflammatory diseases of the central nervous system such as MS. Potential inhibitors of microglia activation are peroxisome proliferator-activated receptor γ (PPAR-γ) agonists, anti-CD200 antibodies, and minocycline. Dr. Khoury discussed the role of reactive microglia in the initiation and propagation of immune responses as inflammatory mediators during inflammation in the CNS.

The acute MS lesion has been classically defined based on the presence of microglia ingesting myelin components and a lymphocyte inflammatory response. The chronic MS lesion, characteristic of the progressive phase of the disease, is dominated by the presence of activated microglia/macrophages without a prominent lymphocytic infiltrate. Human adult microglia can phagocytose myelin vesicles and secrete proinflammatory cytokines such as interleukin 1 (IL‑1), IL-6, and tumor necrosis factor α (TNF-α), and they are also known to undergo oxidative bursts. Diffuse injury of the normal-appearing white matter and cortical demyelination are classic hallmarks of primary and secondary progressive MS. The inflammation consists of mononuclear cells and diffuse infiltration of the tissue by T lymphocytes associated with profound activation of microglia.

Similar to patients with MS, the peak of disease activity in mice with experimental autoimmune encephalomyelitis (EAE)—a widely used animal model in MS—is characterized by T-cell infiltrates that decline during extended follow-up, whereas the microglia are activated persistently throughout the chronic phases. “This activation correlates well with the presence of cortical lesions, alteration of synaptic function, and axonal transport, each indicative of neuronal dysfunction,” said Dr. Khoury, Professor of Neurology at Brigham and Women’s Hospital in Boston. These data suggest that inflammation is sustained by microglia during the chronic phase of EAE.

The contribution of microglia to the progression of MS is evident in the following:
• Progressive MS correlates with the presence of diffuse axonal injury and activated microglia in the cortex and nonlesioned white matter.
• Increased expression of the major histocompatibility complex class II (MHC II) gene is found on microglia in nonlesioned white matter in the brains of patients with MS.
• Proinflammatory mediators released by microglia appear to be important contributors in blocking neurogenesis.
• Activation of microglia results in secretion of nitric oxide and proinflammatory cytokines such as IL-1, IL-6, IL-8, macrophage inflammatory protein 1-α, monocyte chemotactic protein 1, and TNF-α.
• Microglia in the subventricular zone proliferate and closely contact the neural stem cells.
Compounds that inhibit microglia activation include PPAR-γ agonists, anti-CD200 antibodies, and minocycline. PPAR-γ is a nuclear receptor that controls reproduction, metabolism, development, and immune responses. Natural and synthetic PPAR-γ agonists may control brain inflammation by inhibiting microglial activation, noted Dr. Khoury.

CD200 is expressed on neurons, and CD200R is expressed on macrophages/microglia. CD200-null mice experience an earlier onset of EAE, accompanied by an increased number and accumulation of activated macrophages and microglia in the CNS. After facial nerve transection, CD200-null mice have shown accelerated microglial response around neurons. Slow Wallerian degeneration mice have up-regulated CD200 and protection from EAE.

Minocycline has been shown to ameliorate EAE by peripheral immunomodulatory properties. Its mechanisms of action include inhibition of matrix metalloproteinase 2 activity and inhibition of inducible nitric oxide synthase, prostaglandin-E2, caspase-1, caspase-3, and cyclo-oxygenase–2 expressions, as well as the impairment of cytokine production. Some of these mechanisms are manifested, at least in part, by inhibition of mitogen-activated protein kinases. Minocycline also inhibits protein kinase C activation and decreases MHC II expression.

MONTREAL—Macrophages and microglia represent rational targets in the treatment of patients with multiple sclerosis (MS), given that these cells are key effectors for tissue injury in inflammatory conditions in the CNS, said Samia J. Khoury, MD, at the 2008 World Congress on Treatment and Research in Multiple Sclerosis.
Therapies that inhibit microglial activation may be beneficial in chronic inflammatory diseases of the central nervous system such as MS. Potential inhibitors of microglia activation are peroxisome proliferator-activated receptor γ (PPAR-γ) agonists, anti-CD200 antibodies, and minocycline. Dr. Khoury discussed the role of reactive microglia in the initiation and propagation of immune responses as inflammatory mediators during inflammation in the CNS.

The acute MS lesion has been classically defined based on the presence of microglia ingesting myelin components and a lymphocyte inflammatory response. The chronic MS lesion, characteristic of the progressive phase of the disease, is dominated by the presence of activated microglia/macrophages without a prominent lymphocytic infiltrate. Human adult microglia can phagocytose myelin vesicles and secrete proinflammatory cytokines such as interleukin 1 (IL‑1), IL-6, and tumor necrosis factor α (TNF-α), and they are also known to undergo oxidative bursts. Diffuse injury of the normal-appearing white matter and cortical demyelination are classic hallmarks of primary and secondary progressive MS. The inflammation consists of mononuclear cells and diffuse infiltration of the tissue by T lymphocytes associated with profound activation of microglia.

Similar to patients with MS, the peak of disease activity in mice with experimental autoimmune encephalomyelitis (EAE)—a widely used animal model in MS—is characterized by T-cell infiltrates that decline during extended follow-up, whereas the microglia are activated persistently throughout the chronic phases. “This activation correlates well with the presence of cortical lesions, alteration of synaptic function, and axonal transport, each indicative of neuronal dysfunction,” said Dr. Khoury, Professor of Neurology at Brigham and Women’s Hospital in Boston. These data suggest that inflammation is sustained by microglia during the chronic phase of EAE.

The contribution of microglia to the progression of MS is evident in the following:
• Progressive MS correlates with the presence of diffuse axonal injury and activated microglia in the cortex and nonlesioned white matter.
• Increased expression of the major histocompatibility complex class II (MHC II) gene is found on microglia in nonlesioned white matter in the brains of patients with MS.
• Proinflammatory mediators released by microglia appear to be important contributors in blocking neurogenesis.
• Activation of microglia results in secretion of nitric oxide and proinflammatory cytokines such as IL-1, IL-6, IL-8, macrophage inflammatory protein 1-α, monocyte chemotactic protein 1, and TNF-α.
• Microglia in the subventricular zone proliferate and closely contact the neural stem cells.
Compounds that inhibit microglia activation include PPAR-γ agonists, anti-CD200 antibodies, and minocycline. PPAR-γ is a nuclear receptor that controls reproduction, metabolism, development, and immune responses. Natural and synthetic PPAR-γ agonists may control brain inflammation by inhibiting microglial activation, noted Dr. Khoury.

CD200 is expressed on neurons, and CD200R is expressed on macrophages/microglia. CD200-null mice experience an earlier onset of EAE, accompanied by an increased number and accumulation of activated macrophages and microglia in the CNS. After facial nerve transection, CD200-null mice have shown accelerated microglial response around neurons. Slow Wallerian degeneration mice have up-regulated CD200 and protection from EAE.

Minocycline has been shown to ameliorate EAE by peripheral immunomodulatory properties. Its mechanisms of action include inhibition of matrix metalloproteinase 2 activity and inhibition of inducible nitric oxide synthase, prostaglandin-E2, caspase-1, caspase-3, and cyclo-oxygenase–2 expressions, as well as the impairment of cytokine production. Some of these mechanisms are manifested, at least in part, by inhibition of mitogen-activated protein kinases. Minocycline also inhibits protein kinase C activation and decreases MHC II expression.

MONTREAL—Macrophages and microglia represent rational targets in the treatment of patients with multiple sclerosis (MS), given that these cells are key effectors for tissue injury in inflammatory conditions in the CNS, said Samia J. Khoury, MD, at the 2008 World Congress on Treatment and Research in Multiple Sclerosis.
Therapies that inhibit microglial activation may be beneficial in chronic inflammatory diseases of the central nervous system such as MS. Potential inhibitors of microglia activation are peroxisome proliferator-activated receptor γ (PPAR-γ) agonists, anti-CD200 antibodies, and minocycline. Dr. Khoury discussed the role of reactive microglia in the initiation and propagation of immune responses as inflammatory mediators during inflammation in the CNS.

The acute MS lesion has been classically defined based on the presence of microglia ingesting myelin components and a lymphocyte inflammatory response. The chronic MS lesion, characteristic of the progressive phase of the disease, is dominated by the presence of activated microglia/macrophages without a prominent lymphocytic infiltrate. Human adult microglia can phagocytose myelin vesicles and secrete proinflammatory cytokines such as interleukin 1 (IL‑1), IL-6, and tumor necrosis factor α (TNF-α), and they are also known to undergo oxidative bursts. Diffuse injury of the normal-appearing white matter and cortical demyelination are classic hallmarks of primary and secondary progressive MS. The inflammation consists of mononuclear cells and diffuse infiltration of the tissue by T lymphocytes associated with profound activation of microglia.

Similar to patients with MS, the peak of disease activity in mice with experimental autoimmune encephalomyelitis (EAE)—a widely used animal model in MS—is characterized by T-cell infiltrates that decline during extended follow-up, whereas the microglia are activated persistently throughout the chronic phases. “This activation correlates well with the presence of cortical lesions, alteration of synaptic function, and axonal transport, each indicative of neuronal dysfunction,” said Dr. Khoury, Professor of Neurology at Brigham and Women’s Hospital in Boston. These data suggest that inflammation is sustained by microglia during the chronic phase of EAE.

The contribution of microglia to the progression of MS is evident in the following:
• Progressive MS correlates with the presence of diffuse axonal injury and activated microglia in the cortex and nonlesioned white matter.
• Increased expression of the major histocompatibility complex class II (MHC II) gene is found on microglia in nonlesioned white matter in the brains of patients with MS.
• Proinflammatory mediators released by microglia appear to be important contributors in blocking neurogenesis.
• Activation of microglia results in secretion of nitric oxide and proinflammatory cytokines such as IL-1, IL-6, IL-8, macrophage inflammatory protein 1-α, monocyte chemotactic protein 1, and TNF-α.
• Microglia in the subventricular zone proliferate and closely contact the neural stem cells.
Compounds that inhibit microglia activation include PPAR-γ agonists, anti-CD200 antibodies, and minocycline. PPAR-γ is a nuclear receptor that controls reproduction, metabolism, development, and immune responses. Natural and synthetic PPAR-γ agonists may control brain inflammation by inhibiting microglial activation, noted Dr. Khoury.

CD200 is expressed on neurons, and CD200R is expressed on macrophages/microglia. CD200-null mice experience an earlier onset of EAE, accompanied by an increased number and accumulation of activated macrophages and microglia in the CNS. After facial nerve transection, CD200-null mice have shown accelerated microglial response around neurons. Slow Wallerian degeneration mice have up-regulated CD200 and protection from EAE.

Minocycline has been shown to ameliorate EAE by peripheral immunomodulatory properties. Its mechanisms of action include inhibition of matrix metalloproteinase 2 activity and inhibition of inducible nitric oxide synthase, prostaglandin-E2, caspase-1, caspase-3, and cyclo-oxygenase–2 expressions, as well as the impairment of cytokine production. Some of these mechanisms are manifested, at least in part, by inhibition of mitogen-activated protein kinases. Minocycline also inhibits protein kinase C activation and decreases MHC II expression.

Alzheimer’s Pathology Reduced With Combined Diabetes Therapy
NEW YORK, September 9 (Reuters Health)—In a postmortem study of patients with Alzheimer’s disease, diabetic subjects treated with both insulin and oral hypoglycemic agents had lower neuritic plaque densities than did other diabetics and nondiabetics, new research shows.
In several studies, type 2 diabetes has been identified as a risk factor for Alzheimer’s disease. The link between diabetes and Alzheimer’s neuropathology, by contrast, is less clear, according to the report in the September 2 issue of Neurology.
The current study, conducted by Dr. M. S. Beeri, from Mount Sinai School of Medicine in New York City, and colleagues, involved an analysis of neuritic plaques and neurofibrillary tangles in brain specimens from 124 diabetics and 124 nondiabetics.
The diabetic group consisted of 29 patients who had never used antidiabetic agents, 49 who had received insulin only, 28 treated with agents other than insulin, and 18 treated with both insulin and oral antidiabetic medications.
The overall neuritic plaque rating, the rating in the entorhinal cortex and amygdala, and the neuritic plaque count in all regions examined differed significantly among the groups. In all of the analyses, the combined medication group had fewer neuritic plaques than did the other groups.
By contrast, the authors found no significant difference in neurofibrillary tangles between the groups.
The findings provide “evidence of substantially lower neuritic plaque density in diabetic subjects taking both insulin and hypoglycemic medication consistent with the effects of both on the neurobiology of insulin,” the researchers concluded. “These pathways should be considered as potentially mechanistically important in the etiology of β amyloid–associated neuropathology and deposition of neuritic plaques.”
Neurology. 2008;71(10):750-757.
Antiepileptic Drug Use May Contribute to Bone Loss in Older Men
NEW YORK, September 19 (Reuters Health)—Use of non–enzyme-inducing antiepileptic drugs (AEDs) independently raises the risk of bone loss at the hip in older men, results of a prospective study suggest.
In the September 2 issue of Neurology, Dr. Kristine E. Ensrud, from the Veterans Affairs Medical Center in Minneapolis, and colleagues pointed out, “AED use may be associated with higher rates of bone loss because [the drugs] may have adverse effects on bone metabolism. On the other hand, AED use may be a marker of factors such as poor health ... that are associated with greater rates of bone loss.”
In 4,222 older community-dwelling participants in the Osteoporosis Fractures in Men study, the researchers analyzed use of non–enzyme-inducing and enzyme-inducing AEDs. They also measured subjects’ hip bone mineral density (BMD) at baseline and at an average of 4.6 years later.
Among men who didn’t use AEDs at all, the average rate of decline in total hip BMD per year was -0.35%, compared with -0.46% among enzyme-inducing AED users and -0.53% among non–enzyme-inducing AED users.
The rate of loss per year was -0.60% among men who were taking non–enzyme-inducing AEDs at both examinations, -0.51% among men taking non–enzyme-inducing AEDs at one examination only, and -0.35% among nonusers.
The researchers pointed out that these findings were achieved after adjustment for a myriad of potential confounders not accounted for in past studies, including age, race, health status, baseline BMD, physical activity, smoking, alcohol intake, total calcium intake, diabetes, kidney disease, bisphosphonate or SSRI use, and BMI.
“Our results suggest that non–enzyme-inducing AED use is associated in a graded manner with rates of hip bone loss in older men, with lower rates of loss among nonusers of AEDs, intermediate rates of loss among intermittent users, and high rates of loss among continuous users,” the authors wrote.
They added, “These findings are supported by prior studies reporting higher fracture rates among non–enzyme-inducing AED users compared with nonusers of AEDs or a similar fracture risk between patients taking non–enzyme-inducing AEDs versus those taking enzyme-inducing AEDs.”
In particular, the results suggest that men who take gabapentin have a 1.4- to 1.8-fold higher adjusted rate of bone loss at the hip compared with nonusers of AEDs.
Neurology. 2008;71(10):723-730.
Relatives of Patients With Brain Tumors Seem to Be at Increased Risk
NEW YORK, September 22 (Reu­ters Health)—By linking a Utah genealogy database to statewide cancer records, researchers have uncovered evidence of a familial contribution to primary brain cancer risk.
“There has been landmark work done previously using the Utah Population Database resource, in discovering hereditary associations and specific genes for breast cancer, colon cancer, and other nonneoplastic diseases,” Dr. Deborah T. Blumenthal told Reuters Health. “We sought to utilize this unique resource to search for familial relationships in primary brain tumors.”
The database includes more than two million persons with up to 10 generations of genealogic data. Dr. Blumenthal, currently at Tel-Aviv Sourasky Medical Center, and Dr. Lisa A. Cannon-Albright, at the University of Utah in Salt Lake City, examined the risk of brain tumors in the relatives of 744 individuals with astrocytoma, 658 patients with glioblastoma, and one patient with both.
According to their report in the September 23 issue of Neurology, significant excess risk exists among first-degree relatives of patients with astrocytoma or glioblastoma, compared with the rate of disease in the general population.
There was also significantly increased risk among second-degree relatives of patients with astrocytoma.
Noting that cancers with a genetic contribution often occur at an earlier age than sporadic cases, the researchers report that first-degree relatives of patients diagnosed before age 20 were at higher risk. Risk was also elevated for family members of cases with astrocytoma diagnosed before age 15.
“These findings, which remained significant beyond first-degree relations, support the hypothesis of familiality—a common gene or group of genes that may predispose individuals to brain tumors,” Dr. Blumenthal said.
“It needs to be stressed that we are still considering a very small minority (less than 5%) of an already small group of patients (less than 20,000/year in the US) who may have a familial risk for being affected with these tumors,” she added. “However, clinicians should be aware of this association and carefully query family history in their patients. If other family members have neurologic symptoms, the threshold for screening them for a brain tumor should be lower.”
Such symptoms, she explained, may include “new, progressive headaches, nausea or vomiting, seizures (which may be motor or sensory phenomenon, or even episodes of odd smells/tastes or déjà vu, when the temporal lobe is involved), changes in vision, changes in speech or language ability (word-finding difficulty), changes in personality (including apathy or apparent depression), and imbalance or incoordination.”

The researchers now plan prospective follow-up of these high-risk pedigrees.
“If genes or loci responsible for brain tumors could be identified, they could have relevance not only for familial tumors, but for the larger population as well,” Dr. Blumenthal concluded. “Ultimately, with such information, screening and even preventive therapy for malignant brain tumors might be possible in the future.”
Neurology. 2008;71(13):1015-1020.
Engerix B Vaccine May Increase the Risk of Multiple Sclerosis in Children
NEW YORK, September 26 (Reuters Health)—Although most hepatitis B vaccines do not seem to increase the risk of multiple sclerosis (MS) in children, use of one particular brand—Engerix B (GlaxoSmithKline)—may, according to findings from a study conducted in France.
In the study reported in the October 8 online issue of Neurology, the odds ratio (OR) for Engerix B exposure was 2.77 among children with MS, compared with an unaffected control group.
Prior reports have suggested a link between hepatitis B vaccine exposure and CNS inflammatory demyelination, including MS as well as acute disseminated encephalomyelitis and transverse myelitis. In general, however, findings from epidemiologic studies have not supported an association.
The focus of the current case-control study was on the neurologic effects of hepatitis B vaccination in children, since most of the prior investigations involved adults only, lead author Dr. Yann Mikaeloff, from Assistance Publique-Hôpitaux de Paris, and colleagues noted.
Case patients included 349 children with a first episode of CNS inflammatory demyelination between 1994 and 2003. Each subject was matched to up to 12 controls by age, gender, and geographic location.
In the overall analysis, hepatitis B vaccination did not increase the risk of CNS inflammatory demyelination.
However, when the analysis was confined to vaccine-compliant subjects, vaccine exposure more than three years prior to the index date was linked to an elevated risk (OR, 1.50). Further analysis showed that this association was mostly driven by the risk seen with Engerix B use (OR, 1.74).
Vaccine exposure more than three years before the index date was tied to a 2.12-fold increased risk of confirmed MS. Once again, however, this was mostly accounted for by Engerix B use (OR,  2.77).
As to why one brand of hepatitis B vaccine is safe while another may not be, the authors offer two possible explanations: “(1) each vaccine uses a different section of the hepatitis B antigen, and some protein fragments produced by yeasts may induce molecular mimicry, while others do not; (2) the production process varies by brand, and differences in yeast protein content may be crucial if yeast protein may trigger autoimmune reactions.”
The packaging insert (December 2006) for Engerix B mentions reports of patients with MS who experience exacerbations following use of the vaccine, but it points out that causality has not been established. The insert also notes new cases of MS and transverse myelitis that occurred after vaccination and were identified during postmarketing surveillance.
Neurology. 2008 Oct 8; [Epub ahead of print].

Alzheimer’s Pathology Reduced With Combined Diabetes Therapy
NEW YORK, September 9 (Reuters Health)—In a postmortem study of patients with Alzheimer’s disease, diabetic subjects treated with both insulin and oral hypoglycemic agents had lower neuritic plaque densities than did other diabetics and nondiabetics, new research shows.
In several studies, type 2 diabetes has been identified as a risk factor for Alzheimer’s disease. The link between diabetes and Alzheimer’s neuropathology, by contrast, is less clear, according to the report in the September 2 issue of Neurology.
The current study, conducted by Dr. M. S. Beeri, from Mount Sinai School of Medicine in New York City, and colleagues, involved an analysis of neuritic plaques and neurofibrillary tangles in brain specimens from 124 diabetics and 124 nondiabetics.
The diabetic group consisted of 29 patients who had never used antidiabetic agents, 49 who had received insulin only, 28 treated with agents other than insulin, and 18 treated with both insulin and oral antidiabetic medications.
The overall neuritic plaque rating, the rating in the entorhinal cortex and amygdala, and the neuritic plaque count in all regions examined differed significantly among the groups. In all of the analyses, the combined medication group had fewer neuritic plaques than did the other groups.
By contrast, the authors found no significant difference in neurofibrillary tangles between the groups.
The findings provide “evidence of substantially lower neuritic plaque density in diabetic subjects taking both insulin and hypoglycemic medication consistent with the effects of both on the neurobiology of insulin,” the researchers concluded. “These pathways should be considered as potentially mechanistically important in the etiology of β amyloid–associated neuropathology and deposition of neuritic plaques.”
Neurology. 2008;71(10):750-757.
Antiepileptic Drug Use May Contribute to Bone Loss in Older Men
NEW YORK, September 19 (Reuters Health)—Use of non–enzyme-inducing antiepileptic drugs (AEDs) independently raises the risk of bone loss at the hip in older men, results of a prospective study suggest.
In the September 2 issue of Neurology, Dr. Kristine E. Ensrud, from the Veterans Affairs Medical Center in Minneapolis, and colleagues pointed out, “AED use may be associated with higher rates of bone loss because [the drugs] may have adverse effects on bone metabolism. On the other hand, AED use may be a marker of factors such as poor health ... that are associated with greater rates of bone loss.”
In 4,222 older community-dwelling participants in the Osteoporosis Fractures in Men study, the researchers analyzed use of non–enzyme-inducing and enzyme-inducing AEDs. They also measured subjects’ hip bone mineral density (BMD) at baseline and at an average of 4.6 years later.
Among men who didn’t use AEDs at all, the average rate of decline in total hip BMD per year was -0.35%, compared with -0.46% among enzyme-inducing AED users and -0.53% among non–enzyme-inducing AED users.
The rate of loss per year was -0.60% among men who were taking non–enzyme-inducing AEDs at both examinations, -0.51% among men taking non–enzyme-inducing AEDs at one examination only, and -0.35% among nonusers.
The researchers pointed out that these findings were achieved after adjustment for a myriad of potential confounders not accounted for in past studies, including age, race, health status, baseline BMD, physical activity, smoking, alcohol intake, total calcium intake, diabetes, kidney disease, bisphosphonate or SSRI use, and BMI.
“Our results suggest that non–enzyme-inducing AED use is associated in a graded manner with rates of hip bone loss in older men, with lower rates of loss among nonusers of AEDs, intermediate rates of loss among intermittent users, and high rates of loss among continuous users,” the authors wrote.
They added, “These findings are supported by prior studies reporting higher fracture rates among non–enzyme-inducing AED users compared with nonusers of AEDs or a similar fracture risk between patients taking non–enzyme-inducing AEDs versus those taking enzyme-inducing AEDs.”
In particular, the results suggest that men who take gabapentin have a 1.4- to 1.8-fold higher adjusted rate of bone loss at the hip compared with nonusers of AEDs.
Neurology. 2008;71(10):723-730.
Relatives of Patients With Brain Tumors Seem to Be at Increased Risk
NEW YORK, September 22 (Reu­ters Health)—By linking a Utah genealogy database to statewide cancer records, researchers have uncovered evidence of a familial contribution to primary brain cancer risk.
“There has been landmark work done previously using the Utah Population Database resource, in discovering hereditary associations and specific genes for breast cancer, colon cancer, and other nonneoplastic diseases,” Dr. Deborah T. Blumenthal told Reuters Health. “We sought to utilize this unique resource to search for familial relationships in primary brain tumors.”
The database includes more than two million persons with up to 10 generations of genealogic data. Dr. Blumenthal, currently at Tel-Aviv Sourasky Medical Center, and Dr. Lisa A. Cannon-Albright, at the University of Utah in Salt Lake City, examined the risk of brain tumors in the relatives of 744 individuals with astrocytoma, 658 patients with glioblastoma, and one patient with both.
According to their report in the September 23 issue of Neurology, significant excess risk exists among first-degree relatives of patients with astrocytoma or glioblastoma, compared with the rate of disease in the general population.
There was also significantly increased risk among second-degree relatives of patients with astrocytoma.
Noting that cancers with a genetic contribution often occur at an earlier age than sporadic cases, the researchers report that first-degree relatives of patients diagnosed before age 20 were at higher risk. Risk was also elevated for family members of cases with astrocytoma diagnosed before age 15.
“These findings, which remained significant beyond first-degree relations, support the hypothesis of familiality—a common gene or group of genes that may predispose individuals to brain tumors,” Dr. Blumenthal said.
“It needs to be stressed that we are still considering a very small minority (less than 5%) of an already small group of patients (less than 20,000/year in the US) who may have a familial risk for being affected with these tumors,” she added. “However, clinicians should be aware of this association and carefully query family history in their patients. If other family members have neurologic symptoms, the threshold for screening them for a brain tumor should be lower.”
Such symptoms, she explained, may include “new, progressive headaches, nausea or vomiting, seizures (which may be motor or sensory phenomenon, or even episodes of odd smells/tastes or déjà vu, when the temporal lobe is involved), changes in vision, changes in speech or language ability (word-finding difficulty), changes in personality (including apathy or apparent depression), and imbalance or incoordination.”

The researchers now plan prospective follow-up of these high-risk pedigrees.
“If genes or loci responsible for brain tumors could be identified, they could have relevance not only for familial tumors, but for the larger population as well,” Dr. Blumenthal concluded. “Ultimately, with such information, screening and even preventive therapy for malignant brain tumors might be possible in the future.”
Neurology. 2008;71(13):1015-1020.
Engerix B Vaccine May Increase the Risk of Multiple Sclerosis in Children
NEW YORK, September 26 (Reuters Health)—Although most hepatitis B vaccines do not seem to increase the risk of multiple sclerosis (MS) in children, use of one particular brand—Engerix B (GlaxoSmithKline)—may, according to findings from a study conducted in France.
In the study reported in the October 8 online issue of Neurology, the odds ratio (OR) for Engerix B exposure was 2.77 among children with MS, compared with an unaffected control group.
Prior reports have suggested a link between hepatitis B vaccine exposure and CNS inflammatory demyelination, including MS as well as acute disseminated encephalomyelitis and transverse myelitis. In general, however, findings from epidemiologic studies have not supported an association.
The focus of the current case-control study was on the neurologic effects of hepatitis B vaccination in children, since most of the prior investigations involved adults only, lead author Dr. Yann Mikaeloff, from Assistance Publique-Hôpitaux de Paris, and colleagues noted.
Case patients included 349 children with a first episode of CNS inflammatory demyelination between 1994 and 2003. Each subject was matched to up to 12 controls by age, gender, and geographic location.
In the overall analysis, hepatitis B vaccination did not increase the risk of CNS inflammatory demyelination.
However, when the analysis was confined to vaccine-compliant subjects, vaccine exposure more than three years prior to the index date was linked to an elevated risk (OR, 1.50). Further analysis showed that this association was mostly driven by the risk seen with Engerix B use (OR, 1.74).
Vaccine exposure more than three years before the index date was tied to a 2.12-fold increased risk of confirmed MS. Once again, however, this was mostly accounted for by Engerix B use (OR,  2.77).
As to why one brand of hepatitis B vaccine is safe while another may not be, the authors offer two possible explanations: “(1) each vaccine uses a different section of the hepatitis B antigen, and some protein fragments produced by yeasts may induce molecular mimicry, while others do not; (2) the production process varies by brand, and differences in yeast protein content may be crucial if yeast protein may trigger autoimmune reactions.”
The packaging insert (December 2006) for Engerix B mentions reports of patients with MS who experience exacerbations following use of the vaccine, but it points out that causality has not been established. The insert also notes new cases of MS and transverse myelitis that occurred after vaccination and were identified during postmarketing surveillance.
Neurology. 2008 Oct 8; [Epub ahead of print].

Alzheimer’s Pathology Reduced With Combined Diabetes Therapy
NEW YORK, September 9 (Reuters Health)—In a postmortem study of patients with Alzheimer’s disease, diabetic subjects treated with both insulin and oral hypoglycemic agents had lower neuritic plaque densities than did other diabetics and nondiabetics, new research shows.
In several studies, type 2 diabetes has been identified as a risk factor for Alzheimer’s disease. The link between diabetes and Alzheimer’s neuropathology, by contrast, is less clear, according to the report in the September 2 issue of Neurology.
The current study, conducted by Dr. M. S. Beeri, from Mount Sinai School of Medicine in New York City, and colleagues, involved an analysis of neuritic plaques and neurofibrillary tangles in brain specimens from 124 diabetics and 124 nondiabetics.
The diabetic group consisted of 29 patients who had never used antidiabetic agents, 49 who had received insulin only, 28 treated with agents other than insulin, and 18 treated with both insulin and oral antidiabetic medications.
The overall neuritic plaque rating, the rating in the entorhinal cortex and amygdala, and the neuritic plaque count in all regions examined differed significantly among the groups. In all of the analyses, the combined medication group had fewer neuritic plaques than did the other groups.
By contrast, the authors found no significant difference in neurofibrillary tangles between the groups.
The findings provide “evidence of substantially lower neuritic plaque density in diabetic subjects taking both insulin and hypoglycemic medication consistent with the effects of both on the neurobiology of insulin,” the researchers concluded. “These pathways should be considered as potentially mechanistically important in the etiology of β amyloid–associated neuropathology and deposition of neuritic plaques.”
Neurology. 2008;71(10):750-757.
Antiepileptic Drug Use May Contribute to Bone Loss in Older Men
NEW YORK, September 19 (Reuters Health)—Use of non–enzyme-inducing antiepileptic drugs (AEDs) independently raises the risk of bone loss at the hip in older men, results of a prospective study suggest.
In the September 2 issue of Neurology, Dr. Kristine E. Ensrud, from the Veterans Affairs Medical Center in Minneapolis, and colleagues pointed out, “AED use may be associated with higher rates of bone loss because [the drugs] may have adverse effects on bone metabolism. On the other hand, AED use may be a marker of factors such as poor health ... that are associated with greater rates of bone loss.”
In 4,222 older community-dwelling participants in the Osteoporosis Fractures in Men study, the researchers analyzed use of non–enzyme-inducing and enzyme-inducing AEDs. They also measured subjects’ hip bone mineral density (BMD) at baseline and at an average of 4.6 years later.
Among men who didn’t use AEDs at all, the average rate of decline in total hip BMD per year was -0.35%, compared with -0.46% among enzyme-inducing AED users and -0.53% among non–enzyme-inducing AED users.
The rate of loss per year was -0.60% among men who were taking non–enzyme-inducing AEDs at both examinations, -0.51% among men taking non–enzyme-inducing AEDs at one examination only, and -0.35% among nonusers.
The researchers pointed out that these findings were achieved after adjustment for a myriad of potential confounders not accounted for in past studies, including age, race, health status, baseline BMD, physical activity, smoking, alcohol intake, total calcium intake, diabetes, kidney disease, bisphosphonate or SSRI use, and BMI.
“Our results suggest that non–enzyme-inducing AED use is associated in a graded manner with rates of hip bone loss in older men, with lower rates of loss among nonusers of AEDs, intermediate rates of loss among intermittent users, and high rates of loss among continuous users,” the authors wrote.
They added, “These findings are supported by prior studies reporting higher fracture rates among non–enzyme-inducing AED users compared with nonusers of AEDs or a similar fracture risk between patients taking non–enzyme-inducing AEDs versus those taking enzyme-inducing AEDs.”
In particular, the results suggest that men who take gabapentin have a 1.4- to 1.8-fold higher adjusted rate of bone loss at the hip compared with nonusers of AEDs.
Neurology. 2008;71(10):723-730.
Relatives of Patients With Brain Tumors Seem to Be at Increased Risk
NEW YORK, September 22 (Reu­ters Health)—By linking a Utah genealogy database to statewide cancer records, researchers have uncovered evidence of a familial contribution to primary brain cancer risk.
“There has been landmark work done previously using the Utah Population Database resource, in discovering hereditary associations and specific genes for breast cancer, colon cancer, and other nonneoplastic diseases,” Dr. Deborah T. Blumenthal told Reuters Health. “We sought to utilize this unique resource to search for familial relationships in primary brain tumors.”
The database includes more than two million persons with up to 10 generations of genealogic data. Dr. Blumenthal, currently at Tel-Aviv Sourasky Medical Center, and Dr. Lisa A. Cannon-Albright, at the University of Utah in Salt Lake City, examined the risk of brain tumors in the relatives of 744 individuals with astrocytoma, 658 patients with glioblastoma, and one patient with both.
According to their report in the September 23 issue of Neurology, significant excess risk exists among first-degree relatives of patients with astrocytoma or glioblastoma, compared with the rate of disease in the general population.
There was also significantly increased risk among second-degree relatives of patients with astrocytoma.
Noting that cancers with a genetic contribution often occur at an earlier age than sporadic cases, the researchers report that first-degree relatives of patients diagnosed before age 20 were at higher risk. Risk was also elevated for family members of cases with astrocytoma diagnosed before age 15.
“These findings, which remained significant beyond first-degree relations, support the hypothesis of familiality—a common gene or group of genes that may predispose individuals to brain tumors,” Dr. Blumenthal said.
“It needs to be stressed that we are still considering a very small minority (less than 5%) of an already small group of patients (less than 20,000/year in the US) who may have a familial risk for being affected with these tumors,” she added. “However, clinicians should be aware of this association and carefully query family history in their patients. If other family members have neurologic symptoms, the threshold for screening them for a brain tumor should be lower.”
Such symptoms, she explained, may include “new, progressive headaches, nausea or vomiting, seizures (which may be motor or sensory phenomenon, or even episodes of odd smells/tastes or déjà vu, when the temporal lobe is involved), changes in vision, changes in speech or language ability (word-finding difficulty), changes in personality (including apathy or apparent depression), and imbalance or incoordination.”

The researchers now plan prospective follow-up of these high-risk pedigrees.
“If genes or loci responsible for brain tumors could be identified, they could have relevance not only for familial tumors, but for the larger population as well,” Dr. Blumenthal concluded. “Ultimately, with such information, screening and even preventive therapy for malignant brain tumors might be possible in the future.”
Neurology. 2008;71(13):1015-1020.
Engerix B Vaccine May Increase the Risk of Multiple Sclerosis in Children
NEW YORK, September 26 (Reuters Health)—Although most hepatitis B vaccines do not seem to increase the risk of multiple sclerosis (MS) in children, use of one particular brand—Engerix B (GlaxoSmithKline)—may, according to findings from a study conducted in France.
In the study reported in the October 8 online issue of Neurology, the odds ratio (OR) for Engerix B exposure was 2.77 among children with MS, compared with an unaffected control group.
Prior reports have suggested a link between hepatitis B vaccine exposure and CNS inflammatory demyelination, including MS as well as acute disseminated encephalomyelitis and transverse myelitis. In general, however, findings from epidemiologic studies have not supported an association.
The focus of the current case-control study was on the neurologic effects of hepatitis B vaccination in children, since most of the prior investigations involved adults only, lead author Dr. Yann Mikaeloff, from Assistance Publique-Hôpitaux de Paris, and colleagues noted.
Case patients included 349 children with a first episode of CNS inflammatory demyelination between 1994 and 2003. Each subject was matched to up to 12 controls by age, gender, and geographic location.
In the overall analysis, hepatitis B vaccination did not increase the risk of CNS inflammatory demyelination.
However, when the analysis was confined to vaccine-compliant subjects, vaccine exposure more than three years prior to the index date was linked to an elevated risk (OR, 1.50). Further analysis showed that this association was mostly driven by the risk seen with Engerix B use (OR, 1.74).
Vaccine exposure more than three years before the index date was tied to a 2.12-fold increased risk of confirmed MS. Once again, however, this was mostly accounted for by Engerix B use (OR,  2.77).
As to why one brand of hepatitis B vaccine is safe while another may not be, the authors offer two possible explanations: “(1) each vaccine uses a different section of the hepatitis B antigen, and some protein fragments produced by yeasts may induce molecular mimicry, while others do not; (2) the production process varies by brand, and differences in yeast protein content may be crucial if yeast protein may trigger autoimmune reactions.”
The packaging insert (December 2006) for Engerix B mentions reports of patients with MS who experience exacerbations following use of the vaccine, but it points out that causality has not been established. The insert also notes new cases of MS and transverse myelitis that occurred after vaccination and were identified during postmarketing surveillance.
Neurology. 2008 Oct 8; [Epub ahead of print].

CHICAGO—Many of the neuropsychologic tests that target cognitive domains affected in patients with multiple sclerosis (MS) do not appear to be predictive of neuropsychiatric symptoms in these patients, as has been previously hypothesized, reported Jesus Lovera, PhD, and colleagues. Neuropsychiatric symptoms occur in 80% of patients with MS, and depression is the most common of these symptoms, the researchers stated at the 60th Annual Meeting of the American Academy of Neurology.

The investigators studied 109 patients (mean age, 51) who were enrolled in clinical trials of memantine for cognitive impairment in MS. Among the inclusion criteria were significant cognitive complaints, a score 1 SD below the normal population average on the Paced Auditory Serial Addition Test (PASAT) or the California Verbal Learning Test-II (CVLT-II), and a Beck Depression Inventory–IA score of less than 19.

Neuropsychologic tests included a three-second version of the PASAT, the CVLT-II, the Symbol Digits Modalities Test, the Delis-Kaplan Executive Function System (D-KEFS) sorting test, the Controlled Oral Word Association Test (COWAT), and the Victoria version of the Stroop test. Neuropsychiatric symptoms were assessed using the Modified Neuropsychiatric Inventory.

According to Dr. Lovera, who is an Instructor in the Department of Neurology at Oregon Health and Science University in Portland, and colleagues, 55 patients had one or more neuropsychiatric symptoms: 42 had irritability, 31 anxiety, 24 agitation/aggression, 23 apathy, 18 disinhibition, and 11 euphoria. Tests of attention and processing speed (PASAT), verbal fluency (COWAT), sorting (D-KEFS), and verbal learning and recall (CVLT-II) were not predictive of neuropsychiatric symptoms.

Perseveration and intrusions, as measured by the Stroop test and the CVLT-II, were highly predictive of neuropsychiatric symptoms.

Physicians should consider screening for neuropsychiatric symptoms in patients with MS, particularly in those with cognitive complaints, commented the researchers. They also advised that patients with MS who have impairment on the Stroop test or intrusions or repetitions on the CVLT-II be screened for neuropsychiatric symptoms.

CHICAGO—Many of the neuropsychologic tests that target cognitive domains affected in patients with multiple sclerosis (MS) do not appear to be predictive of neuropsychiatric symptoms in these patients, as has been previously hypothesized, reported Jesus Lovera, PhD, and colleagues. Neuropsychiatric symptoms occur in 80% of patients with MS, and depression is the most common of these symptoms, the researchers stated at the 60th Annual Meeting of the American Academy of Neurology.

The investigators studied 109 patients (mean age, 51) who were enrolled in clinical trials of memantine for cognitive impairment in MS. Among the inclusion criteria were significant cognitive complaints, a score 1 SD below the normal population average on the Paced Auditory Serial Addition Test (PASAT) or the California Verbal Learning Test-II (CVLT-II), and a Beck Depression Inventory–IA score of less than 19.

Neuropsychologic tests included a three-second version of the PASAT, the CVLT-II, the Symbol Digits Modalities Test, the Delis-Kaplan Executive Function System (D-KEFS) sorting test, the Controlled Oral Word Association Test (COWAT), and the Victoria version of the Stroop test. Neuropsychiatric symptoms were assessed using the Modified Neuropsychiatric Inventory.

According to Dr. Lovera, who is an Instructor in the Department of Neurology at Oregon Health and Science University in Portland, and colleagues, 55 patients had one or more neuropsychiatric symptoms: 42 had irritability, 31 anxiety, 24 agitation/aggression, 23 apathy, 18 disinhibition, and 11 euphoria. Tests of attention and processing speed (PASAT), verbal fluency (COWAT), sorting (D-KEFS), and verbal learning and recall (CVLT-II) were not predictive of neuropsychiatric symptoms.

Perseveration and intrusions, as measured by the Stroop test and the CVLT-II, were highly predictive of neuropsychiatric symptoms.

Physicians should consider screening for neuropsychiatric symptoms in patients with MS, particularly in those with cognitive complaints, commented the researchers. They also advised that patients with MS who have impairment on the Stroop test or intrusions or repetitions on the CVLT-II be screened for neuropsychiatric symptoms.

CHICAGO—Many of the neuropsychologic tests that target cognitive domains affected in patients with multiple sclerosis (MS) do not appear to be predictive of neuropsychiatric symptoms in these patients, as has been previously hypothesized, reported Jesus Lovera, PhD, and colleagues. Neuropsychiatric symptoms occur in 80% of patients with MS, and depression is the most common of these symptoms, the researchers stated at the 60th Annual Meeting of the American Academy of Neurology.

The investigators studied 109 patients (mean age, 51) who were enrolled in clinical trials of memantine for cognitive impairment in MS. Among the inclusion criteria were significant cognitive complaints, a score 1 SD below the normal population average on the Paced Auditory Serial Addition Test (PASAT) or the California Verbal Learning Test-II (CVLT-II), and a Beck Depression Inventory–IA score of less than 19.

Neuropsychologic tests included a three-second version of the PASAT, the CVLT-II, the Symbol Digits Modalities Test, the Delis-Kaplan Executive Function System (D-KEFS) sorting test, the Controlled Oral Word Association Test (COWAT), and the Victoria version of the Stroop test. Neuropsychiatric symptoms were assessed using the Modified Neuropsychiatric Inventory.

According to Dr. Lovera, who is an Instructor in the Department of Neurology at Oregon Health and Science University in Portland, and colleagues, 55 patients had one or more neuropsychiatric symptoms: 42 had irritability, 31 anxiety, 24 agitation/aggression, 23 apathy, 18 disinhibition, and 11 euphoria. Tests of attention and processing speed (PASAT), verbal fluency (COWAT), sorting (D-KEFS), and verbal learning and recall (CVLT-II) were not predictive of neuropsychiatric symptoms.

Perseveration and intrusions, as measured by the Stroop test and the CVLT-II, were highly predictive of neuropsychiatric symptoms.

Physicians should consider screening for neuropsychiatric symptoms in patients with MS, particularly in those with cognitive complaints, commented the researchers. They also advised that patients with MS who have impairment on the Stroop test or intrusions or repetitions on the CVLT-II be screened for neuropsychiatric symptoms.

DENVER—Several “red flags” in neurologic examinations can provide valuable information that helps to accurately diagnose and direct the care of patients with multiple sclerosis (MS) who complain about certain symptoms, according to Stephen S. Kamin, MD. These red flags may “aid in diagnosis of disease, detect improvements or worsening of an already established disease, and discover unexpected deficits in the patient we may not even be aware of that require explanation, further investigation, or intervention,” he reported at the 22nd Annual Meeting of the Consortium of Multiple Sclerosis Centers.
Patients often complain of vague symptoms that may, at first, be difficult to interpret or treat. Patients’ descriptions of symptoms “don’t have necessarily very specific meanings, or they have rather personalized meanings,” said Dr. Kamin, Associate Medical Director of the Multiple Sclerosis Center at Holy Name Hospital in Teaneck, New Jersey, and Clinical Associate Professor in Neuroscience at the University of Medicine and Dentistry of New Jersey in Newark. “Not everybody uses the words in the same way,” he continued. “Some of these that you hear a lot are blurry vision, weakness, stiffness, tightness, stabbing, or unsteady gait. These are things that patients often complain about but that may mean a number of different things.” He recommended using a variety of tests as a way of distinguishing among the different possible explanations for these symptoms, including those that may be unrelated to MS.
Blurry Vision
Many patients older than 40 who complain of blurry vision, for example, simply need reading glasses; the cause is aging, not disease. In other cases, visual field defects can be interpreted as blurriness. Dr. Kamin suggested that in addition to Snellen cards, pinhole testing and computerized visual field testing are often useful. “In cases where you’re not sure exactly what’s going on,” he added, “you certainly shouldn’t hesitate to refer a person to an ophthalmologist or neuro-ophthalmologist for some more detailed formal testing.”
Many patients who complain of blurry vision have some form of diplopia. As a first approach, Dr. Kamin advised determining whether it occurs in one or both eyes, confirming that there is actual doubling and ascertaining its direction. “If [patients] see double with only one eye open, it’s not neurologic,” he explained. “It’s either ophthalmologic or psychiatric. You can help figure out exactly the nature of the diplopia by asking them, ‘Which direction of vision is the diplopia worse?’ and it will be in the direction of the weakness of the eye muscle involved. Often these are situations where you wind up sending people to a neuro-ophthalmologist for analysis.”
Dr. Kamin noted that the most common cause of diplopia in patients with MS is internuclear ophthalmoplegia caused by a lesion in the medial longitudinal fasciculus. Other causes, such as third or sixth nerve palsy, might be indicative of comorbidities such as diabetes or aneurysm. More rarely, blurry vision turns out to be oscillopsia, a subjective sense of visual field movement. This is produced by nystagmus and can sometimes be treated with topir­amate, baclofen, or clonazepam.
Weakness, Numbness, and Stiffness
Another common, vague complaint is weakness. “Weakness isn’t always weakness,” Dr. Kamin pointed out. “Sometimes it’s muscle weakness, fatigue, numbness, or incoordination. Numbness isn’t always numbness. Sometimes it’s weakness. So it’s really important, obviously, to get a good history and make sure you’re speaking the same language.
“But then you can use your neurologic examination to see, ‘Is this person really weak?’ or ‘Is what they have ataxia, and they’re calling that weakness?’ … ‘I can’t use my hand. It’s weak.’ Well, maybe it’s not weak; maybe it’s incoordinated, but the strength is actually fine,” he said. “And again, that’s going to be important. It reflects a disease in a different part of the nervous system, and your approach may be different.”
Likewise, stiffness may refer to contracture, spasticity, or sensations of swollenness or tightness in a limb. Dr. Kamin emphasized the importance of distinguishing between sensory problems and motor problems before attempting a course of treatment. True spasticity can be gauged using the Ashworth scale, and patients can be treated with stretching exercises and medications, such as baclofen and tizanidine. Contracture also responds well to stretching and may sometimes require tendon release or casting. Dr. Kamin noted that sensory problems are “much harder to treat” and named a variety of medications that may be helpful, from tricyclic antidepressants to anticonvulsants such as topiramate and gabapentin.
Unexpected and Unrelated Conditions
Neurologic examinations may also be especially helpful in identifying unexpected and unrelated conditions, said Dr. Kamin. One common difficulty is determining whether a sudden new neurologic problem is caused by MS or by a stroke. “Strokes are usually very rapid—minutes, hours, rarely longer than that,” Dr. Kamin explained. “MS attacks occur over hours, and they progress over days or even longer. So the tempo of the onset can be very helpful in swaying you one way or the other.” Other symptoms that are more common in stroke-related hemiparesis than in MS-related hemiparesis are flaccidity, complete plegia, visual field deficits, and aphasia or other language problems.
In the case of paraparesis, Dr. Kamin advised asking patients about back pain and fever, more common in spinal cord compression than MS. He added that for anyone with a history of cancer, metastatic cord compression is the most likely cause, even if physicians believed that the cancer had been cured. If a patient has language difficulties, a language examination can distinguish between dysarthria, which is common with MS, and dysphasia or aphasia, which are more likely to be caused by tumors or other neurologic problems. For ocular problems, pain and a swollen optic nerve head are often signs of optic neuritis, while ischemic optic neuropathy is painless. “None of these is an all-or-nothing situation,” he added. “It’s all a matter of probabilities and putting it all together. But these are some of the things that you can use.”

DENVER—Several “red flags” in neurologic examinations can provide valuable information that helps to accurately diagnose and direct the care of patients with multiple sclerosis (MS) who complain about certain symptoms, according to Stephen S. Kamin, MD. These red flags may “aid in diagnosis of disease, detect improvements or worsening of an already established disease, and discover unexpected deficits in the patient we may not even be aware of that require explanation, further investigation, or intervention,” he reported at the 22nd Annual Meeting of the Consortium of Multiple Sclerosis Centers.
Patients often complain of vague symptoms that may, at first, be difficult to interpret or treat. Patients’ descriptions of symptoms “don’t have necessarily very specific meanings, or they have rather personalized meanings,” said Dr. Kamin, Associate Medical Director of the Multiple Sclerosis Center at Holy Name Hospital in Teaneck, New Jersey, and Clinical Associate Professor in Neuroscience at the University of Medicine and Dentistry of New Jersey in Newark. “Not everybody uses the words in the same way,” he continued. “Some of these that you hear a lot are blurry vision, weakness, stiffness, tightness, stabbing, or unsteady gait. These are things that patients often complain about but that may mean a number of different things.” He recommended using a variety of tests as a way of distinguishing among the different possible explanations for these symptoms, including those that may be unrelated to MS.
Blurry Vision
Many patients older than 40 who complain of blurry vision, for example, simply need reading glasses; the cause is aging, not disease. In other cases, visual field defects can be interpreted as blurriness. Dr. Kamin suggested that in addition to Snellen cards, pinhole testing and computerized visual field testing are often useful. “In cases where you’re not sure exactly what’s going on,” he added, “you certainly shouldn’t hesitate to refer a person to an ophthalmologist or neuro-ophthalmologist for some more detailed formal testing.”
Many patients who complain of blurry vision have some form of diplopia. As a first approach, Dr. Kamin advised determining whether it occurs in one or both eyes, confirming that there is actual doubling and ascertaining its direction. “If [patients] see double with only one eye open, it’s not neurologic,” he explained. “It’s either ophthalmologic or psychiatric. You can help figure out exactly the nature of the diplopia by asking them, ‘Which direction of vision is the diplopia worse?’ and it will be in the direction of the weakness of the eye muscle involved. Often these are situations where you wind up sending people to a neuro-ophthalmologist for analysis.”
Dr. Kamin noted that the most common cause of diplopia in patients with MS is internuclear ophthalmoplegia caused by a lesion in the medial longitudinal fasciculus. Other causes, such as third or sixth nerve palsy, might be indicative of comorbidities such as diabetes or aneurysm. More rarely, blurry vision turns out to be oscillopsia, a subjective sense of visual field movement. This is produced by nystagmus and can sometimes be treated with topir­amate, baclofen, or clonazepam.
Weakness, Numbness, and Stiffness
Another common, vague complaint is weakness. “Weakness isn’t always weakness,” Dr. Kamin pointed out. “Sometimes it’s muscle weakness, fatigue, numbness, or incoordination. Numbness isn’t always numbness. Sometimes it’s weakness. So it’s really important, obviously, to get a good history and make sure you’re speaking the same language.
“But then you can use your neurologic examination to see, ‘Is this person really weak?’ or ‘Is what they have ataxia, and they’re calling that weakness?’ … ‘I can’t use my hand. It’s weak.’ Well, maybe it’s not weak; maybe it’s incoordinated, but the strength is actually fine,” he said. “And again, that’s going to be important. It reflects a disease in a different part of the nervous system, and your approach may be different.”
Likewise, stiffness may refer to contracture, spasticity, or sensations of swollenness or tightness in a limb. Dr. Kamin emphasized the importance of distinguishing between sensory problems and motor problems before attempting a course of treatment. True spasticity can be gauged using the Ashworth scale, and patients can be treated with stretching exercises and medications, such as baclofen and tizanidine. Contracture also responds well to stretching and may sometimes require tendon release or casting. Dr. Kamin noted that sensory problems are “much harder to treat” and named a variety of medications that may be helpful, from tricyclic antidepressants to anticonvulsants such as topiramate and gabapentin.
Unexpected and Unrelated Conditions
Neurologic examinations may also be especially helpful in identifying unexpected and unrelated conditions, said Dr. Kamin. One common difficulty is determining whether a sudden new neurologic problem is caused by MS or by a stroke. “Strokes are usually very rapid—minutes, hours, rarely longer than that,” Dr. Kamin explained. “MS attacks occur over hours, and they progress over days or even longer. So the tempo of the onset can be very helpful in swaying you one way or the other.” Other symptoms that are more common in stroke-related hemiparesis than in MS-related hemiparesis are flaccidity, complete plegia, visual field deficits, and aphasia or other language problems.
In the case of paraparesis, Dr. Kamin advised asking patients about back pain and fever, more common in spinal cord compression than MS. He added that for anyone with a history of cancer, metastatic cord compression is the most likely cause, even if physicians believed that the cancer had been cured. If a patient has language difficulties, a language examination can distinguish between dysarthria, which is common with MS, and dysphasia or aphasia, which are more likely to be caused by tumors or other neurologic problems. For ocular problems, pain and a swollen optic nerve head are often signs of optic neuritis, while ischemic optic neuropathy is painless. “None of these is an all-or-nothing situation,” he added. “It’s all a matter of probabilities and putting it all together. But these are some of the things that you can use.”

DENVER—Several “red flags” in neurologic examinations can provide valuable information that helps to accurately diagnose and direct the care of patients with multiple sclerosis (MS) who complain about certain symptoms, according to Stephen S. Kamin, MD. These red flags may “aid in diagnosis of disease, detect improvements or worsening of an already established disease, and discover unexpected deficits in the patient we may not even be aware of that require explanation, further investigation, or intervention,” he reported at the 22nd Annual Meeting of the Consortium of Multiple Sclerosis Centers.
Patients often complain of vague symptoms that may, at first, be difficult to interpret or treat. Patients’ descriptions of symptoms “don’t have necessarily very specific meanings, or they have rather personalized meanings,” said Dr. Kamin, Associate Medical Director of the Multiple Sclerosis Center at Holy Name Hospital in Teaneck, New Jersey, and Clinical Associate Professor in Neuroscience at the University of Medicine and Dentistry of New Jersey in Newark. “Not everybody uses the words in the same way,” he continued. “Some of these that you hear a lot are blurry vision, weakness, stiffness, tightness, stabbing, or unsteady gait. These are things that patients often complain about but that may mean a number of different things.” He recommended using a variety of tests as a way of distinguishing among the different possible explanations for these symptoms, including those that may be unrelated to MS.
Blurry Vision
Many patients older than 40 who complain of blurry vision, for example, simply need reading glasses; the cause is aging, not disease. In other cases, visual field defects can be interpreted as blurriness. Dr. Kamin suggested that in addition to Snellen cards, pinhole testing and computerized visual field testing are often useful. “In cases where you’re not sure exactly what’s going on,” he added, “you certainly shouldn’t hesitate to refer a person to an ophthalmologist or neuro-ophthalmologist for some more detailed formal testing.”
Many patients who complain of blurry vision have some form of diplopia. As a first approach, Dr. Kamin advised determining whether it occurs in one or both eyes, confirming that there is actual doubling and ascertaining its direction. “If [patients] see double with only one eye open, it’s not neurologic,” he explained. “It’s either ophthalmologic or psychiatric. You can help figure out exactly the nature of the diplopia by asking them, ‘Which direction of vision is the diplopia worse?’ and it will be in the direction of the weakness of the eye muscle involved. Often these are situations where you wind up sending people to a neuro-ophthalmologist for analysis.”
Dr. Kamin noted that the most common cause of diplopia in patients with MS is internuclear ophthalmoplegia caused by a lesion in the medial longitudinal fasciculus. Other causes, such as third or sixth nerve palsy, might be indicative of comorbidities such as diabetes or aneurysm. More rarely, blurry vision turns out to be oscillopsia, a subjective sense of visual field movement. This is produced by nystagmus and can sometimes be treated with topir­amate, baclofen, or clonazepam.
Weakness, Numbness, and Stiffness
Another common, vague complaint is weakness. “Weakness isn’t always weakness,” Dr. Kamin pointed out. “Sometimes it’s muscle weakness, fatigue, numbness, or incoordination. Numbness isn’t always numbness. Sometimes it’s weakness. So it’s really important, obviously, to get a good history and make sure you’re speaking the same language.
“But then you can use your neurologic examination to see, ‘Is this person really weak?’ or ‘Is what they have ataxia, and they’re calling that weakness?’ … ‘I can’t use my hand. It’s weak.’ Well, maybe it’s not weak; maybe it’s incoordinated, but the strength is actually fine,” he said. “And again, that’s going to be important. It reflects a disease in a different part of the nervous system, and your approach may be different.”
Likewise, stiffness may refer to contracture, spasticity, or sensations of swollenness or tightness in a limb. Dr. Kamin emphasized the importance of distinguishing between sensory problems and motor problems before attempting a course of treatment. True spasticity can be gauged using the Ashworth scale, and patients can be treated with stretching exercises and medications, such as baclofen and tizanidine. Contracture also responds well to stretching and may sometimes require tendon release or casting. Dr. Kamin noted that sensory problems are “much harder to treat” and named a variety of medications that may be helpful, from tricyclic antidepressants to anticonvulsants such as topiramate and gabapentin.
Unexpected and Unrelated Conditions
Neurologic examinations may also be especially helpful in identifying unexpected and unrelated conditions, said Dr. Kamin. One common difficulty is determining whether a sudden new neurologic problem is caused by MS or by a stroke. “Strokes are usually very rapid—minutes, hours, rarely longer than that,” Dr. Kamin explained. “MS attacks occur over hours, and they progress over days or even longer. So the tempo of the onset can be very helpful in swaying you one way or the other.” Other symptoms that are more common in stroke-related hemiparesis than in MS-related hemiparesis are flaccidity, complete plegia, visual field deficits, and aphasia or other language problems.
In the case of paraparesis, Dr. Kamin advised asking patients about back pain and fever, more common in spinal cord compression than MS. He added that for anyone with a history of cancer, metastatic cord compression is the most likely cause, even if physicians believed that the cancer had been cured. If a patient has language difficulties, a language examination can distinguish between dysarthria, which is common with MS, and dysphasia or aphasia, which are more likely to be caused by tumors or other neurologic problems. For ocular problems, pain and a swollen optic nerve head are often signs of optic neuritis, while ischemic optic neuropathy is painless. “None of these is an all-or-nothing situation,” he added. “It’s all a matter of probabilities and putting it all together. But these are some of the things that you can use.”

DENVER—A weak correlation was found between physical and patient-reported outcome measures among patients with multiple sclerosis (MS), according to results of a study presented at the 22nd Annual Meeting of the Consortium of Multiple Sclerosis Centers. Stephen Kirzinger, MD, and colleagues suggested that the true disease impact might be underrepresented, as clinical trials and office evaluations tend to focus on physical measures. Dr. Kirzinger is an Assistant Professor of Neurology and Director of the Multiple Sclerosis Program at the University of Louisville.

Clinical trials involving patients with MS generally focus on the severity and frequency of relapses, as well as on use of MRI to measure disease activity. However, evaluating clinical outcomes by assessing lesions is challenging, as the effects can vary and be unpredictable. Physical assessments, such as the Expanded Disability Status Scale (EDSS), are also commonly used in clinical practice.

Patient-reported outcomes are increasingly being incorporated into clinical trials. They can provide valuable insights by revealing patient perception of disease progression, treatment, and quality of life, noted Dr. Kirzinger. However, he pointed out that relationships between disease progression, physical outcomes, and patient-reported outcomes have been unclear.

Physical Versus Patient-Reported Outcomes
Dr. Kirzinger and colleagues conducted a retrospective chart review of 151 randomly selected patients who were observed for the past decade at the Multiple Sclerosis Center of Baptist Hospital East in Louisville. The investigators sought to determine if correlations existed between patient-reported outcomes of fatigue, depression, and sleepiness with objective measures of fine and gross motor control.

A majority of patients were female (75%), with a median age of 38.8 at diagnosis. Nine percent did not have a disease type noted; 72% had relapsing-remitting MS, 13% had secondary progressive MS, and 5% had primary progressive MS. The most commonly reported symptoms at baseline were fatigue (78%), numbness and tingling (71%), balance problems (70%), weakness (70%), and bladder problems (60%).

Baseline and follow-up data were obtained for five physical disability measures and three patient-reported outcomes. Fine motor control was evaluated with use of the Box and Block Test and the Nine-Hole Peg Test of arm and hand function. Gross motor control was assessed with the 25-ft timed walk; the Tinetti test of gait and balance; and the EDSS, for ambulation ability and disease severity. Patient-reported outcomes were determined with use of the Modified Fatigue Impact Scale (MFIS), Beck Depression Inventory, and Epworth Sleepiness Scale.

The Spearman’s rank correlation test was used to determine the rank coefficient (r) between the physical measures and the patient-reported outcome tests during the patients’ most recent visit, with an r of 1 being a perfect positive correlation and -1 representing a perfect negative correlation. Moderate to strong positive correlations were found among the physical measures, with the strongest correlations occurring between the Box and Block and Nine-Hole Peg tests (r, 0.86). Moderate to strong positive correlations were also observed among the patient-reported outcomes. However, physical and patient-reported outcome measures only weakly correlated with each other, and the only statistically significant r correlations were seen with the MFIS, in comparison with the 25-ft timed walk and the EDSS.

An algorithm was used to determine whether any demographic, disease, or physical factors could be identified as predictors of fatigue. The physical outcome that was most predictive of fatigue was EDSS score, with scores of 1.5 or lower associated with lesser degrees of fatigue and scores of 1.5 or above associated with greater degrees of fatigue.

True Impact of MS  Underestimated
The researchers theorized that aspects of MS measured by patient-reported outcomes and physical assessments may develop independently of one another. Also, it is likely that clinicians do not fully understand the true impact of MS on patients. They recommended that future studies expand on relationships between patient-reported outcomes, physical measures, and other aspects, such as cognition, to develop more comprehensive and accurate insights into disease activity and treatment strategies.

—Beth Tansey Peller

DENVER—A weak correlation was found between physical and patient-reported outcome measures among patients with multiple sclerosis (MS), according to results of a study presented at the 22nd Annual Meeting of the Consortium of Multiple Sclerosis Centers. Stephen Kirzinger, MD, and colleagues suggested that the true disease impact might be underrepresented, as clinical trials and office evaluations tend to focus on physical measures. Dr. Kirzinger is an Assistant Professor of Neurology and Director of the Multiple Sclerosis Program at the University of Louisville.

Clinical trials involving patients with MS generally focus on the severity and frequency of relapses, as well as on use of MRI to measure disease activity. However, evaluating clinical outcomes by assessing lesions is challenging, as the effects can vary and be unpredictable. Physical assessments, such as the Expanded Disability Status Scale (EDSS), are also commonly used in clinical practice.

Patient-reported outcomes are increasingly being incorporated into clinical trials. They can provide valuable insights by revealing patient perception of disease progression, treatment, and quality of life, noted Dr. Kirzinger. However, he pointed out that relationships between disease progression, physical outcomes, and patient-reported outcomes have been unclear.

Physical Versus Patient-Reported Outcomes
Dr. Kirzinger and colleagues conducted a retrospective chart review of 151 randomly selected patients who were observed for the past decade at the Multiple Sclerosis Center of Baptist Hospital East in Louisville. The investigators sought to determine if correlations existed between patient-reported outcomes of fatigue, depression, and sleepiness with objective measures of fine and gross motor control.

A majority of patients were female (75%), with a median age of 38.8 at diagnosis. Nine percent did not have a disease type noted; 72% had relapsing-remitting MS, 13% had secondary progressive MS, and 5% had primary progressive MS. The most commonly reported symptoms at baseline were fatigue (78%), numbness and tingling (71%), balance problems (70%), weakness (70%), and bladder problems (60%).

Baseline and follow-up data were obtained for five physical disability measures and three patient-reported outcomes. Fine motor control was evaluated with use of the Box and Block Test and the Nine-Hole Peg Test of arm and hand function. Gross motor control was assessed with the 25-ft timed walk; the Tinetti test of gait and balance; and the EDSS, for ambulation ability and disease severity. Patient-reported outcomes were determined with use of the Modified Fatigue Impact Scale (MFIS), Beck Depression Inventory, and Epworth Sleepiness Scale.

The Spearman’s rank correlation test was used to determine the rank coefficient (r) between the physical measures and the patient-reported outcome tests during the patients’ most recent visit, with an r of 1 being a perfect positive correlation and -1 representing a perfect negative correlation. Moderate to strong positive correlations were found among the physical measures, with the strongest correlations occurring between the Box and Block and Nine-Hole Peg tests (r, 0.86). Moderate to strong positive correlations were also observed among the patient-reported outcomes. However, physical and patient-reported outcome measures only weakly correlated with each other, and the only statistically significant r correlations were seen with the MFIS, in comparison with the 25-ft timed walk and the EDSS.

An algorithm was used to determine whether any demographic, disease, or physical factors could be identified as predictors of fatigue. The physical outcome that was most predictive of fatigue was EDSS score, with scores of 1.5 or lower associated with lesser degrees of fatigue and scores of 1.5 or above associated with greater degrees of fatigue.

True Impact of MS  Underestimated
The researchers theorized that aspects of MS measured by patient-reported outcomes and physical assessments may develop independently of one another. Also, it is likely that clinicians do not fully understand the true impact of MS on patients. They recommended that future studies expand on relationships between patient-reported outcomes, physical measures, and other aspects, such as cognition, to develop more comprehensive and accurate insights into disease activity and treatment strategies.

—Beth Tansey Peller

DENVER—A weak correlation was found between physical and patient-reported outcome measures among patients with multiple sclerosis (MS), according to results of a study presented at the 22nd Annual Meeting of the Consortium of Multiple Sclerosis Centers. Stephen Kirzinger, MD, and colleagues suggested that the true disease impact might be underrepresented, as clinical trials and office evaluations tend to focus on physical measures. Dr. Kirzinger is an Assistant Professor of Neurology and Director of the Multiple Sclerosis Program at the University of Louisville.

Clinical trials involving patients with MS generally focus on the severity and frequency of relapses, as well as on use of MRI to measure disease activity. However, evaluating clinical outcomes by assessing lesions is challenging, as the effects can vary and be unpredictable. Physical assessments, such as the Expanded Disability Status Scale (EDSS), are also commonly used in clinical practice.

Patient-reported outcomes are increasingly being incorporated into clinical trials. They can provide valuable insights by revealing patient perception of disease progression, treatment, and quality of life, noted Dr. Kirzinger. However, he pointed out that relationships between disease progression, physical outcomes, and patient-reported outcomes have been unclear.

Physical Versus Patient-Reported Outcomes
Dr. Kirzinger and colleagues conducted a retrospective chart review of 151 randomly selected patients who were observed for the past decade at the Multiple Sclerosis Center of Baptist Hospital East in Louisville. The investigators sought to determine if correlations existed between patient-reported outcomes of fatigue, depression, and sleepiness with objective measures of fine and gross motor control.

A majority of patients were female (75%), with a median age of 38.8 at diagnosis. Nine percent did not have a disease type noted; 72% had relapsing-remitting MS, 13% had secondary progressive MS, and 5% had primary progressive MS. The most commonly reported symptoms at baseline were fatigue (78%), numbness and tingling (71%), balance problems (70%), weakness (70%), and bladder problems (60%).

Baseline and follow-up data were obtained for five physical disability measures and three patient-reported outcomes. Fine motor control was evaluated with use of the Box and Block Test and the Nine-Hole Peg Test of arm and hand function. Gross motor control was assessed with the 25-ft timed walk; the Tinetti test of gait and balance; and the EDSS, for ambulation ability and disease severity. Patient-reported outcomes were determined with use of the Modified Fatigue Impact Scale (MFIS), Beck Depression Inventory, and Epworth Sleepiness Scale.

The Spearman’s rank correlation test was used to determine the rank coefficient (r) between the physical measures and the patient-reported outcome tests during the patients’ most recent visit, with an r of 1 being a perfect positive correlation and -1 representing a perfect negative correlation. Moderate to strong positive correlations were found among the physical measures, with the strongest correlations occurring between the Box and Block and Nine-Hole Peg tests (r, 0.86). Moderate to strong positive correlations were also observed among the patient-reported outcomes. However, physical and patient-reported outcome measures only weakly correlated with each other, and the only statistically significant r correlations were seen with the MFIS, in comparison with the 25-ft timed walk and the EDSS.

An algorithm was used to determine whether any demographic, disease, or physical factors could be identified as predictors of fatigue. The physical outcome that was most predictive of fatigue was EDSS score, with scores of 1.5 or lower associated with lesser degrees of fatigue and scores of 1.5 or above associated with greater degrees of fatigue.

True Impact of MS  Underestimated
The researchers theorized that aspects of MS measured by patient-reported outcomes and physical assessments may develop independently of one another. Also, it is likely that clinicians do not fully understand the true impact of MS on patients. They recommended that future studies expand on relationships between patient-reported outcomes, physical measures, and other aspects, such as cognition, to develop more comprehensive and accurate insights into disease activity and treatment strategies.

—Beth Tansey Peller

DENVER—Stopping CNS inflammation may not be enough to block brain pathology in patients with multiple sclerosis (MS), said Richard A. ­Rudick, MD, at the 22nd Annual Meeting of the Consortium of Multiple Sclerosis Centers. Dr. Rudick also challenged the long-held notion that MS is mainly a white matter disease. Instead, he said, gray matter pathology is a larger component of MS than is generally appreciated and deserves further study.

Inflammation in MS
Dr. Rudick, Director of the Mellen Center for MS and Vice Chairman of the Neurological Institute at the Cleveland Clinic Foundation, noted that around 1999, researchers were surprised by the level of axonal pathology and brain atrophy present in patients with relatively early MS. “The question is, what is the relationship between tissue injury and inflammatory lesions?” he said. “It’s plausible to suggest that [the inflammatory lesions] are causing this tissue loss. But on the other hand, we were beginning to appreciate the presence of a progressive, destructive pathology early in the course of MS.”

In one interpretation of MS pathology, Dr. Rudick suggested that a dysfunctional immune system causes brain inflammation. This leads to inflammation-mediated CNS injury and later to degenerative brain disease. The effects loop back around on each other, and the degenerative process eventually drives the disimmune process. “In this scenario, if you block inflammatory CNS injury completely, you’ll block CNS degeneration completely,” he said.

However, a second model is also possible. “In this scenario, there is a degenerative CNS process, which then induces some form of immune dysregulation leading to CNS injury,” said Dr. Rudick. “And then again, this is going to continue to loop.” This presents a problem, however, for those who treat patients with MS. “If this scenario is true, blocking inflammation will not completely block CNS degeneration,” he commented.

Can Anti-Inflammatory Drugs Block MS Pathology?
Results from a phase III, placebo-controlled trial of natalizumab in patients with relapsing-remitting MS suggest that this second, more problematic hypothesis needs careful consideration. Although about a 92% reduction in gadolinium-enhancing lesions and a 68% relapse reduction were observed in the first two years of the study, disability progression only improved by 54%. Furthermore, there was only a 41% reduction in brain atrophy in the second year of the study, after fluid shifts had attenuated. This raises the possibility of a continuing degenerative process not requiring ongoing inflammation.

Use of the humanized monoclonal antibody alemtuzumab, however, may be instructive, based on early study results, said Dr. Rudick. The patients included in phase II studies were younger and less disabled than patients in the natalizumab study, and they were treated earlier in the course of relapsing-remitting MS, while the disease was still active. “The whole concept of this study was to try to take this very potent immunomodulatory drug to the very early stage of MS,” related Dr. Rudick. “The idea here is to attempt to interrupt inflammation at a stage where it may have maximal benefit.”

Alemtuzumab nearly eliminated disease relapses in the first two years of treatment and had an 88% risk reduction in time to sustained disability, compared with high-dose interferon beta-1a. Dr. Rudick noted that brain atrophy findings have not yet been reported and that a phase III trial is in the planning stage. In terms of whether CNS inflammation is sufficient and necessary to explain MS pathology, “I think the jury’s out on this one,” he said. “I worry that anti-inflammatory strategies may not be fully effective, regardless of when we [initiate them].”

A Gray Matter Disease?
Cortical lesions may be virtually invisible on MRI, because there is no increase in water content, but according to Dr. Rudick, the effect of demyelination in this area is a very important—and relatively ignored—component of MS. He shared the results of a four-year longitudinal study of patients with MS in various stages to illustrate the disproportionate occurrence of gray matter atrophy. All MS groups had a white matter atrophy rate about three times greater than healthy controls; however, not only was relative gray matter atrophy greater than white matter atrophy, but it began in the relapsing-remitting stage and increased with disease state.

In all patient groups studied, white matter atrophy progressed about three times faster than in healthy controls. Gray matter atrophy accelerated as the disease worsened. Patients who converted during the study period from clinically isolated syndrome to relapsing-remitting MS had a 3.4-times greater rate of gray matter atrophy relative to healthy controls. Patients with stable relapsing-remitting MS had gray matter atrophy rates that were 8.1 times greater than those in healthy controls. Patients who converted to secondary progressive MS had gray matter atrophy rates that were 12.4 times greater than those in healthy controls. Patients with secondary progressive MS for the entire four years of the study had gray matter atrophy rates that were 14 times greater than those in healthy controls.

“So as this disease moves along, there’s accelerating gray matter atrophy,” said Dr. Rudick. “And in all stages of MS, gray matter atrophy is at least as significant quantitatively as white matter atrophy.”

Gray matter pathology is also trickier to detect directly and appears to change throughout the course of the disease, according to Dr. Rudick. One study found that disability significantly correlated with gray matter atrophy as early as the clinically isolated syndrome. “Gray matter pathology probably explains disability more than white matter [atrophy],” noted Dr. Rudick. In his four-year study, gray matter atrophy correlated with MR measures in the relapsing-remitting phase but not in the secondary progressive phase.

“Based on atrophy studies, MS is predominantly a gray matter disease,” concluded Dr. Rudick. “It’s not that [MS is] not a white matter disease; there’s a lot going on in the white matter. But gray matter pathology has been relatively unrecognized and seems to be a dominant feature of the disease based on what we’ve seen.”

Dr. Rudick added that as clinical trials for MS therapies continue, ways to measure gray matter atrophy will only become more important. “There’s no real reason to think that a disease-modifying drug with a particular mechanism of action is going to have the same effect in the white matter and the gray matter,” he said. “We’ve been looking at the whole brain, but we really need to start looking at compartments of the brain in terms of effective interventions.… Gray matter atrophy measures should be included in clinical trials if we’re going to be measuring atrophy, so that we can determine the effects of intervention in these different compartments.

DENVER—Stopping CNS inflammation may not be enough to block brain pathology in patients with multiple sclerosis (MS), said Richard A. ­Rudick, MD, at the 22nd Annual Meeting of the Consortium of Multiple Sclerosis Centers. Dr. Rudick also challenged the long-held notion that MS is mainly a white matter disease. Instead, he said, gray matter pathology is a larger component of MS than is generally appreciated and deserves further study.

Inflammation in MS
Dr. Rudick, Director of the Mellen Center for MS and Vice Chairman of the Neurological Institute at the Cleveland Clinic Foundation, noted that around 1999, researchers were surprised by the level of axonal pathology and brain atrophy present in patients with relatively early MS. “The question is, what is the relationship between tissue injury and inflammatory lesions?” he said. “It’s plausible to suggest that [the inflammatory lesions] are causing this tissue loss. But on the other hand, we were beginning to appreciate the presence of a progressive, destructive pathology early in the course of MS.”

In one interpretation of MS pathology, Dr. Rudick suggested that a dysfunctional immune system causes brain inflammation. This leads to inflammation-mediated CNS injury and later to degenerative brain disease. The effects loop back around on each other, and the degenerative process eventually drives the disimmune process. “In this scenario, if you block inflammatory CNS injury completely, you’ll block CNS degeneration completely,” he said.

However, a second model is also possible. “In this scenario, there is a degenerative CNS process, which then induces some form of immune dysregulation leading to CNS injury,” said Dr. Rudick. “And then again, this is going to continue to loop.” This presents a problem, however, for those who treat patients with MS. “If this scenario is true, blocking inflammation will not completely block CNS degeneration,” he commented.

Can Anti-Inflammatory Drugs Block MS Pathology?
Results from a phase III, placebo-controlled trial of natalizumab in patients with relapsing-remitting MS suggest that this second, more problematic hypothesis needs careful consideration. Although about a 92% reduction in gadolinium-enhancing lesions and a 68% relapse reduction were observed in the first two years of the study, disability progression only improved by 54%. Furthermore, there was only a 41% reduction in brain atrophy in the second year of the study, after fluid shifts had attenuated. This raises the possibility of a continuing degenerative process not requiring ongoing inflammation.

Use of the humanized monoclonal antibody alemtuzumab, however, may be instructive, based on early study results, said Dr. Rudick. The patients included in phase II studies were younger and less disabled than patients in the natalizumab study, and they were treated earlier in the course of relapsing-remitting MS, while the disease was still active. “The whole concept of this study was to try to take this very potent immunomodulatory drug to the very early stage of MS,” related Dr. Rudick. “The idea here is to attempt to interrupt inflammation at a stage where it may have maximal benefit.”

Alemtuzumab nearly eliminated disease relapses in the first two years of treatment and had an 88% risk reduction in time to sustained disability, compared with high-dose interferon beta-1a. Dr. Rudick noted that brain atrophy findings have not yet been reported and that a phase III trial is in the planning stage. In terms of whether CNS inflammation is sufficient and necessary to explain MS pathology, “I think the jury’s out on this one,” he said. “I worry that anti-inflammatory strategies may not be fully effective, regardless of when we [initiate them].”

A Gray Matter Disease?
Cortical lesions may be virtually invisible on MRI, because there is no increase in water content, but according to Dr. Rudick, the effect of demyelination in this area is a very important—and relatively ignored—component of MS. He shared the results of a four-year longitudinal study of patients with MS in various stages to illustrate the disproportionate occurrence of gray matter atrophy. All MS groups had a white matter atrophy rate about three times greater than healthy controls; however, not only was relative gray matter atrophy greater than white matter atrophy, but it began in the relapsing-remitting stage and increased with disease state.

In all patient groups studied, white matter atrophy progressed about three times faster than in healthy controls. Gray matter atrophy accelerated as the disease worsened. Patients who converted during the study period from clinically isolated syndrome to relapsing-remitting MS had a 3.4-times greater rate of gray matter atrophy relative to healthy controls. Patients with stable relapsing-remitting MS had gray matter atrophy rates that were 8.1 times greater than those in healthy controls. Patients who converted to secondary progressive MS had gray matter atrophy rates that were 12.4 times greater than those in healthy controls. Patients with secondary progressive MS for the entire four years of the study had gray matter atrophy rates that were 14 times greater than those in healthy controls.

“So as this disease moves along, there’s accelerating gray matter atrophy,” said Dr. Rudick. “And in all stages of MS, gray matter atrophy is at least as significant quantitatively as white matter atrophy.”

Gray matter pathology is also trickier to detect directly and appears to change throughout the course of the disease, according to Dr. Rudick. One study found that disability significantly correlated with gray matter atrophy as early as the clinically isolated syndrome. “Gray matter pathology probably explains disability more than white matter [atrophy],” noted Dr. Rudick. In his four-year study, gray matter atrophy correlated with MR measures in the relapsing-remitting phase but not in the secondary progressive phase.

“Based on atrophy studies, MS is predominantly a gray matter disease,” concluded Dr. Rudick. “It’s not that [MS is] not a white matter disease; there’s a lot going on in the white matter. But gray matter pathology has been relatively unrecognized and seems to be a dominant feature of the disease based on what we’ve seen.”

Dr. Rudick added that as clinical trials for MS therapies continue, ways to measure gray matter atrophy will only become more important. “There’s no real reason to think that a disease-modifying drug with a particular mechanism of action is going to have the same effect in the white matter and the gray matter,” he said. “We’ve been looking at the whole brain, but we really need to start looking at compartments of the brain in terms of effective interventions.… Gray matter atrophy measures should be included in clinical trials if we’re going to be measuring atrophy, so that we can determine the effects of intervention in these different compartments.

DENVER—Stopping CNS inflammation may not be enough to block brain pathology in patients with multiple sclerosis (MS), said Richard A. ­Rudick, MD, at the 22nd Annual Meeting of the Consortium of Multiple Sclerosis Centers. Dr. Rudick also challenged the long-held notion that MS is mainly a white matter disease. Instead, he said, gray matter pathology is a larger component of MS than is generally appreciated and deserves further study.

Inflammation in MS
Dr. Rudick, Director of the Mellen Center for MS and Vice Chairman of the Neurological Institute at the Cleveland Clinic Foundation, noted that around 1999, researchers were surprised by the level of axonal pathology and brain atrophy present in patients with relatively early MS. “The question is, what is the relationship between tissue injury and inflammatory lesions?” he said. “It’s plausible to suggest that [the inflammatory lesions] are causing this tissue loss. But on the other hand, we were beginning to appreciate the presence of a progressive, destructive pathology early in the course of MS.”

In one interpretation of MS pathology, Dr. Rudick suggested that a dysfunctional immune system causes brain inflammation. This leads to inflammation-mediated CNS injury and later to degenerative brain disease. The effects loop back around on each other, and the degenerative process eventually drives the disimmune process. “In this scenario, if you block inflammatory CNS injury completely, you’ll block CNS degeneration completely,” he said.

However, a second model is also possible. “In this scenario, there is a degenerative CNS process, which then induces some form of immune dysregulation leading to CNS injury,” said Dr. Rudick. “And then again, this is going to continue to loop.” This presents a problem, however, for those who treat patients with MS. “If this scenario is true, blocking inflammation will not completely block CNS degeneration,” he commented.

Can Anti-Inflammatory Drugs Block MS Pathology?
Results from a phase III, placebo-controlled trial of natalizumab in patients with relapsing-remitting MS suggest that this second, more problematic hypothesis needs careful consideration. Although about a 92% reduction in gadolinium-enhancing lesions and a 68% relapse reduction were observed in the first two years of the study, disability progression only improved by 54%. Furthermore, there was only a 41% reduction in brain atrophy in the second year of the study, after fluid shifts had attenuated. This raises the possibility of a continuing degenerative process not requiring ongoing inflammation.

Use of the humanized monoclonal antibody alemtuzumab, however, may be instructive, based on early study results, said Dr. Rudick. The patients included in phase II studies were younger and less disabled than patients in the natalizumab study, and they were treated earlier in the course of relapsing-remitting MS, while the disease was still active. “The whole concept of this study was to try to take this very potent immunomodulatory drug to the very early stage of MS,” related Dr. Rudick. “The idea here is to attempt to interrupt inflammation at a stage where it may have maximal benefit.”

Alemtuzumab nearly eliminated disease relapses in the first two years of treatment and had an 88% risk reduction in time to sustained disability, compared with high-dose interferon beta-1a. Dr. Rudick noted that brain atrophy findings have not yet been reported and that a phase III trial is in the planning stage. In terms of whether CNS inflammation is sufficient and necessary to explain MS pathology, “I think the jury’s out on this one,” he said. “I worry that anti-inflammatory strategies may not be fully effective, regardless of when we [initiate them].”

A Gray Matter Disease?
Cortical lesions may be virtually invisible on MRI, because there is no increase in water content, but according to Dr. Rudick, the effect of demyelination in this area is a very important—and relatively ignored—component of MS. He shared the results of a four-year longitudinal study of patients with MS in various stages to illustrate the disproportionate occurrence of gray matter atrophy. All MS groups had a white matter atrophy rate about three times greater than healthy controls; however, not only was relative gray matter atrophy greater than white matter atrophy, but it began in the relapsing-remitting stage and increased with disease state.

In all patient groups studied, white matter atrophy progressed about three times faster than in healthy controls. Gray matter atrophy accelerated as the disease worsened. Patients who converted during the study period from clinically isolated syndrome to relapsing-remitting MS had a 3.4-times greater rate of gray matter atrophy relative to healthy controls. Patients with stable relapsing-remitting MS had gray matter atrophy rates that were 8.1 times greater than those in healthy controls. Patients who converted to secondary progressive MS had gray matter atrophy rates that were 12.4 times greater than those in healthy controls. Patients with secondary progressive MS for the entire four years of the study had gray matter atrophy rates that were 14 times greater than those in healthy controls.

“So as this disease moves along, there’s accelerating gray matter atrophy,” said Dr. Rudick. “And in all stages of MS, gray matter atrophy is at least as significant quantitatively as white matter atrophy.”

Gray matter pathology is also trickier to detect directly and appears to change throughout the course of the disease, according to Dr. Rudick. One study found that disability significantly correlated with gray matter atrophy as early as the clinically isolated syndrome. “Gray matter pathology probably explains disability more than white matter [atrophy],” noted Dr. Rudick. In his four-year study, gray matter atrophy correlated with MR measures in the relapsing-remitting phase but not in the secondary progressive phase.

“Based on atrophy studies, MS is predominantly a gray matter disease,” concluded Dr. Rudick. “It’s not that [MS is] not a white matter disease; there’s a lot going on in the white matter. But gray matter pathology has been relatively unrecognized and seems to be a dominant feature of the disease based on what we’ve seen.”

Dr. Rudick added that as clinical trials for MS therapies continue, ways to measure gray matter atrophy will only become more important. “There’s no real reason to think that a disease-modifying drug with a particular mechanism of action is going to have the same effect in the white matter and the gray matter,” he said. “We’ve been looking at the whole brain, but we really need to start looking at compartments of the brain in terms of effective interventions.… Gray matter atrophy measures should be included in clinical trials if we’re going to be measuring atrophy, so that we can determine the effects of intervention in these different compartments.

Most Strokes After TIA Occur Within 90 Days
NEW YORK, June 9 (Reuters Health)—Sixty percent of strokes seen after a transient ischemic attack (TIA) in patients with intracranial atherosclerotic disease occur within 90 days of the index event, according to a report in the June Archives of Neurology. Moreover, the risk of an early stroke after a TIA is comparable to the risk seen after a prior stroke.

“We are unaware of any prior studies that have attempted to quantify or qualify the early risk of stroke (within three to four months) after the occurrence of a TIA due to narrowing of a large brain artery,” lead author Dr. Bruce Ovbiagele, from the University of California at Los Angeles, told Reuters Health.

“We found that those with a TIA and those with a stroke ... carried the same early risk of future stroke, and that evidence of infarcts on brain imaging predicted early stroke risk after a TIA,” he noted. These findings “indicate that TIA patients should be taken just as seriously as stroke patients, since they carry similar early stroke risks, and that brain imaging can delineate future stroke risk.”

The findings are based on analysis of data for 569 patients enrolled in the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) study, a randomized trial conducted at 59 sites. The subjects included 222 with a TIA in the preceding three months, 241 with a stroke, and 106 with both. All of the subjects had angiography-verified 50% to 99% narrowing of a major intracranial artery.

The 90-day risk of a stroke after TIA was 6.9%, which is statistically comparable to the 4.7% rate seen after a stroke. Among TIA-only patients, 60% of all strokes occurred within 90 days of the index event, compared with 34.4% of strokes seen after a prior stroke. Patients with both a stroke and TIA at baseline were roughly twice as likely as subjects with either condition alone to experience an early stroke, the researchers found. In TIA patients, the only significant predictor of an early stroke (HR = 4.7) was the presence of cerebral infarct on baseline neuroimaging, the report indicated.

Further research is needed, Dr. Ovbiagele said, to confirm the current findings and “to identify specific interventions that can be given promptly to reduce the early risk of stroke in these types of TIA patients. We are currently exploring the latter.”

Arch Neurol. 2008;65(6):733-737.

MRI Activity and Antibody Levels Chart MS Therapy Progress
NEW YORK, June 10 (Reuters Health)—During the initial stages of interferon beta treatment in patients with relapsing-remitting multiple sclerosis, monitoring by means of MRI scans and anti–interferon beta neutralizing antibodies (NAb) can be useful in predicting clinical response, Italian researchers reported in the June issue of the Journal of Neurology, Neurosurgery, and Psychiatry.

“Either having an MRI scan with signs of disease activity or a positive NAb test will predict a bad clinical response over the next two years of interferon beta treatment,” lead investigator Dr. Luca Durelli told Reuters Health.

Dr. Durelli, of Ospedale San Luigi Gonzaga, Turin, and colleagues studied 147 patients who underwent repeated MRI scans and NAb assays during the first six months of interferon beta therapy.

The researchers found a positive scan had a predictive sensitivity of 52% and a specificity of 80% for clinical disease activity in the following 18 months. The negative predictive value was 73%, and the positive predictive value was 62%. For NAb positivity, the corresponding values were 71% and 66%, and 92% and 29%. The combination of an active scan and NAb positivity had a sensitivity of 71%, a specificity of 86%, a negative predictive value of 94%, and a positive predictive value of 50%.

In other words, continued Dr. Durelli, “Patients developing both MRI activity as well as NAb positivity carry a 50% risk of developing clinical activity.... This could be an indication to switch them to a different immune-modulatory or immune-suppressive treatment.”

J Neurol Neurosurg Psychiatry. 2008;79(6):646-651.

Horizontal Head Impulse Test Helps Spot Stroke
NEW YORK, June 27 (Reuters Health)—The horizontal head impulse test (h-HIT) is useful in differentiating acute cerebellar strokes from vestibular neuritis, researchers reported in the June 10 issue of Neurology.

The test consists of a rapid, passive head rotation while the patient fixates on a central object. The normal vestibulo-ocular reflex is an equal and opposite eye movement that keeps the eyes stationary in space. Fixation cannot be maintained, however, if there is loss of vestibular afferent input.

“Thousands of patients are seen annually in US emergency departments with acute vestibular syndrome,” investigator Dr. Jorge C. Kattah told Reuters Health. This involves “vertigo, nausea and vomiting with nystagmus, unsteady gait, and head motion intolerance.

“Intact vestibulo-ocular reflex function and a negative h-HIT in a patient with acute vestibular syndrome,” he advised, “is a strong predictor of stroke even when initial MRI suggests otherwise.”

Dr. Kattah, of the University of Illinois College of Medicine at Peoria, and colleagues studied data on 43 subjects with acute vestibular syndrome at high risk for stroke who had undergone a variety of testing including MRI and h-HIT. One subject had equivocal h-HIT results, but all eight patients with acute peripheral vestibulopathy had a positive h-HIT test.

“Our study,” said the investigators, “confirms the utility of h-HIT in distinguishing peripheral from central causes of the acute vestibular syndrome, but departs from current neuro-otologic thinking by suggesting that the sign’s absence may be more helpful than its presence.”

Neurology. 2008;70(24 Pt 2):2378-2385.

Most Strokes After TIA Occur Within 90 Days
NEW YORK, June 9 (Reuters Health)—Sixty percent of strokes seen after a transient ischemic attack (TIA) in patients with intracranial atherosclerotic disease occur within 90 days of the index event, according to a report in the June Archives of Neurology. Moreover, the risk of an early stroke after a TIA is comparable to the risk seen after a prior stroke.

“We are unaware of any prior studies that have attempted to quantify or qualify the early risk of stroke (within three to four months) after the occurrence of a TIA due to narrowing of a large brain artery,” lead author Dr. Bruce Ovbiagele, from the University of California at Los Angeles, told Reuters Health.

“We found that those with a TIA and those with a stroke ... carried the same early risk of future stroke, and that evidence of infarcts on brain imaging predicted early stroke risk after a TIA,” he noted. These findings “indicate that TIA patients should be taken just as seriously as stroke patients, since they carry similar early stroke risks, and that brain imaging can delineate future stroke risk.”

The findings are based on analysis of data for 569 patients enrolled in the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) study, a randomized trial conducted at 59 sites. The subjects included 222 with a TIA in the preceding three months, 241 with a stroke, and 106 with both. All of the subjects had angiography-verified 50% to 99% narrowing of a major intracranial artery.

The 90-day risk of a stroke after TIA was 6.9%, which is statistically comparable to the 4.7% rate seen after a stroke. Among TIA-only patients, 60% of all strokes occurred within 90 days of the index event, compared with 34.4% of strokes seen after a prior stroke. Patients with both a stroke and TIA at baseline were roughly twice as likely as subjects with either condition alone to experience an early stroke, the researchers found. In TIA patients, the only significant predictor of an early stroke (HR = 4.7) was the presence of cerebral infarct on baseline neuroimaging, the report indicated.

Further research is needed, Dr. Ovbiagele said, to confirm the current findings and “to identify specific interventions that can be given promptly to reduce the early risk of stroke in these types of TIA patients. We are currently exploring the latter.”

Arch Neurol. 2008;65(6):733-737.

MRI Activity and Antibody Levels Chart MS Therapy Progress
NEW YORK, June 10 (Reuters Health)—During the initial stages of interferon beta treatment in patients with relapsing-remitting multiple sclerosis, monitoring by means of MRI scans and anti–interferon beta neutralizing antibodies (NAb) can be useful in predicting clinical response, Italian researchers reported in the June issue of the Journal of Neurology, Neurosurgery, and Psychiatry.

“Either having an MRI scan with signs of disease activity or a positive NAb test will predict a bad clinical response over the next two years of interferon beta treatment,” lead investigator Dr. Luca Durelli told Reuters Health.

Dr. Durelli, of Ospedale San Luigi Gonzaga, Turin, and colleagues studied 147 patients who underwent repeated MRI scans and NAb assays during the first six months of interferon beta therapy.

The researchers found a positive scan had a predictive sensitivity of 52% and a specificity of 80% for clinical disease activity in the following 18 months. The negative predictive value was 73%, and the positive predictive value was 62%. For NAb positivity, the corresponding values were 71% and 66%, and 92% and 29%. The combination of an active scan and NAb positivity had a sensitivity of 71%, a specificity of 86%, a negative predictive value of 94%, and a positive predictive value of 50%.

In other words, continued Dr. Durelli, “Patients developing both MRI activity as well as NAb positivity carry a 50% risk of developing clinical activity.... This could be an indication to switch them to a different immune-modulatory or immune-suppressive treatment.”

J Neurol Neurosurg Psychiatry. 2008;79(6):646-651.

Horizontal Head Impulse Test Helps Spot Stroke
NEW YORK, June 27 (Reuters Health)—The horizontal head impulse test (h-HIT) is useful in differentiating acute cerebellar strokes from vestibular neuritis, researchers reported in the June 10 issue of Neurology.

The test consists of a rapid, passive head rotation while the patient fixates on a central object. The normal vestibulo-ocular reflex is an equal and opposite eye movement that keeps the eyes stationary in space. Fixation cannot be maintained, however, if there is loss of vestibular afferent input.

“Thousands of patients are seen annually in US emergency departments with acute vestibular syndrome,” investigator Dr. Jorge C. Kattah told Reuters Health. This involves “vertigo, nausea and vomiting with nystagmus, unsteady gait, and head motion intolerance.

“Intact vestibulo-ocular reflex function and a negative h-HIT in a patient with acute vestibular syndrome,” he advised, “is a strong predictor of stroke even when initial MRI suggests otherwise.”

Dr. Kattah, of the University of Illinois College of Medicine at Peoria, and colleagues studied data on 43 subjects with acute vestibular syndrome at high risk for stroke who had undergone a variety of testing including MRI and h-HIT. One subject had equivocal h-HIT results, but all eight patients with acute peripheral vestibulopathy had a positive h-HIT test.

“Our study,” said the investigators, “confirms the utility of h-HIT in distinguishing peripheral from central causes of the acute vestibular syndrome, but departs from current neuro-otologic thinking by suggesting that the sign’s absence may be more helpful than its presence.”

Neurology. 2008;70(24 Pt 2):2378-2385.

Most Strokes After TIA Occur Within 90 Days
NEW YORK, June 9 (Reuters Health)—Sixty percent of strokes seen after a transient ischemic attack (TIA) in patients with intracranial atherosclerotic disease occur within 90 days of the index event, according to a report in the June Archives of Neurology. Moreover, the risk of an early stroke after a TIA is comparable to the risk seen after a prior stroke.

“We are unaware of any prior studies that have attempted to quantify or qualify the early risk of stroke (within three to four months) after the occurrence of a TIA due to narrowing of a large brain artery,” lead author Dr. Bruce Ovbiagele, from the University of California at Los Angeles, told Reuters Health.

“We found that those with a TIA and those with a stroke ... carried the same early risk of future stroke, and that evidence of infarcts on brain imaging predicted early stroke risk after a TIA,” he noted. These findings “indicate that TIA patients should be taken just as seriously as stroke patients, since they carry similar early stroke risks, and that brain imaging can delineate future stroke risk.”

The findings are based on analysis of data for 569 patients enrolled in the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) study, a randomized trial conducted at 59 sites. The subjects included 222 with a TIA in the preceding three months, 241 with a stroke, and 106 with both. All of the subjects had angiography-verified 50% to 99% narrowing of a major intracranial artery.

The 90-day risk of a stroke after TIA was 6.9%, which is statistically comparable to the 4.7% rate seen after a stroke. Among TIA-only patients, 60% of all strokes occurred within 90 days of the index event, compared with 34.4% of strokes seen after a prior stroke. Patients with both a stroke and TIA at baseline were roughly twice as likely as subjects with either condition alone to experience an early stroke, the researchers found. In TIA patients, the only significant predictor of an early stroke (HR = 4.7) was the presence of cerebral infarct on baseline neuroimaging, the report indicated.

Further research is needed, Dr. Ovbiagele said, to confirm the current findings and “to identify specific interventions that can be given promptly to reduce the early risk of stroke in these types of TIA patients. We are currently exploring the latter.”

Arch Neurol. 2008;65(6):733-737.

MRI Activity and Antibody Levels Chart MS Therapy Progress
NEW YORK, June 10 (Reuters Health)—During the initial stages of interferon beta treatment in patients with relapsing-remitting multiple sclerosis, monitoring by means of MRI scans and anti–interferon beta neutralizing antibodies (NAb) can be useful in predicting clinical response, Italian researchers reported in the June issue of the Journal of Neurology, Neurosurgery, and Psychiatry.

“Either having an MRI scan with signs of disease activity or a positive NAb test will predict a bad clinical response over the next two years of interferon beta treatment,” lead investigator Dr. Luca Durelli told Reuters Health.

Dr. Durelli, of Ospedale San Luigi Gonzaga, Turin, and colleagues studied 147 patients who underwent repeated MRI scans and NAb assays during the first six months of interferon beta therapy.

The researchers found a positive scan had a predictive sensitivity of 52% and a specificity of 80% for clinical disease activity in the following 18 months. The negative predictive value was 73%, and the positive predictive value was 62%. For NAb positivity, the corresponding values were 71% and 66%, and 92% and 29%. The combination of an active scan and NAb positivity had a sensitivity of 71%, a specificity of 86%, a negative predictive value of 94%, and a positive predictive value of 50%.

In other words, continued Dr. Durelli, “Patients developing both MRI activity as well as NAb positivity carry a 50% risk of developing clinical activity.... This could be an indication to switch them to a different immune-modulatory or immune-suppressive treatment.”

J Neurol Neurosurg Psychiatry. 2008;79(6):646-651.

Horizontal Head Impulse Test Helps Spot Stroke
NEW YORK, June 27 (Reuters Health)—The horizontal head impulse test (h-HIT) is useful in differentiating acute cerebellar strokes from vestibular neuritis, researchers reported in the June 10 issue of Neurology.

The test consists of a rapid, passive head rotation while the patient fixates on a central object. The normal vestibulo-ocular reflex is an equal and opposite eye movement that keeps the eyes stationary in space. Fixation cannot be maintained, however, if there is loss of vestibular afferent input.

“Thousands of patients are seen annually in US emergency departments with acute vestibular syndrome,” investigator Dr. Jorge C. Kattah told Reuters Health. This involves “vertigo, nausea and vomiting with nystagmus, unsteady gait, and head motion intolerance.

“Intact vestibulo-ocular reflex function and a negative h-HIT in a patient with acute vestibular syndrome,” he advised, “is a strong predictor of stroke even when initial MRI suggests otherwise.”

Dr. Kattah, of the University of Illinois College of Medicine at Peoria, and colleagues studied data on 43 subjects with acute vestibular syndrome at high risk for stroke who had undergone a variety of testing including MRI and h-HIT. One subject had equivocal h-HIT results, but all eight patients with acute peripheral vestibulopathy had a positive h-HIT test.

“Our study,” said the investigators, “confirms the utility of h-HIT in distinguishing peripheral from central causes of the acute vestibular syndrome, but departs from current neuro-otologic thinking by suggesting that the sign’s absence may be more helpful than its presence.”

Neurology. 2008;70(24 Pt 2):2378-2385.

CHICAGO—Glatiramer acetate can be used in the treatment of patients with clinically isolated syndrome to safely delay the progression to multiple sclerosis (MS), according to the results of a randomized, double-blind, placebo-controlled study presented at the 60th Annual Meeting of the American Academy of Neurology. Giancarlo Comi, MD, and Massimo Filippi, MD, reported that glatiramer acetate reduced the risk of conversion to clinically definite MS by 45%.

“The aim of the [Study to Evaluate the Effect of Early Glatiramer Acetate Treatment in Delaying the Conversion to CDMS in Subjects Presenting With a Clinically Isolated Syndrome (PreCISe)] is to evaluate the effect of treatment if given at the onset of the disease,” said Dr. Comi, Professor of Neurology and Chairman of the Department of Neurology at Vita-Salute San Raffaele University in Milan. A total of 481 patients who presented with their first clinical event and had at least two T2-weighted lesions 6 mm or larger in diameter were randomized to receive 20 mg/day of glatiramer acetate subcutaneously or placebo (mean time from first event to randomization, 74 days). Participants in the entire study group had a mean age of 31 and were not disabled (mean Expanded Disability Status Scale score, 1.0), and the majority used corticosteroids to treat their first attack.

Safety and Efficacy of Glatiramer Acetate
By the interim analysis, 2.4 years after the beginning of the study, only one quarter of the patients in the gla­tiramer acetate arm had converted to clinically definite MS (ie, they had a second attack), a significantly smaller proportion than those who were given placebo (43%). In addition, reported Dr. Comi, those who converted did so about one year later than the patients in the placebo arm. The 25th percentile of time to clinically definite MS was 722 days in the glatiramer acetate arm, 115% longer than the 336 days to conversion in the placebo arm.

Disease activity was also monitored with MRI every three months, and treatment appeared to have a beneficial effect. Dr. Comi’s group observed a significant reduction in new T2 lesions with glatiramer acetate, as well as a significant drop in the number of gadolinium-enhancing lesions seen at the last MRI scans before the conversion.

There were no unexpected safety concerns, reported the researchers. “Glatiramer acetate was well tolerated, with 16% overall withdrawals to the time of the interim analysis, and had a safety profile similar to that observed in relapsing-remitting MS,” they said.

Long-Term Benefits?
Dr. Comi added that as a result of the interim analysis, it was recommended that all participants who were randomized to receive placebo be offered glatiramer acetate and continue to be followed up via the original protocol. There was also a two-year extension planned “to understand if positive results of the early phase will [persist as] beneficial consequences of the long term,” he said.

CHICAGO—Glatiramer acetate can be used in the treatment of patients with clinically isolated syndrome to safely delay the progression to multiple sclerosis (MS), according to the results of a randomized, double-blind, placebo-controlled study presented at the 60th Annual Meeting of the American Academy of Neurology. Giancarlo Comi, MD, and Massimo Filippi, MD, reported that glatiramer acetate reduced the risk of conversion to clinically definite MS by 45%.

“The aim of the [Study to Evaluate the Effect of Early Glatiramer Acetate Treatment in Delaying the Conversion to CDMS in Subjects Presenting With a Clinically Isolated Syndrome (PreCISe)] is to evaluate the effect of treatment if given at the onset of the disease,” said Dr. Comi, Professor of Neurology and Chairman of the Department of Neurology at Vita-Salute San Raffaele University in Milan. A total of 481 patients who presented with their first clinical event and had at least two T2-weighted lesions 6 mm or larger in diameter were randomized to receive 20 mg/day of glatiramer acetate subcutaneously or placebo (mean time from first event to randomization, 74 days). Participants in the entire study group had a mean age of 31 and were not disabled (mean Expanded Disability Status Scale score, 1.0), and the majority used corticosteroids to treat their first attack.

Safety and Efficacy of Glatiramer Acetate
By the interim analysis, 2.4 years after the beginning of the study, only one quarter of the patients in the gla­tiramer acetate arm had converted to clinically definite MS (ie, they had a second attack), a significantly smaller proportion than those who were given placebo (43%). In addition, reported Dr. Comi, those who converted did so about one year later than the patients in the placebo arm. The 25th percentile of time to clinically definite MS was 722 days in the glatiramer acetate arm, 115% longer than the 336 days to conversion in the placebo arm.

Disease activity was also monitored with MRI every three months, and treatment appeared to have a beneficial effect. Dr. Comi’s group observed a significant reduction in new T2 lesions with glatiramer acetate, as well as a significant drop in the number of gadolinium-enhancing lesions seen at the last MRI scans before the conversion.

There were no unexpected safety concerns, reported the researchers. “Glatiramer acetate was well tolerated, with 16% overall withdrawals to the time of the interim analysis, and had a safety profile similar to that observed in relapsing-remitting MS,” they said.

Long-Term Benefits?
Dr. Comi added that as a result of the interim analysis, it was recommended that all participants who were randomized to receive placebo be offered glatiramer acetate and continue to be followed up via the original protocol. There was also a two-year extension planned “to understand if positive results of the early phase will [persist as] beneficial consequences of the long term,” he said.

CHICAGO—Glatiramer acetate can be used in the treatment of patients with clinically isolated syndrome to safely delay the progression to multiple sclerosis (MS), according to the results of a randomized, double-blind, placebo-controlled study presented at the 60th Annual Meeting of the American Academy of Neurology. Giancarlo Comi, MD, and Massimo Filippi, MD, reported that glatiramer acetate reduced the risk of conversion to clinically definite MS by 45%.

“The aim of the [Study to Evaluate the Effect of Early Glatiramer Acetate Treatment in Delaying the Conversion to CDMS in Subjects Presenting With a Clinically Isolated Syndrome (PreCISe)] is to evaluate the effect of treatment if given at the onset of the disease,” said Dr. Comi, Professor of Neurology and Chairman of the Department of Neurology at Vita-Salute San Raffaele University in Milan. A total of 481 patients who presented with their first clinical event and had at least two T2-weighted lesions 6 mm or larger in diameter were randomized to receive 20 mg/day of glatiramer acetate subcutaneously or placebo (mean time from first event to randomization, 74 days). Participants in the entire study group had a mean age of 31 and were not disabled (mean Expanded Disability Status Scale score, 1.0), and the majority used corticosteroids to treat their first attack.

Safety and Efficacy of Glatiramer Acetate
By the interim analysis, 2.4 years after the beginning of the study, only one quarter of the patients in the gla­tiramer acetate arm had converted to clinically definite MS (ie, they had a second attack), a significantly smaller proportion than those who were given placebo (43%). In addition, reported Dr. Comi, those who converted did so about one year later than the patients in the placebo arm. The 25th percentile of time to clinically definite MS was 722 days in the glatiramer acetate arm, 115% longer than the 336 days to conversion in the placebo arm.

Disease activity was also monitored with MRI every three months, and treatment appeared to have a beneficial effect. Dr. Comi’s group observed a significant reduction in new T2 lesions with glatiramer acetate, as well as a significant drop in the number of gadolinium-enhancing lesions seen at the last MRI scans before the conversion.

There were no unexpected safety concerns, reported the researchers. “Glatiramer acetate was well tolerated, with 16% overall withdrawals to the time of the interim analysis, and had a safety profile similar to that observed in relapsing-remitting MS,” they said.

Long-Term Benefits?
Dr. Comi added that as a result of the interim analysis, it was recommended that all participants who were randomized to receive placebo be offered glatiramer acetate and continue to be followed up via the original protocol. There was also a two-year extension planned “to understand if positive results of the early phase will [persist as] beneficial consequences of the long term,” he said.

Clinical and molecular neurogenetics and neuromics have achieved considerable success recently in providing a clearer understanding of gene interactions responsible for neurologic disorders such as Alzheimer’s disease, multiple sclerosis (MS), and cortical brain malformations. “Clearly, the field of neurogenetics/neuromics is alive and well, prospering with an avalanche of new concepts and innovative data,” said Roger N. Rosenberg, MD, Editor of Archives of Neurology, in an editorial highlighting the wide range of original scientific reports in the March and April issues of the journal. Dr. Rosenberg is a Professor of Neurology at the University of Texas Southwestern Medical Center at Dallas.

Genetics and Risk for Alzheimer’s Disease
If both parents have a clinical diagnosis of Alzheimer’s disease, are their children at increased risk? That was the question Suman Jayadev, MD, and colleagues attempted to answer in a retrospective study of 111 conjugal couples who had 297 children surviving to adulthood. Of the 297 offspring, 22.6% had developed Alzheimer’s disease, with the risk increasing as they aged. Among those older than 60, 31% (58 of 137) had Alzheimer’s disease; among those older than 70, 41.8% (41 of 98) had the disease. Dr. Jayadev, Assistant Professor of Neurology, University of Washington, Seattle, pointed out that because 79% of the offspring are younger than 70, the risk of occurrence will only increase. This work confirmed results of a small pilot study involving the offspring of 31 of the couples, which found a higher rate of Alzheimer’s disease than would be expected in the general population.

“A family history of Alzheimer’s disease beyond the parents did not change the risk of Alzheimer’s disease in the children but did reduce the median age at onset in affected children,” Dr. Jayadev and colleagues said. In addition, although the apolipoprotein E ε4 allele has an important role, it “did not account for all Alzheimer’s disease cases in offspring, supporting the hypothesis that this is a complex polygenic phenomenon” and calling for a better definition of the role of family history and specific genes involved, they concluded.

Genome-wide association studies are being used as a tool for identifying genetic contributions to complex diseases and have shown success, for example, in helping to identify risk for age-related macular generation and diabetes mellitus. “Whether this will hold true for a genetically complex and heterogeneous disease such as Alzheimer’s disease is not known, although early reports are encouraging,” noted Dr. Rosenberg and ­Stephen C. Waring, DVM, PhD, Assistant Professor in the Department of Epidemiology at the University of Texas School of Public Health at Houston and a researcher with the Texas Alz­heimer’s Research Consortium. Drs. Rosenberg and Waring reported on results of genome-wide association studies to date that combine high-throughput arrays, bioinformatics, and advances in software to investigate significant markers associated with the risk of Alzheimer’s disease.

Examining Single-Gene Neurogenetic Disorders
In another study, Thomas D. Bird, MD, and colleagues conducted a retrospective review to describe the occurrence of single-gene neurogenetic disorders in eight elderly patients. Seven patients were men—two had Huntington’s disease (ages 85 and 87), three had spinocerebellar ataxia types 5, 6, and 14 (ages 86, 78, 78, respectively), one had presenilin 1 familial Alzheimer’s disease mutation (age 85), and one had autosomal dominant hereditary neuropathy (age 87). An 84-year-old woman had limb-girdle muscular dystrophy type 2A.

“Three patients had no family history of neurologic disease,” said Dr. Bird, a Professor of Neurology at the University of Washington, Seattle, and colleagues. “Their median age of 83 years is remarkable because genetic diseases are generally assumed to be relegated to much younger populations.” Five patients had late symptom onset; the other three “had onset of symptoms at much younger ages but survived many decades and did not receive specific genetic diagnoses until relevant genetics tests became available in their senior years.”

The researchers noted that recognition of single-gene diseases in elderly patients can be explained by the aging of the population, increased awareness of symptom onset, and DNA-based genetic testing. “The specific diagnosis of genetic diseases is readily available to a degree completely unknown a few years ago,” they said. “Patients in this study would have been considered to have senile chorea, senile dementia, and unexplained myopathy before the advent of such testing.”

Parent-of-Origin Effect
Ilse A. Hoppenbrouwers, MD, from the Department of Neurology, MS Centre Erasmus, Rotterdam, the Netherlands, and colleagues investigated parental relationships among patients with MS using extensive genealogic information from the Genetic Research in Isolated Populations program. Fewer than 400 individuals comprised the mid-18th-century founding population of a region located in the southwest Netherlands. To date, approximately 20,000 descendants live in eight adjacent communities and are generally related. More than 90,000 people spanning 23 generations are included in a genealogic database. Of these, 24 patients (19 women) with MS “could be linked to the most recent common ancestor in 14 generations.”

Reconstruction of a pedigree of these 24 patients with common clinical phenotypes of MS found that “the shortest connection to a common ancestor between two individuals with MS was significantly more often through their nonaffected mother than through their nonaffected father, suggesting a maternal parent-of-origin effect” that was specific for MS, noted Dr. Hoppenbrouwers and colleagues. “Mothers of the 24 MS patients were also more closely related to each other than their fathers.”

Maternal transmission of MS can be a result of genetic factors, environmental factors, or both. These data suggest that “the most likely explanation is a gene-environment effect that takes place in utero,” the researchers concluded. “Dense genotyping in this pedigree can help to unravel the genetic combination, thus aiding in resolving the nature-nurture dilemma in MS.”

Malformations of Cortical Development
In another study from the Erasmus Medical Center–Sophia Children’s Hospital, Rotterdam, Marie Claire Yvette de Wit, MD, of the Department of Pediatric Neurology, and colleagues evaluated the etiology of malformations of cortical development in children to determine whether a combined radiologic, clinical, and syndrome classification could provide a molecularly confirmed diagnosis.

A case series of 113 children who had a radiologic diagnosis of malformations of cortical development from 1992 to 2006 was included in the study. Each child had a complete radiologic, clinical, and neurologic assessment and was tested for phenotypically appropriate genes known to be involved in the pathogenesis of malformations of cortical development.

An etiologic diagnosis was established in 45 of the 113 children (40%). Diagnoses included molecular and/or genetic confirmation in 21 patients (19%) of ­Miller­-­Dieker syndrome; LIS1, DCX, FLNA, ­EIF2AK3, or KIAA1279 mutations; or an inborn error of metabolism. A syndrome with an unknown genetic defect was diagnosed in 17 children (15%), and evidence of gestational insult was found in seven (6%). “Of the remaining 68 patients, 34 probably have a yet-unknown genetic disorder based on the presence of multiple congenital anomalies (15 patients), a family history of multiple affected persons (12 patients), or consanguineous parents (seven patients),” the investigators wrote.

Most patients were diagnosed as having malformations of cortical development when they developed seizures; 26 of 63 patients (41%) were previously misdiagnosed, demonstrating that “a quality MRI of the brain and a skilled neuroradiologist are essential for a correct classification and the choice of diagnostic tests.”

Dr. de Wit’s group concluded that “classification based on radiological, clinical genetic, and neurological examinations combined with genetic testing can yield important information about monogenetic, syndromal, and metabolic causes and can lead to improvement of patient care and genetic counseling. This requires a multidisciplinary team specialized in neuroradiology, pediatric neurology, and genetics. Even then, the underlying cause remains elusive in more than 50% of patients, and the suspicion of an underlying genetic cause remains in many of our unclassified cases. This encourages exploitation of new genome-wide techniques.”

Additional articles in the theme issues also focused on stem cells, the human HapMap, primary and amyotrophic lateral sclerosis, Huntington’s disease, frontotemporal disease, Parkinson’s disease, cryptogenic epileptic syndromes, fragile X, spinocerebellar ataxia, Machado-Joseph disease, Troyer syndrome, MELAS, Leigh syndrome, and hereditary spastic paraplegia.

Clinical and molecular neurogenetics and neuromics have achieved considerable success recently in providing a clearer understanding of gene interactions responsible for neurologic disorders such as Alzheimer’s disease, multiple sclerosis (MS), and cortical brain malformations. “Clearly, the field of neurogenetics/neuromics is alive and well, prospering with an avalanche of new concepts and innovative data,” said Roger N. Rosenberg, MD, Editor of Archives of Neurology, in an editorial highlighting the wide range of original scientific reports in the March and April issues of the journal. Dr. Rosenberg is a Professor of Neurology at the University of Texas Southwestern Medical Center at Dallas.

Genetics and Risk for Alzheimer’s Disease
If both parents have a clinical diagnosis of Alzheimer’s disease, are their children at increased risk? That was the question Suman Jayadev, MD, and colleagues attempted to answer in a retrospective study of 111 conjugal couples who had 297 children surviving to adulthood. Of the 297 offspring, 22.6% had developed Alzheimer’s disease, with the risk increasing as they aged. Among those older than 60, 31% (58 of 137) had Alzheimer’s disease; among those older than 70, 41.8% (41 of 98) had the disease. Dr. Jayadev, Assistant Professor of Neurology, University of Washington, Seattle, pointed out that because 79% of the offspring are younger than 70, the risk of occurrence will only increase. This work confirmed results of a small pilot study involving the offspring of 31 of the couples, which found a higher rate of Alzheimer’s disease than would be expected in the general population.

“A family history of Alzheimer’s disease beyond the parents did not change the risk of Alzheimer’s disease in the children but did reduce the median age at onset in affected children,” Dr. Jayadev and colleagues said. In addition, although the apolipoprotein E ε4 allele has an important role, it “did not account for all Alzheimer’s disease cases in offspring, supporting the hypothesis that this is a complex polygenic phenomenon” and calling for a better definition of the role of family history and specific genes involved, they concluded.

Genome-wide association studies are being used as a tool for identifying genetic contributions to complex diseases and have shown success, for example, in helping to identify risk for age-related macular generation and diabetes mellitus. “Whether this will hold true for a genetically complex and heterogeneous disease such as Alzheimer’s disease is not known, although early reports are encouraging,” noted Dr. Rosenberg and ­Stephen C. Waring, DVM, PhD, Assistant Professor in the Department of Epidemiology at the University of Texas School of Public Health at Houston and a researcher with the Texas Alz­heimer’s Research Consortium. Drs. Rosenberg and Waring reported on results of genome-wide association studies to date that combine high-throughput arrays, bioinformatics, and advances in software to investigate significant markers associated with the risk of Alzheimer’s disease.

Examining Single-Gene Neurogenetic Disorders
In another study, Thomas D. Bird, MD, and colleagues conducted a retrospective review to describe the occurrence of single-gene neurogenetic disorders in eight elderly patients. Seven patients were men—two had Huntington’s disease (ages 85 and 87), three had spinocerebellar ataxia types 5, 6, and 14 (ages 86, 78, 78, respectively), one had presenilin 1 familial Alzheimer’s disease mutation (age 85), and one had autosomal dominant hereditary neuropathy (age 87). An 84-year-old woman had limb-girdle muscular dystrophy type 2A.

“Three patients had no family history of neurologic disease,” said Dr. Bird, a Professor of Neurology at the University of Washington, Seattle, and colleagues. “Their median age of 83 years is remarkable because genetic diseases are generally assumed to be relegated to much younger populations.” Five patients had late symptom onset; the other three “had onset of symptoms at much younger ages but survived many decades and did not receive specific genetic diagnoses until relevant genetics tests became available in their senior years.”

The researchers noted that recognition of single-gene diseases in elderly patients can be explained by the aging of the population, increased awareness of symptom onset, and DNA-based genetic testing. “The specific diagnosis of genetic diseases is readily available to a degree completely unknown a few years ago,” they said. “Patients in this study would have been considered to have senile chorea, senile dementia, and unexplained myopathy before the advent of such testing.”

Parent-of-Origin Effect
Ilse A. Hoppenbrouwers, MD, from the Department of Neurology, MS Centre Erasmus, Rotterdam, the Netherlands, and colleagues investigated parental relationships among patients with MS using extensive genealogic information from the Genetic Research in Isolated Populations program. Fewer than 400 individuals comprised the mid-18th-century founding population of a region located in the southwest Netherlands. To date, approximately 20,000 descendants live in eight adjacent communities and are generally related. More than 90,000 people spanning 23 generations are included in a genealogic database. Of these, 24 patients (19 women) with MS “could be linked to the most recent common ancestor in 14 generations.”

Reconstruction of a pedigree of these 24 patients with common clinical phenotypes of MS found that “the shortest connection to a common ancestor between two individuals with MS was significantly more often through their nonaffected mother than through their nonaffected father, suggesting a maternal parent-of-origin effect” that was specific for MS, noted Dr. Hoppenbrouwers and colleagues. “Mothers of the 24 MS patients were also more closely related to each other than their fathers.”

Maternal transmission of MS can be a result of genetic factors, environmental factors, or both. These data suggest that “the most likely explanation is a gene-environment effect that takes place in utero,” the researchers concluded. “Dense genotyping in this pedigree can help to unravel the genetic combination, thus aiding in resolving the nature-nurture dilemma in MS.”

Malformations of Cortical Development
In another study from the Erasmus Medical Center–Sophia Children’s Hospital, Rotterdam, Marie Claire Yvette de Wit, MD, of the Department of Pediatric Neurology, and colleagues evaluated the etiology of malformations of cortical development in children to determine whether a combined radiologic, clinical, and syndrome classification could provide a molecularly confirmed diagnosis.

A case series of 113 children who had a radiologic diagnosis of malformations of cortical development from 1992 to 2006 was included in the study. Each child had a complete radiologic, clinical, and neurologic assessment and was tested for phenotypically appropriate genes known to be involved in the pathogenesis of malformations of cortical development.

An etiologic diagnosis was established in 45 of the 113 children (40%). Diagnoses included molecular and/or genetic confirmation in 21 patients (19%) of ­Miller­-­Dieker syndrome; LIS1, DCX, FLNA, ­EIF2AK3, or KIAA1279 mutations; or an inborn error of metabolism. A syndrome with an unknown genetic defect was diagnosed in 17 children (15%), and evidence of gestational insult was found in seven (6%). “Of the remaining 68 patients, 34 probably have a yet-unknown genetic disorder based on the presence of multiple congenital anomalies (15 patients), a family history of multiple affected persons (12 patients), or consanguineous parents (seven patients),” the investigators wrote.

Most patients were diagnosed as having malformations of cortical development when they developed seizures; 26 of 63 patients (41%) were previously misdiagnosed, demonstrating that “a quality MRI of the brain and a skilled neuroradiologist are essential for a correct classification and the choice of diagnostic tests.”

Dr. de Wit’s group concluded that “classification based on radiological, clinical genetic, and neurological examinations combined with genetic testing can yield important information about monogenetic, syndromal, and metabolic causes and can lead to improvement of patient care and genetic counseling. This requires a multidisciplinary team specialized in neuroradiology, pediatric neurology, and genetics. Even then, the underlying cause remains elusive in more than 50% of patients, and the suspicion of an underlying genetic cause remains in many of our unclassified cases. This encourages exploitation of new genome-wide techniques.”

Additional articles in the theme issues also focused on stem cells, the human HapMap, primary and amyotrophic lateral sclerosis, Huntington’s disease, frontotemporal disease, Parkinson’s disease, cryptogenic epileptic syndromes, fragile X, spinocerebellar ataxia, Machado-Joseph disease, Troyer syndrome, MELAS, Leigh syndrome, and hereditary spastic paraplegia.

Clinical and molecular neurogenetics and neuromics have achieved considerable success recently in providing a clearer understanding of gene interactions responsible for neurologic disorders such as Alzheimer’s disease, multiple sclerosis (MS), and cortical brain malformations. “Clearly, the field of neurogenetics/neuromics is alive and well, prospering with an avalanche of new concepts and innovative data,” said Roger N. Rosenberg, MD, Editor of Archives of Neurology, in an editorial highlighting the wide range of original scientific reports in the March and April issues of the journal. Dr. Rosenberg is a Professor of Neurology at the University of Texas Southwestern Medical Center at Dallas.

Genetics and Risk for Alzheimer’s Disease
If both parents have a clinical diagnosis of Alzheimer’s disease, are their children at increased risk? That was the question Suman Jayadev, MD, and colleagues attempted to answer in a retrospective study of 111 conjugal couples who had 297 children surviving to adulthood. Of the 297 offspring, 22.6% had developed Alzheimer’s disease, with the risk increasing as they aged. Among those older than 60, 31% (58 of 137) had Alzheimer’s disease; among those older than 70, 41.8% (41 of 98) had the disease. Dr. Jayadev, Assistant Professor of Neurology, University of Washington, Seattle, pointed out that because 79% of the offspring are younger than 70, the risk of occurrence will only increase. This work confirmed results of a small pilot study involving the offspring of 31 of the couples, which found a higher rate of Alzheimer’s disease than would be expected in the general population.

“A family history of Alzheimer’s disease beyond the parents did not change the risk of Alzheimer’s disease in the children but did reduce the median age at onset in affected children,” Dr. Jayadev and colleagues said. In addition, although the apolipoprotein E ε4 allele has an important role, it “did not account for all Alzheimer’s disease cases in offspring, supporting the hypothesis that this is a complex polygenic phenomenon” and calling for a better definition of the role of family history and specific genes involved, they concluded.

Genome-wide association studies are being used as a tool for identifying genetic contributions to complex diseases and have shown success, for example, in helping to identify risk for age-related macular generation and diabetes mellitus. “Whether this will hold true for a genetically complex and heterogeneous disease such as Alzheimer’s disease is not known, although early reports are encouraging,” noted Dr. Rosenberg and ­Stephen C. Waring, DVM, PhD, Assistant Professor in the Department of Epidemiology at the University of Texas School of Public Health at Houston and a researcher with the Texas Alz­heimer’s Research Consortium. Drs. Rosenberg and Waring reported on results of genome-wide association studies to date that combine high-throughput arrays, bioinformatics, and advances in software to investigate significant markers associated with the risk of Alzheimer’s disease.

Examining Single-Gene Neurogenetic Disorders
In another study, Thomas D. Bird, MD, and colleagues conducted a retrospective review to describe the occurrence of single-gene neurogenetic disorders in eight elderly patients. Seven patients were men—two had Huntington’s disease (ages 85 and 87), three had spinocerebellar ataxia types 5, 6, and 14 (ages 86, 78, 78, respectively), one had presenilin 1 familial Alzheimer’s disease mutation (age 85), and one had autosomal dominant hereditary neuropathy (age 87). An 84-year-old woman had limb-girdle muscular dystrophy type 2A.

“Three patients had no family history of neurologic disease,” said Dr. Bird, a Professor of Neurology at the University of Washington, Seattle, and colleagues. “Their median age of 83 years is remarkable because genetic diseases are generally assumed to be relegated to much younger populations.” Five patients had late symptom onset; the other three “had onset of symptoms at much younger ages but survived many decades and did not receive specific genetic diagnoses until relevant genetics tests became available in their senior years.”

The researchers noted that recognition of single-gene diseases in elderly patients can be explained by the aging of the population, increased awareness of symptom onset, and DNA-based genetic testing. “The specific diagnosis of genetic diseases is readily available to a degree completely unknown a few years ago,” they said. “Patients in this study would have been considered to have senile chorea, senile dementia, and unexplained myopathy before the advent of such testing.”

Parent-of-Origin Effect
Ilse A. Hoppenbrouwers, MD, from the Department of Neurology, MS Centre Erasmus, Rotterdam, the Netherlands, and colleagues investigated parental relationships among patients with MS using extensive genealogic information from the Genetic Research in Isolated Populations program. Fewer than 400 individuals comprised the mid-18th-century founding population of a region located in the southwest Netherlands. To date, approximately 20,000 descendants live in eight adjacent communities and are generally related. More than 90,000 people spanning 23 generations are included in a genealogic database. Of these, 24 patients (19 women) with MS “could be linked to the most recent common ancestor in 14 generations.”

Reconstruction of a pedigree of these 24 patients with common clinical phenotypes of MS found that “the shortest connection to a common ancestor between two individuals with MS was significantly more often through their nonaffected mother than through their nonaffected father, suggesting a maternal parent-of-origin effect” that was specific for MS, noted Dr. Hoppenbrouwers and colleagues. “Mothers of the 24 MS patients were also more closely related to each other than their fathers.”

Maternal transmission of MS can be a result of genetic factors, environmental factors, or both. These data suggest that “the most likely explanation is a gene-environment effect that takes place in utero,” the researchers concluded. “Dense genotyping in this pedigree can help to unravel the genetic combination, thus aiding in resolving the nature-nurture dilemma in MS.”

Malformations of Cortical Development
In another study from the Erasmus Medical Center–Sophia Children’s Hospital, Rotterdam, Marie Claire Yvette de Wit, MD, of the Department of Pediatric Neurology, and colleagues evaluated the etiology of malformations of cortical development in children to determine whether a combined radiologic, clinical, and syndrome classification could provide a molecularly confirmed diagnosis.

A case series of 113 children who had a radiologic diagnosis of malformations of cortical development from 1992 to 2006 was included in the study. Each child had a complete radiologic, clinical, and neurologic assessment and was tested for phenotypically appropriate genes known to be involved in the pathogenesis of malformations of cortical development.

An etiologic diagnosis was established in 45 of the 113 children (40%). Diagnoses included molecular and/or genetic confirmation in 21 patients (19%) of ­Miller­-­Dieker syndrome; LIS1, DCX, FLNA, ­EIF2AK3, or KIAA1279 mutations; or an inborn error of metabolism. A syndrome with an unknown genetic defect was diagnosed in 17 children (15%), and evidence of gestational insult was found in seven (6%). “Of the remaining 68 patients, 34 probably have a yet-unknown genetic disorder based on the presence of multiple congenital anomalies (15 patients), a family history of multiple affected persons (12 patients), or consanguineous parents (seven patients),” the investigators wrote.

Most patients were diagnosed as having malformations of cortical development when they developed seizures; 26 of 63 patients (41%) were previously misdiagnosed, demonstrating that “a quality MRI of the brain and a skilled neuroradiologist are essential for a correct classification and the choice of diagnostic tests.”

Dr. de Wit’s group concluded that “classification based on radiological, clinical genetic, and neurological examinations combined with genetic testing can yield important information about monogenetic, syndromal, and metabolic causes and can lead to improvement of patient care and genetic counseling. This requires a multidisciplinary team specialized in neuroradiology, pediatric neurology, and genetics. Even then, the underlying cause remains elusive in more than 50% of patients, and the suspicion of an underlying genetic cause remains in many of our unclassified cases. This encourages exploitation of new genome-wide techniques.”

Additional articles in the theme issues also focused on stem cells, the human HapMap, primary and amyotrophic lateral sclerosis, Huntington’s disease, frontotemporal disease, Parkinson’s disease, cryptogenic epileptic syndromes, fragile X, spinocerebellar ataxia, Machado-Joseph disease, Troyer syndrome, MELAS, Leigh syndrome, and hereditary spastic paraplegia.