Diana Mahoney

Major Finding: Functional magnetic resonance imaging correlated with EEG in children with absence epilepsy and matched healthy controls.

Data Source: Results from Continuous Performance Task test done by 34 children (aged 7 to 8 years) and 21 healthy controls

Disclosures: The study was supported by a National Institutes of Health, the Betsy and Jonathan Blattmachr family, and a Howard Hughes Medical Institute fellowship. The authors reported no conflicts of interest.

BOSTON — Interictal attention problems in children with absence epilepsy may be linked to functional aberrations in specific areas of the brain.

Matthew Vestal, a medical student and research fellow, and Dr. Hal Blumenfeld of Yale University, New Haven, Conn., and their colleagues found that, between seizures, the function of the medial and bilateral frontal cortices of patients with childhood absence epilepsy (CAE) was impaired during the performance of attention tasks.

This finding suggests that dysfunction in specific brain networks may play a role in the attention deficits in this population. If confirmed, the findings could lead to the development of innovative regional therapies targeted at improving impaired attention in CAE, which in turn could improve patients' quality of life by minimizing school performance deficits, injury potential, and the social stigma associated with attentional problems, Dr. Blumenfeld said in an interview.

Absence seizures are characterized by 3- to 4-Hz spike-wave discharges on electroencephalogram (EEG) that cause impaired consciousness. In school-aged children, the disease is associated with attention problems and social dysfunction, he explained.

In 34 patients with CAE aged between 7 and 8 years and 21 age-, gender-, IQ-, and socioeconomically matched healthy controls, the investigators performed functional magnetic resonance imaging correlated with electroencephalography while the participants completed the Continuous Performance Task (CPT) test of attentional vigilance, Mr. Vestal reported at the annual meeting of the American Epilepsy Society.

The CPT test involves showing subjects a string of letters on a computer and instructing them to press a button whenever they see a particular stimulus letter. Behavioral performance during the CPT is measured by reviewing omission and commission errors and reaction time.

The investigators monitored all of the CAE subjects for seizure episodes with EEG during the CPT testing and adjusted for all seizure-related fMRI signal changes during CPT.

Subjects in the CAE group made more omission errors than did the control subjects, although there was no difference between the groups in commission errors or reaction time. “Our hypothesis is that brain areas such as the frontal lobes and anterior insula, which are important for normal attention, are not functioning properly in these children,” Dr. Blumenfeld said.

In both the CAE and control subjects, CPT-associated increases in fMRI blood-oxygen-level dependent (BOLD) signal were observed in the medial frontal cortex and the medial and anterior insula, whereas CPT-associated decreases in fMRI BOLD signal occurred in the bilateral medial and lateral parietal cortices.

“By knowing which brain areas are not working in [these] children, we hope treatments can be developed to improve the function of these areas and attention in these children,” Dr. Blumenfeld stated.

Absence seizures overlapped with areas of increased (red) and decreased (green) brain activity in a 12-year-old girl during fMRI imaging of attention tasks.

Source Courtesy Hal Blumenfeld, M.D., Ph.D. and Rachel Berman

Major Finding: Functional magnetic resonance imaging correlated with EEG in children with absence epilepsy and matched healthy controls.

Data Source: Results from Continuous Performance Task test done by 34 children (aged 7 to 8 years) and 21 healthy controls

Disclosures: The study was supported by a National Institutes of Health, the Betsy and Jonathan Blattmachr family, and a Howard Hughes Medical Institute fellowship. The authors reported no conflicts of interest.

BOSTON — Interictal attention problems in children with absence epilepsy may be linked to functional aberrations in specific areas of the brain.

Matthew Vestal, a medical student and research fellow, and Dr. Hal Blumenfeld of Yale University, New Haven, Conn., and their colleagues found that, between seizures, the function of the medial and bilateral frontal cortices of patients with childhood absence epilepsy (CAE) was impaired during the performance of attention tasks.

This finding suggests that dysfunction in specific brain networks may play a role in the attention deficits in this population. If confirmed, the findings could lead to the development of innovative regional therapies targeted at improving impaired attention in CAE, which in turn could improve patients' quality of life by minimizing school performance deficits, injury potential, and the social stigma associated with attentional problems, Dr. Blumenfeld said in an interview.

Absence seizures are characterized by 3- to 4-Hz spike-wave discharges on electroencephalogram (EEG) that cause impaired consciousness. In school-aged children, the disease is associated with attention problems and social dysfunction, he explained.

In 34 patients with CAE aged between 7 and 8 years and 21 age-, gender-, IQ-, and socioeconomically matched healthy controls, the investigators performed functional magnetic resonance imaging correlated with electroencephalography while the participants completed the Continuous Performance Task (CPT) test of attentional vigilance, Mr. Vestal reported at the annual meeting of the American Epilepsy Society.

The CPT test involves showing subjects a string of letters on a computer and instructing them to press a button whenever they see a particular stimulus letter. Behavioral performance during the CPT is measured by reviewing omission and commission errors and reaction time.

The investigators monitored all of the CAE subjects for seizure episodes with EEG during the CPT testing and adjusted for all seizure-related fMRI signal changes during CPT.

Subjects in the CAE group made more omission errors than did the control subjects, although there was no difference between the groups in commission errors or reaction time. “Our hypothesis is that brain areas such as the frontal lobes and anterior insula, which are important for normal attention, are not functioning properly in these children,” Dr. Blumenfeld said.

In both the CAE and control subjects, CPT-associated increases in fMRI blood-oxygen-level dependent (BOLD) signal were observed in the medial frontal cortex and the medial and anterior insula, whereas CPT-associated decreases in fMRI BOLD signal occurred in the bilateral medial and lateral parietal cortices.

“By knowing which brain areas are not working in [these] children, we hope treatments can be developed to improve the function of these areas and attention in these children,” Dr. Blumenfeld stated.

Absence seizures overlapped with areas of increased (red) and decreased (green) brain activity in a 12-year-old girl during fMRI imaging of attention tasks.

Source Courtesy Hal Blumenfeld, M.D., Ph.D. and Rachel Berman

Major Finding: Functional magnetic resonance imaging correlated with EEG in children with absence epilepsy and matched healthy controls.

Data Source: Results from Continuous Performance Task test done by 34 children (aged 7 to 8 years) and 21 healthy controls

Disclosures: The study was supported by a National Institutes of Health, the Betsy and Jonathan Blattmachr family, and a Howard Hughes Medical Institute fellowship. The authors reported no conflicts of interest.

BOSTON — Interictal attention problems in children with absence epilepsy may be linked to functional aberrations in specific areas of the brain.

Matthew Vestal, a medical student and research fellow, and Dr. Hal Blumenfeld of Yale University, New Haven, Conn., and their colleagues found that, between seizures, the function of the medial and bilateral frontal cortices of patients with childhood absence epilepsy (CAE) was impaired during the performance of attention tasks.

This finding suggests that dysfunction in specific brain networks may play a role in the attention deficits in this population. If confirmed, the findings could lead to the development of innovative regional therapies targeted at improving impaired attention in CAE, which in turn could improve patients' quality of life by minimizing school performance deficits, injury potential, and the social stigma associated with attentional problems, Dr. Blumenfeld said in an interview.

Absence seizures are characterized by 3- to 4-Hz spike-wave discharges on electroencephalogram (EEG) that cause impaired consciousness. In school-aged children, the disease is associated with attention problems and social dysfunction, he explained.

In 34 patients with CAE aged between 7 and 8 years and 21 age-, gender-, IQ-, and socioeconomically matched healthy controls, the investigators performed functional magnetic resonance imaging correlated with electroencephalography while the participants completed the Continuous Performance Task (CPT) test of attentional vigilance, Mr. Vestal reported at the annual meeting of the American Epilepsy Society.

The CPT test involves showing subjects a string of letters on a computer and instructing them to press a button whenever they see a particular stimulus letter. Behavioral performance during the CPT is measured by reviewing omission and commission errors and reaction time.

The investigators monitored all of the CAE subjects for seizure episodes with EEG during the CPT testing and adjusted for all seizure-related fMRI signal changes during CPT.

Subjects in the CAE group made more omission errors than did the control subjects, although there was no difference between the groups in commission errors or reaction time. “Our hypothesis is that brain areas such as the frontal lobes and anterior insula, which are important for normal attention, are not functioning properly in these children,” Dr. Blumenfeld said.

In both the CAE and control subjects, CPT-associated increases in fMRI blood-oxygen-level dependent (BOLD) signal were observed in the medial frontal cortex and the medial and anterior insula, whereas CPT-associated decreases in fMRI BOLD signal occurred in the bilateral medial and lateral parietal cortices.

“By knowing which brain areas are not working in [these] children, we hope treatments can be developed to improve the function of these areas and attention in these children,” Dr. Blumenfeld stated.

Absence seizures overlapped with areas of increased (red) and decreased (green) brain activity in a 12-year-old girl during fMRI imaging of attention tasks.

Source Courtesy Hal Blumenfeld, M.D., Ph.D. and Rachel Berman

The monoclonal antibody tocilizumab has received approval by the U.S. Food and Drug Administration for the treatment of moderate to severely active rheumatoid arthritis in adult patients who have failed one or more tumor necrosis factor blockers, according to an announcement made Jan. 11 by the drug's manufacturer, Roche Holding AG.

Tocilizumab (Actemra) is the first interleukin-6 (IL-6) receptor inhibitor to be approved for the treatment of RA, and it can be used alone or in combination with methotrexate or other disease-modifying antirheumatic drugs (DMARDs), according to the statement. The drug was codeveloped by Chugai Pharmaceutical Co. and its parent company, Roche.

The approval comes on the heels of an extensive clinical development program comprising five phase III trials, as well as a resubmission of documents, including a proposal for a risk evaluation and mitigation strategy. The pivotal clinical trials include RADIATE (Research on Actemra Determining Efficacy after Anti-TNF Failures), OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders), TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy), AMBITION (Actemra vs. Methotrexate Double-Blind Investigative Trial in Monotherapy), and LITHE (Tocilizumab Safety and the Prevention of Structural Joint Damage).

In the RADIATE trial, 30% of patients who received tocilizumab in combination with methotrexate achieved disease remission, compared with 1.6% of patients receiving methotrexate alone. Lead investigator Dr. Paul Emery, professor of rheumatology at the University of Leeds (England), and colleagues wrote that the findings were especially promising for that subset of RA patients who have failed to achieve adequate symptom relief with anti-TNF agents (Ann. Rheum. Dis. 2008;67:1516–23).

The results from the OPTION trial showed that 59% of the patients with RA who had incomplete responses to methotrexate achieved an ACR 20 response following treatment with tocilizumab 8 mg/kg, compared with 26% of patients treated with placebo, and 27% of the patients on tocilizumab achieved remission, compared with 0.8% in the placebo group (Lancet 2008;371:987–97).

Similarly, in the TOWARD trial, 61% of patients who received tocilizumab in a dose of 8 mg/kg achieved an ACR 20 response at 24 weeks, compared with 25% of patients treated with placebo plus DMARDs, and approximately 38% of tocilizumab-treated patients met ACR 50 criteria for symptom improvement, compared with 9% of patients receiving placebo (Arthritis Rheum. 2008;58:2968–80).

The AMBITION study, in which 70% of patients who received a dose of 8 mg/kg achieved an ACR 20 response at 24 weeks, was the first to show that treatment with a single biologic agent was superior to methotrexate alone for the treatment of RA at 6 months, according to a press release issued by Roche when the phase III results were released in 2008 at the annual Congress of the European League Against Rheumatism.

Findings from the LITHE study, which were presented by lead investigator Dr. Roy M. Fleischmann of the department of internal medicine at the University of Texas Southwestern Medical Center, Dallas, at the 2009 annual meeting of the American College of Rheumatology, showed that over a 2-year period, there was no radiographic progression or joint damage in 75% of RA patients taking tocilizumab 4 mg/kg plus methotrexate, or in 85% of those taking tocilizumab 8 mg/kg and methotrexate, compared with 66% of patients taking methotrexate alone.

Among the serious tocilizumab-related adverse events that have been reported in the clinical trials are infections (including tuberculosis) that led to hospitalization or death, and bacterial, invasive fungal, viral, and other infections; gastrointestinal perforations; hypersensitivity reactions; and cellulitis.

Some of the common side effects included upper respiratory infections, including pneumonia; inflammation of the nose and throat; headache; high blood pressure; increased liver enzymes; increased cholesterol levels; neutrophil decreases; and platelet decreases, according to the press release.

Tocilizumab is expected to become available in the United States soon.

My Take

Insurance Coverage May Be an Issue

Rheumatologists have been hearing a lot of preapproval hype about this agent from Roche.

Our interest is piqued by the novelty of the mechanism of action of tocilizumab. There are multiple anti-TNF medications currently, and their manufacturers are trying hard to convince clinicians to choose one medication over another, even though they are probably more similar than different. As an IL-6 blocker, tocilizumab is different.

The new-drug hype notwithstanding, there are still a number of questions to be answered before clinicians can consider the potential clinical impact of tocilizumab. The main questions for me are: Is this medication any safer or more dangerous than the current biologic drugs? Is this medication more or less affordable, or accessible, than the current biologics? Where does this medication belong in the treatment algorithm?

Undoubtedly, the company is going to try to convince doctors to use this medication immediately after methotrexate failure, but they will first have to convince doctors, and insurers, that this strategy is warranted.

LARRY GREENBAUM, M.D., is a private practice rheumatologist in Indianapolis. He has no financial disclosures to make that are relevant to the approval of tocilizumab.

The monoclonal antibody tocilizumab has received approval by the U.S. Food and Drug Administration for the treatment of moderate to severely active rheumatoid arthritis in adult patients who have failed one or more tumor necrosis factor blockers, according to an announcement made Jan. 11 by the drug's manufacturer, Roche Holding AG.

Tocilizumab (Actemra) is the first interleukin-6 (IL-6) receptor inhibitor to be approved for the treatment of RA, and it can be used alone or in combination with methotrexate or other disease-modifying antirheumatic drugs (DMARDs), according to the statement. The drug was codeveloped by Chugai Pharmaceutical Co. and its parent company, Roche.

The approval comes on the heels of an extensive clinical development program comprising five phase III trials, as well as a resubmission of documents, including a proposal for a risk evaluation and mitigation strategy. The pivotal clinical trials include RADIATE (Research on Actemra Determining Efficacy after Anti-TNF Failures), OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders), TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy), AMBITION (Actemra vs. Methotrexate Double-Blind Investigative Trial in Monotherapy), and LITHE (Tocilizumab Safety and the Prevention of Structural Joint Damage).

In the RADIATE trial, 30% of patients who received tocilizumab in combination with methotrexate achieved disease remission, compared with 1.6% of patients receiving methotrexate alone. Lead investigator Dr. Paul Emery, professor of rheumatology at the University of Leeds (England), and colleagues wrote that the findings were especially promising for that subset of RA patients who have failed to achieve adequate symptom relief with anti-TNF agents (Ann. Rheum. Dis. 2008;67:1516–23).

The results from the OPTION trial showed that 59% of the patients with RA who had incomplete responses to methotrexate achieved an ACR 20 response following treatment with tocilizumab 8 mg/kg, compared with 26% of patients treated with placebo, and 27% of the patients on tocilizumab achieved remission, compared with 0.8% in the placebo group (Lancet 2008;371:987–97).

Similarly, in the TOWARD trial, 61% of patients who received tocilizumab in a dose of 8 mg/kg achieved an ACR 20 response at 24 weeks, compared with 25% of patients treated with placebo plus DMARDs, and approximately 38% of tocilizumab-treated patients met ACR 50 criteria for symptom improvement, compared with 9% of patients receiving placebo (Arthritis Rheum. 2008;58:2968–80).

The AMBITION study, in which 70% of patients who received a dose of 8 mg/kg achieved an ACR 20 response at 24 weeks, was the first to show that treatment with a single biologic agent was superior to methotrexate alone for the treatment of RA at 6 months, according to a press release issued by Roche when the phase III results were released in 2008 at the annual Congress of the European League Against Rheumatism.

Findings from the LITHE study, which were presented by lead investigator Dr. Roy M. Fleischmann of the department of internal medicine at the University of Texas Southwestern Medical Center, Dallas, at the 2009 annual meeting of the American College of Rheumatology, showed that over a 2-year period, there was no radiographic progression or joint damage in 75% of RA patients taking tocilizumab 4 mg/kg plus methotrexate, or in 85% of those taking tocilizumab 8 mg/kg and methotrexate, compared with 66% of patients taking methotrexate alone.

Among the serious tocilizumab-related adverse events that have been reported in the clinical trials are infections (including tuberculosis) that led to hospitalization or death, and bacterial, invasive fungal, viral, and other infections; gastrointestinal perforations; hypersensitivity reactions; and cellulitis.

Some of the common side effects included upper respiratory infections, including pneumonia; inflammation of the nose and throat; headache; high blood pressure; increased liver enzymes; increased cholesterol levels; neutrophil decreases; and platelet decreases, according to the press release.

Tocilizumab is expected to become available in the United States soon.

My Take

Insurance Coverage May Be an Issue

Rheumatologists have been hearing a lot of preapproval hype about this agent from Roche.

Our interest is piqued by the novelty of the mechanism of action of tocilizumab. There are multiple anti-TNF medications currently, and their manufacturers are trying hard to convince clinicians to choose one medication over another, even though they are probably more similar than different. As an IL-6 blocker, tocilizumab is different.

The new-drug hype notwithstanding, there are still a number of questions to be answered before clinicians can consider the potential clinical impact of tocilizumab. The main questions for me are: Is this medication any safer or more dangerous than the current biologic drugs? Is this medication more or less affordable, or accessible, than the current biologics? Where does this medication belong in the treatment algorithm?

Undoubtedly, the company is going to try to convince doctors to use this medication immediately after methotrexate failure, but they will first have to convince doctors, and insurers, that this strategy is warranted.

LARRY GREENBAUM, M.D., is a private practice rheumatologist in Indianapolis. He has no financial disclosures to make that are relevant to the approval of tocilizumab.

The monoclonal antibody tocilizumab has received approval by the U.S. Food and Drug Administration for the treatment of moderate to severely active rheumatoid arthritis in adult patients who have failed one or more tumor necrosis factor blockers, according to an announcement made Jan. 11 by the drug's manufacturer, Roche Holding AG.

Tocilizumab (Actemra) is the first interleukin-6 (IL-6) receptor inhibitor to be approved for the treatment of RA, and it can be used alone or in combination with methotrexate or other disease-modifying antirheumatic drugs (DMARDs), according to the statement. The drug was codeveloped by Chugai Pharmaceutical Co. and its parent company, Roche.

The approval comes on the heels of an extensive clinical development program comprising five phase III trials, as well as a resubmission of documents, including a proposal for a risk evaluation and mitigation strategy. The pivotal clinical trials include RADIATE (Research on Actemra Determining Efficacy after Anti-TNF Failures), OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders), TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy), AMBITION (Actemra vs. Methotrexate Double-Blind Investigative Trial in Monotherapy), and LITHE (Tocilizumab Safety and the Prevention of Structural Joint Damage).

In the RADIATE trial, 30% of patients who received tocilizumab in combination with methotrexate achieved disease remission, compared with 1.6% of patients receiving methotrexate alone. Lead investigator Dr. Paul Emery, professor of rheumatology at the University of Leeds (England), and colleagues wrote that the findings were especially promising for that subset of RA patients who have failed to achieve adequate symptom relief with anti-TNF agents (Ann. Rheum. Dis. 2008;67:1516–23).

The results from the OPTION trial showed that 59% of the patients with RA who had incomplete responses to methotrexate achieved an ACR 20 response following treatment with tocilizumab 8 mg/kg, compared with 26% of patients treated with placebo, and 27% of the patients on tocilizumab achieved remission, compared with 0.8% in the placebo group (Lancet 2008;371:987–97).

Similarly, in the TOWARD trial, 61% of patients who received tocilizumab in a dose of 8 mg/kg achieved an ACR 20 response at 24 weeks, compared with 25% of patients treated with placebo plus DMARDs, and approximately 38% of tocilizumab-treated patients met ACR 50 criteria for symptom improvement, compared with 9% of patients receiving placebo (Arthritis Rheum. 2008;58:2968–80).

The AMBITION study, in which 70% of patients who received a dose of 8 mg/kg achieved an ACR 20 response at 24 weeks, was the first to show that treatment with a single biologic agent was superior to methotrexate alone for the treatment of RA at 6 months, according to a press release issued by Roche when the phase III results were released in 2008 at the annual Congress of the European League Against Rheumatism.

Findings from the LITHE study, which were presented by lead investigator Dr. Roy M. Fleischmann of the department of internal medicine at the University of Texas Southwestern Medical Center, Dallas, at the 2009 annual meeting of the American College of Rheumatology, showed that over a 2-year period, there was no radiographic progression or joint damage in 75% of RA patients taking tocilizumab 4 mg/kg plus methotrexate, or in 85% of those taking tocilizumab 8 mg/kg and methotrexate, compared with 66% of patients taking methotrexate alone.

Among the serious tocilizumab-related adverse events that have been reported in the clinical trials are infections (including tuberculosis) that led to hospitalization or death, and bacterial, invasive fungal, viral, and other infections; gastrointestinal perforations; hypersensitivity reactions; and cellulitis.

Some of the common side effects included upper respiratory infections, including pneumonia; inflammation of the nose and throat; headache; high blood pressure; increased liver enzymes; increased cholesterol levels; neutrophil decreases; and platelet decreases, according to the press release.

Tocilizumab is expected to become available in the United States soon.

My Take

Insurance Coverage May Be an Issue

Rheumatologists have been hearing a lot of preapproval hype about this agent from Roche.

Our interest is piqued by the novelty of the mechanism of action of tocilizumab. There are multiple anti-TNF medications currently, and their manufacturers are trying hard to convince clinicians to choose one medication over another, even though they are probably more similar than different. As an IL-6 blocker, tocilizumab is different.

The new-drug hype notwithstanding, there are still a number of questions to be answered before clinicians can consider the potential clinical impact of tocilizumab. The main questions for me are: Is this medication any safer or more dangerous than the current biologic drugs? Is this medication more or less affordable, or accessible, than the current biologics? Where does this medication belong in the treatment algorithm?

Undoubtedly, the company is going to try to convince doctors to use this medication immediately after methotrexate failure, but they will first have to convince doctors, and insurers, that this strategy is warranted.

LARRY GREENBAUM, M.D., is a private practice rheumatologist in Indianapolis. He has no financial disclosures to make that are relevant to the approval of tocilizumab.

The timing of influenza and pneumococcal vaccinations can substantially influence the degree of antibody response in rheumatoid arthritis patients taking rituximab, concluded investigators in two independent studies.

Rituximab, which acts by depleting B cells, also reduces patients' humoral and cellular immune responses, they said.

In one of the two studies reported in Arthritis & Rheumatism, Dr. Sander van Assen of the University Medical Center Groningen (the Netherlands) and colleagues investigated the efficacy of influenza vaccination in RA patients who are treated with rituximab. They also assessed the duration of the possible suppression of the humoral immune response following rituximab treatment, and observed a decreased humoral response following vaccination that was modestly restored 6–10 months after rituximab administration (Arthritis Rheum., 2010;62:75–81).

The study comprised two groups of RA patients—a rituximab group and a methotrexate group—and one group of 29 healthy controls. The rituximab group consisted of 23 patients, 22 of whom received two cycles of 1,000 mg of the biologic with 100 mg intravenous methylprednisolone, and 1 patient with mixed cryoglobulinemia who received four cycles of 375 mg/m

Immediately before and a mean 28 days after vaccination, blood was drawn from all patients to measure CD19+ cell counts, C-reactive protein levels, erythrocyte sedimentation rates, and anti-influenza antibodies. Compared with baseline measures, geometric mean titres (GMTs) for all three influenza strains tested (A[H3N2], A[H1N1], and B) increased significantly in the healthy controls and the methotrexate group, but not in the rituximab group as a whole, the authors reported. In the late rituximab subgroup, a rise was noted in the GMTs for the A(H3N2) and A(H1N1) flu strains, “indicating some recovery of the humoral immune response 6–10 months after treatment with rituximab,” they wrote.

With respect to CD19+ cell counts, the baseline measures for both the early and late rituximab subgroups were comparable. At 28 days after vaccination, however, significantly more B cells were present in the late vs. early group, according to the authors.

Seroconversion and seroprotection occurred less often in the rituximab group than in the methotrexate-treated group for both influenza A strains. Seroprotection occurred less often in the rituximab group than in the healthy controls for the A(H1N1) strains, the authors wrote. Of the three cases of seroconversion and six cases of seroprotection observed in the rituximab group, all but one of the seroprotection cases occurred in the late rituximab subgroup, they stated.

An examination of vaccination safety showed no differences among the three groups regarding the occurrence of side effects, the authors wrote. Also, disease activity in the methotrexate and rituximab groups, assessed with the DAS28 prior to and 7 and 28 days after vaccination, was not influenced by vaccination.

Because patients who were treated with rituximab appear to have a “severely hampered” humoral immune response to the trivalent subunit influenza vaccination, preemptive influenza vaccination should be considered prior to rituximab administration, the authors wrote, noting the importance of yearly influenza vaccination, given the increase in anti-influenza titers observed in previously vaccinated patients.

In the second study, a controlled trial by Dr. Clifton O. Bingham III of Johns Hopkins University, Baltimore, and colleagues, the investigators examined the immunization responses (humoral immunity and the cellular immune response) of rituximab-treated RA patients who received tetanus toxoid, 23-valent pneumococcal polysaccharide (PPV23), and keyhole limpet hemocyanin (KLH) vaccines, and they evaluated the effects of rituximab-induced CD20+ B-cell depletion on immune responses to these vaccinations (Arthritis Rheum. 2010;62:62–74).

The study enrolled 103 patients aged 18–65 years who had active RA and were receiving a stable dosage of 10–25 mg/wk of methotrexate from 26 U.S. centers between January 2006 and December 2007. Patients were stratified by site and age (18–50 years and 51–65 years) and then were randomized in a 2:1 manner to receive either two cycles of 1,000 mg rituximab (open label) 2 weeks apart plus a stable dose of methotrexate (68 patients), or methotrexate alone (32 patients). In the rituximab-plus-methotrexate group, 100 mg of methylprednisolone was administered intravenously before each rituximab infusion, the authors wrote.

Patients in both groups received the tetanus toxoid adsorbed vaccine, PPV23, KLH, and a Candida albicans skin test according to the protocol schedule. Antitetanus, antipneumonococcal, and anti-KLH serum IgG levels were measured prior to and 4 weeks following each respective vaccine administration, and the delayed-type hypersensitivity (DTH) skin test response was measured 2–3 days following placement, the authors wrote.

An analysis of the results showed that patients in both groups responded similarly to tetanus toxoid vaccine, with 25 patients in the rituximab group (39%) and 11 patients in the methotrexate-only group (42%) showing a more than fourfold risk in antitetanus IgG titer, and 35 rituximab patients and 16 methotrexate patients demonstrating a more than twofold rise, the authors reported. Similarly, they wrote, “the ability to maintain a positive DTH response to the C. albicans skin test was comparable in both groups,” confirming that rituximab had no incremental effect on the patients'ability to mount a DTH response.

Significant differences were observed in the responses to PPV23 between the two groups, with only 57% of patients in the rituximab group demonstrating a twofold rise in titer in response to one or more serotypes, compared with 82% of the methotrexate-only patients, the authors reported. Similarly, only 47% of the rituximab patients had detectable anti-KLH IgG, compared with 93% of the methotrexate-only group, they noted.

“Because neoantigen and polysaccharide responses are B-cell dependent, decreased responses to KLH and [PPV23] are consistent with rituximab's mechanism of action,” the authors observed. “Despite peripheral B-cell depletion, however, responses to the KLH and [PPV23] vaccine were not completely abrogated in the present study,” they wrote, referring to the 47% of rituximab patients who had a quantifiable anti-KLH response and the 57% and 43% of rituximab patients who mounted responses to at least one and two pneumococcal serotypes, respectively. The authors concluded that for maximized vaccination response, “polysaccharide and primary immunizations should be administered prior to rituximab infusions.”

Although both of these studies provide some insight into the effects of rituximab therapy on immune function, “they fall short in offering clues about the causal mechanisms,” Dr. E. William St. Claire of Duke University Medical Center in Durham, N.C., wrote in an editorial (Arthritis Rheum. 2010;62:1–5).

Disclosures: The study reported by Dr. van Assen and colleagues was supported by Roche Nederland and Solvay Pharmaceuticals. The authors reported no additional conflicts of interest. The study reported by Dr. Bingham and colleagues was supported by Genentech Inc. The authors reported having financial relationships with Genentech, Roche, and Merck & Co. One of the authors served on Merck's data and safety monitoring board, and three of the authors own stock or stock options in Genentech. Dr. St. Clair disclosed having financial relationships with Biogen Idec Inc.

The timing of influenza and pneumococcal vaccinations can substantially influence the degree of antibody response in rheumatoid arthritis patients taking rituximab, concluded investigators in two independent studies.

Rituximab, which acts by depleting B cells, also reduces patients' humoral and cellular immune responses, they said.

In one of the two studies reported in Arthritis & Rheumatism, Dr. Sander van Assen of the University Medical Center Groningen (the Netherlands) and colleagues investigated the efficacy of influenza vaccination in RA patients who are treated with rituximab. They also assessed the duration of the possible suppression of the humoral immune response following rituximab treatment, and observed a decreased humoral response following vaccination that was modestly restored 6–10 months after rituximab administration (Arthritis Rheum., 2010;62:75–81).

The study comprised two groups of RA patients—a rituximab group and a methotrexate group—and one group of 29 healthy controls. The rituximab group consisted of 23 patients, 22 of whom received two cycles of 1,000 mg of the biologic with 100 mg intravenous methylprednisolone, and 1 patient with mixed cryoglobulinemia who received four cycles of 375 mg/m

Immediately before and a mean 28 days after vaccination, blood was drawn from all patients to measure CD19+ cell counts, C-reactive protein levels, erythrocyte sedimentation rates, and anti-influenza antibodies. Compared with baseline measures, geometric mean titres (GMTs) for all three influenza strains tested (A[H3N2], A[H1N1], and B) increased significantly in the healthy controls and the methotrexate group, but not in the rituximab group as a whole, the authors reported. In the late rituximab subgroup, a rise was noted in the GMTs for the A(H3N2) and A(H1N1) flu strains, “indicating some recovery of the humoral immune response 6–10 months after treatment with rituximab,” they wrote.

With respect to CD19+ cell counts, the baseline measures for both the early and late rituximab subgroups were comparable. At 28 days after vaccination, however, significantly more B cells were present in the late vs. early group, according to the authors.

Seroconversion and seroprotection occurred less often in the rituximab group than in the methotrexate-treated group for both influenza A strains. Seroprotection occurred less often in the rituximab group than in the healthy controls for the A(H1N1) strains, the authors wrote. Of the three cases of seroconversion and six cases of seroprotection observed in the rituximab group, all but one of the seroprotection cases occurred in the late rituximab subgroup, they stated.

An examination of vaccination safety showed no differences among the three groups regarding the occurrence of side effects, the authors wrote. Also, disease activity in the methotrexate and rituximab groups, assessed with the DAS28 prior to and 7 and 28 days after vaccination, was not influenced by vaccination.

Because patients who were treated with rituximab appear to have a “severely hampered” humoral immune response to the trivalent subunit influenza vaccination, preemptive influenza vaccination should be considered prior to rituximab administration, the authors wrote, noting the importance of yearly influenza vaccination, given the increase in anti-influenza titers observed in previously vaccinated patients.

In the second study, a controlled trial by Dr. Clifton O. Bingham III of Johns Hopkins University, Baltimore, and colleagues, the investigators examined the immunization responses (humoral immunity and the cellular immune response) of rituximab-treated RA patients who received tetanus toxoid, 23-valent pneumococcal polysaccharide (PPV23), and keyhole limpet hemocyanin (KLH) vaccines, and they evaluated the effects of rituximab-induced CD20+ B-cell depletion on immune responses to these vaccinations (Arthritis Rheum. 2010;62:62–74).

The study enrolled 103 patients aged 18–65 years who had active RA and were receiving a stable dosage of 10–25 mg/wk of methotrexate from 26 U.S. centers between January 2006 and December 2007. Patients were stratified by site and age (18–50 years and 51–65 years) and then were randomized in a 2:1 manner to receive either two cycles of 1,000 mg rituximab (open label) 2 weeks apart plus a stable dose of methotrexate (68 patients), or methotrexate alone (32 patients). In the rituximab-plus-methotrexate group, 100 mg of methylprednisolone was administered intravenously before each rituximab infusion, the authors wrote.

Patients in both groups received the tetanus toxoid adsorbed vaccine, PPV23, KLH, and a Candida albicans skin test according to the protocol schedule. Antitetanus, antipneumonococcal, and anti-KLH serum IgG levels were measured prior to and 4 weeks following each respective vaccine administration, and the delayed-type hypersensitivity (DTH) skin test response was measured 2–3 days following placement, the authors wrote.

An analysis of the results showed that patients in both groups responded similarly to tetanus toxoid vaccine, with 25 patients in the rituximab group (39%) and 11 patients in the methotrexate-only group (42%) showing a more than fourfold risk in antitetanus IgG titer, and 35 rituximab patients and 16 methotrexate patients demonstrating a more than twofold rise, the authors reported. Similarly, they wrote, “the ability to maintain a positive DTH response to the C. albicans skin test was comparable in both groups,” confirming that rituximab had no incremental effect on the patients'ability to mount a DTH response.

Significant differences were observed in the responses to PPV23 between the two groups, with only 57% of patients in the rituximab group demonstrating a twofold rise in titer in response to one or more serotypes, compared with 82% of the methotrexate-only patients, the authors reported. Similarly, only 47% of the rituximab patients had detectable anti-KLH IgG, compared with 93% of the methotrexate-only group, they noted.

“Because neoantigen and polysaccharide responses are B-cell dependent, decreased responses to KLH and [PPV23] are consistent with rituximab's mechanism of action,” the authors observed. “Despite peripheral B-cell depletion, however, responses to the KLH and [PPV23] vaccine were not completely abrogated in the present study,” they wrote, referring to the 47% of rituximab patients who had a quantifiable anti-KLH response and the 57% and 43% of rituximab patients who mounted responses to at least one and two pneumococcal serotypes, respectively. The authors concluded that for maximized vaccination response, “polysaccharide and primary immunizations should be administered prior to rituximab infusions.”

Although both of these studies provide some insight into the effects of rituximab therapy on immune function, “they fall short in offering clues about the causal mechanisms,” Dr. E. William St. Claire of Duke University Medical Center in Durham, N.C., wrote in an editorial (Arthritis Rheum. 2010;62:1–5).

Disclosures: The study reported by Dr. van Assen and colleagues was supported by Roche Nederland and Solvay Pharmaceuticals. The authors reported no additional conflicts of interest. The study reported by Dr. Bingham and colleagues was supported by Genentech Inc. The authors reported having financial relationships with Genentech, Roche, and Merck & Co. One of the authors served on Merck's data and safety monitoring board, and three of the authors own stock or stock options in Genentech. Dr. St. Clair disclosed having financial relationships with Biogen Idec Inc.

The timing of influenza and pneumococcal vaccinations can substantially influence the degree of antibody response in rheumatoid arthritis patients taking rituximab, concluded investigators in two independent studies.

Rituximab, which acts by depleting B cells, also reduces patients' humoral and cellular immune responses, they said.

In one of the two studies reported in Arthritis & Rheumatism, Dr. Sander van Assen of the University Medical Center Groningen (the Netherlands) and colleagues investigated the efficacy of influenza vaccination in RA patients who are treated with rituximab. They also assessed the duration of the possible suppression of the humoral immune response following rituximab treatment, and observed a decreased humoral response following vaccination that was modestly restored 6–10 months after rituximab administration (Arthritis Rheum., 2010;62:75–81).

The study comprised two groups of RA patients—a rituximab group and a methotrexate group—and one group of 29 healthy controls. The rituximab group consisted of 23 patients, 22 of whom received two cycles of 1,000 mg of the biologic with 100 mg intravenous methylprednisolone, and 1 patient with mixed cryoglobulinemia who received four cycles of 375 mg/m

Immediately before and a mean 28 days after vaccination, blood was drawn from all patients to measure CD19+ cell counts, C-reactive protein levels, erythrocyte sedimentation rates, and anti-influenza antibodies. Compared with baseline measures, geometric mean titres (GMTs) for all three influenza strains tested (A[H3N2], A[H1N1], and B) increased significantly in the healthy controls and the methotrexate group, but not in the rituximab group as a whole, the authors reported. In the late rituximab subgroup, a rise was noted in the GMTs for the A(H3N2) and A(H1N1) flu strains, “indicating some recovery of the humoral immune response 6–10 months after treatment with rituximab,” they wrote.

With respect to CD19+ cell counts, the baseline measures for both the early and late rituximab subgroups were comparable. At 28 days after vaccination, however, significantly more B cells were present in the late vs. early group, according to the authors.

Seroconversion and seroprotection occurred less often in the rituximab group than in the methotrexate-treated group for both influenza A strains. Seroprotection occurred less often in the rituximab group than in the healthy controls for the A(H1N1) strains, the authors wrote. Of the three cases of seroconversion and six cases of seroprotection observed in the rituximab group, all but one of the seroprotection cases occurred in the late rituximab subgroup, they stated.

An examination of vaccination safety showed no differences among the three groups regarding the occurrence of side effects, the authors wrote. Also, disease activity in the methotrexate and rituximab groups, assessed with the DAS28 prior to and 7 and 28 days after vaccination, was not influenced by vaccination.

Because patients who were treated with rituximab appear to have a “severely hampered” humoral immune response to the trivalent subunit influenza vaccination, preemptive influenza vaccination should be considered prior to rituximab administration, the authors wrote, noting the importance of yearly influenza vaccination, given the increase in anti-influenza titers observed in previously vaccinated patients.

In the second study, a controlled trial by Dr. Clifton O. Bingham III of Johns Hopkins University, Baltimore, and colleagues, the investigators examined the immunization responses (humoral immunity and the cellular immune response) of rituximab-treated RA patients who received tetanus toxoid, 23-valent pneumococcal polysaccharide (PPV23), and keyhole limpet hemocyanin (KLH) vaccines, and they evaluated the effects of rituximab-induced CD20+ B-cell depletion on immune responses to these vaccinations (Arthritis Rheum. 2010;62:62–74).

The study enrolled 103 patients aged 18–65 years who had active RA and were receiving a stable dosage of 10–25 mg/wk of methotrexate from 26 U.S. centers between January 2006 and December 2007. Patients were stratified by site and age (18–50 years and 51–65 years) and then were randomized in a 2:1 manner to receive either two cycles of 1,000 mg rituximab (open label) 2 weeks apart plus a stable dose of methotrexate (68 patients), or methotrexate alone (32 patients). In the rituximab-plus-methotrexate group, 100 mg of methylprednisolone was administered intravenously before each rituximab infusion, the authors wrote.

Patients in both groups received the tetanus toxoid adsorbed vaccine, PPV23, KLH, and a Candida albicans skin test according to the protocol schedule. Antitetanus, antipneumonococcal, and anti-KLH serum IgG levels were measured prior to and 4 weeks following each respective vaccine administration, and the delayed-type hypersensitivity (DTH) skin test response was measured 2–3 days following placement, the authors wrote.

An analysis of the results showed that patients in both groups responded similarly to tetanus toxoid vaccine, with 25 patients in the rituximab group (39%) and 11 patients in the methotrexate-only group (42%) showing a more than fourfold risk in antitetanus IgG titer, and 35 rituximab patients and 16 methotrexate patients demonstrating a more than twofold rise, the authors reported. Similarly, they wrote, “the ability to maintain a positive DTH response to the C. albicans skin test was comparable in both groups,” confirming that rituximab had no incremental effect on the patients'ability to mount a DTH response.

Significant differences were observed in the responses to PPV23 between the two groups, with only 57% of patients in the rituximab group demonstrating a twofold rise in titer in response to one or more serotypes, compared with 82% of the methotrexate-only patients, the authors reported. Similarly, only 47% of the rituximab patients had detectable anti-KLH IgG, compared with 93% of the methotrexate-only group, they noted.

“Because neoantigen and polysaccharide responses are B-cell dependent, decreased responses to KLH and [PPV23] are consistent with rituximab's mechanism of action,” the authors observed. “Despite peripheral B-cell depletion, however, responses to the KLH and [PPV23] vaccine were not completely abrogated in the present study,” they wrote, referring to the 47% of rituximab patients who had a quantifiable anti-KLH response and the 57% and 43% of rituximab patients who mounted responses to at least one and two pneumococcal serotypes, respectively. The authors concluded that for maximized vaccination response, “polysaccharide and primary immunizations should be administered prior to rituximab infusions.”

Although both of these studies provide some insight into the effects of rituximab therapy on immune function, “they fall short in offering clues about the causal mechanisms,” Dr. E. William St. Claire of Duke University Medical Center in Durham, N.C., wrote in an editorial (Arthritis Rheum. 2010;62:1–5).

Disclosures: The study reported by Dr. van Assen and colleagues was supported by Roche Nederland and Solvay Pharmaceuticals. The authors reported no additional conflicts of interest. The study reported by Dr. Bingham and colleagues was supported by Genentech Inc. The authors reported having financial relationships with Genentech, Roche, and Merck & Co. One of the authors served on Merck's data and safety monitoring board, and three of the authors own stock or stock options in Genentech. Dr. St. Clair disclosed having financial relationships with Biogen Idec Inc.

Major Finding: Particular CNS-related comorbidities are more prevalent in people with self-reported epilepsy than in people in the general population.

Data Source: A national survey of 172,959 adults.

Disclosures: The study was sponsored by Ortho-McNeil Janssen Scientific Affairs, LLC. Dr. Ottman reported no conflicts of interest.

BOSTON — Certain central nervous system–related comorbidities occur significantly more often among people with self-reported epilepsy than in the general population, according to a large survey of U.S. households.

Individuals who reported ever having had epilepsy or a seizure disorder were more likely than those without a self-reported epilepsy diagnosis to have ever had depression, anxiety, bipolar disorder, attention-deficit/hyperactivity disorder, sleep disorder, or migraine—a finding that could be an important consideration in the clinical management of epilepsy, Ruth Ottman, Ph.D., reported at the annual meeting of the American Epilepsy Society.

Overall, 2% of 172,959 adults in the National Survey of Epilepsy, Comorbidities and Health Outcomes self-reported an epilepsy diagnosis.

Dr. Ottman, professor of epidemiology and neurology at Columbia University, New York, and her colleagues developed the 11-item screening survey, which was mailed in 2008 to 340,000 households from two national panels selected to be representative of the U.S. population.

The investigators used propensity score matching to balance the epilepsy and non-epilepsy cohorts with respect to baseline characteristics, risk factors, and panel differences associated with epilepsy, including age, gender, income, population density, geographic region, severe head injury, stroke, and the main effect of panel and interaction terms.

To estimate the association of epilepsy with comorbidities, they calculated prevalence ratios using log-binomial generalized linear models, Dr. Ottman explained.

Of the 3,488 people who reported having ever had epilepsy or a seizure disorder, 61% were female, the mean age was 48 years, 35% had a seizure or convulsion within the previous 12 months, and 27% reported having had a febrile seizure or convulsion as a child, Dr. Ottman said.

Using the propensity matched sample, the investigators determined that 33% of the epilepsy cohort reported ever having depression, compared with 26% of the nonepilepsy controls. Similarly, 22% of the epilepsy cohort vs. 14% of the controls reported a history of anxiety disorder; 14% vs. 7% reported a history of bipolar disorder; and 13% vs. 6% reported having previously been diagnosed with ADHD. Compared with the control group, patients in the epilepsy cohort more frequently reported sleep disorder (20% vs. 14%) or migraine (28% vs. 21%).

Although the survey did not collect information on specific medications, “it is possible that some of the comorbidity in our study could be related to medications,” Dr. Ottman said.

“However, for several of the comorbid disorders we described, other studies have found significantly increased occurrences even before the first seizure, suggesting that medications do not explain all of the comorbidity.”

For example, she said, “the prevalence of depression is higher in people with epilepsy than in people without it, even before the first seizure occurs, and this is also true for migraine.”

The precise mechanisms underlying the increased prevalence of certain CNS comorbidities has not been established, but one explanation might be “shared pathogenic mechanism underlying epilepsy and the other disorders, possibly due to shared genetic susceptibilities or to common environmental risk factors,” Dr. Ottman noted.

Clinicians should be aware of the potential for CNS-related comorbidities “so they can be sensitive to patients' reports of symptoms possibly reflecting other disorders and so they can consider medications that have been found to be effective in treating both epilepsy and some of the comorbid disorders,” Dr. Ottman said.

Comorbidities have been highlighted by the National Institute of Neurological Disorders and Stroke as a priority for epilepsy research “and we hope our research will increase awareness of comorbidities even further.”

Major Finding: Particular CNS-related comorbidities are more prevalent in people with self-reported epilepsy than in people in the general population.

Data Source: A national survey of 172,959 adults.

Disclosures: The study was sponsored by Ortho-McNeil Janssen Scientific Affairs, LLC. Dr. Ottman reported no conflicts of interest.

BOSTON — Certain central nervous system–related comorbidities occur significantly more often among people with self-reported epilepsy than in the general population, according to a large survey of U.S. households.

Individuals who reported ever having had epilepsy or a seizure disorder were more likely than those without a self-reported epilepsy diagnosis to have ever had depression, anxiety, bipolar disorder, attention-deficit/hyperactivity disorder, sleep disorder, or migraine—a finding that could be an important consideration in the clinical management of epilepsy, Ruth Ottman, Ph.D., reported at the annual meeting of the American Epilepsy Society.

Overall, 2% of 172,959 adults in the National Survey of Epilepsy, Comorbidities and Health Outcomes self-reported an epilepsy diagnosis.

Dr. Ottman, professor of epidemiology and neurology at Columbia University, New York, and her colleagues developed the 11-item screening survey, which was mailed in 2008 to 340,000 households from two national panels selected to be representative of the U.S. population.

The investigators used propensity score matching to balance the epilepsy and non-epilepsy cohorts with respect to baseline characteristics, risk factors, and panel differences associated with epilepsy, including age, gender, income, population density, geographic region, severe head injury, stroke, and the main effect of panel and interaction terms.

To estimate the association of epilepsy with comorbidities, they calculated prevalence ratios using log-binomial generalized linear models, Dr. Ottman explained.

Of the 3,488 people who reported having ever had epilepsy or a seizure disorder, 61% were female, the mean age was 48 years, 35% had a seizure or convulsion within the previous 12 months, and 27% reported having had a febrile seizure or convulsion as a child, Dr. Ottman said.

Using the propensity matched sample, the investigators determined that 33% of the epilepsy cohort reported ever having depression, compared with 26% of the nonepilepsy controls. Similarly, 22% of the epilepsy cohort vs. 14% of the controls reported a history of anxiety disorder; 14% vs. 7% reported a history of bipolar disorder; and 13% vs. 6% reported having previously been diagnosed with ADHD. Compared with the control group, patients in the epilepsy cohort more frequently reported sleep disorder (20% vs. 14%) or migraine (28% vs. 21%).

Although the survey did not collect information on specific medications, “it is possible that some of the comorbidity in our study could be related to medications,” Dr. Ottman said.

“However, for several of the comorbid disorders we described, other studies have found significantly increased occurrences even before the first seizure, suggesting that medications do not explain all of the comorbidity.”

For example, she said, “the prevalence of depression is higher in people with epilepsy than in people without it, even before the first seizure occurs, and this is also true for migraine.”

The precise mechanisms underlying the increased prevalence of certain CNS comorbidities has not been established, but one explanation might be “shared pathogenic mechanism underlying epilepsy and the other disorders, possibly due to shared genetic susceptibilities or to common environmental risk factors,” Dr. Ottman noted.

Clinicians should be aware of the potential for CNS-related comorbidities “so they can be sensitive to patients' reports of symptoms possibly reflecting other disorders and so they can consider medications that have been found to be effective in treating both epilepsy and some of the comorbid disorders,” Dr. Ottman said.

Comorbidities have been highlighted by the National Institute of Neurological Disorders and Stroke as a priority for epilepsy research “and we hope our research will increase awareness of comorbidities even further.”

Major Finding: Particular CNS-related comorbidities are more prevalent in people with self-reported epilepsy than in people in the general population.

Data Source: A national survey of 172,959 adults.

Disclosures: The study was sponsored by Ortho-McNeil Janssen Scientific Affairs, LLC. Dr. Ottman reported no conflicts of interest.

BOSTON — Certain central nervous system–related comorbidities occur significantly more often among people with self-reported epilepsy than in the general population, according to a large survey of U.S. households.

Individuals who reported ever having had epilepsy or a seizure disorder were more likely than those without a self-reported epilepsy diagnosis to have ever had depression, anxiety, bipolar disorder, attention-deficit/hyperactivity disorder, sleep disorder, or migraine—a finding that could be an important consideration in the clinical management of epilepsy, Ruth Ottman, Ph.D., reported at the annual meeting of the American Epilepsy Society.

Overall, 2% of 172,959 adults in the National Survey of Epilepsy, Comorbidities and Health Outcomes self-reported an epilepsy diagnosis.

Dr. Ottman, professor of epidemiology and neurology at Columbia University, New York, and her colleagues developed the 11-item screening survey, which was mailed in 2008 to 340,000 households from two national panels selected to be representative of the U.S. population.

The investigators used propensity score matching to balance the epilepsy and non-epilepsy cohorts with respect to baseline characteristics, risk factors, and panel differences associated with epilepsy, including age, gender, income, population density, geographic region, severe head injury, stroke, and the main effect of panel and interaction terms.

To estimate the association of epilepsy with comorbidities, they calculated prevalence ratios using log-binomial generalized linear models, Dr. Ottman explained.

Of the 3,488 people who reported having ever had epilepsy or a seizure disorder, 61% were female, the mean age was 48 years, 35% had a seizure or convulsion within the previous 12 months, and 27% reported having had a febrile seizure or convulsion as a child, Dr. Ottman said.

Using the propensity matched sample, the investigators determined that 33% of the epilepsy cohort reported ever having depression, compared with 26% of the nonepilepsy controls. Similarly, 22% of the epilepsy cohort vs. 14% of the controls reported a history of anxiety disorder; 14% vs. 7% reported a history of bipolar disorder; and 13% vs. 6% reported having previously been diagnosed with ADHD. Compared with the control group, patients in the epilepsy cohort more frequently reported sleep disorder (20% vs. 14%) or migraine (28% vs. 21%).

Although the survey did not collect information on specific medications, “it is possible that some of the comorbidity in our study could be related to medications,” Dr. Ottman said.

“However, for several of the comorbid disorders we described, other studies have found significantly increased occurrences even before the first seizure, suggesting that medications do not explain all of the comorbidity.”

For example, she said, “the prevalence of depression is higher in people with epilepsy than in people without it, even before the first seizure occurs, and this is also true for migraine.”

The precise mechanisms underlying the increased prevalence of certain CNS comorbidities has not been established, but one explanation might be “shared pathogenic mechanism underlying epilepsy and the other disorders, possibly due to shared genetic susceptibilities or to common environmental risk factors,” Dr. Ottman noted.

Clinicians should be aware of the potential for CNS-related comorbidities “so they can be sensitive to patients' reports of symptoms possibly reflecting other disorders and so they can consider medications that have been found to be effective in treating both epilepsy and some of the comorbid disorders,” Dr. Ottman said.

Comorbidities have been highlighted by the National Institute of Neurological Disorders and Stroke as a priority for epilepsy research “and we hope our research will increase awareness of comorbidities even further.”

Major Finding: The prevalence of co-existing psychiatric problems was 9.4% among patients with epilepsy compared with the estimated 1%–4% prevalence of psychiatric problems seen in the general pediatric population.

Data Source: The investigators reviewed consecutive routine EEGs from 1995 through 2004 for pediatric patients with benign focal epileptiform discharges and identified 117 whose seizures were consistent with BECTS. They then compared comorbidity rates among those children with the general age-matched population.

Disclosures: The investigator reported no conflicts of interest with respect to her presentation and said that no specific funding was used to conduct the study.

BOSTON — An increased incidence of psychiatric and developmental comorbidities in children with a common form of childhood epilepsy might support the hypothesis that the benign epilepsies of childhood and epilepsy syndromes exist on a continuum, according to a retrospective study of EEGs.

In the study, children with benign focal epilepsy with centro-temporal spikes (BECTS)—the most common childhood epilepsy syndrome—had a higher incidence of psychiatric illnesses, attention-deficit/hyperactivity disorder (ADHD), and developmental delay than estimates from the general population, Dr. Shalaka Indulkar reported in a poster presentation at the annual meeting of the American Epilepsy Society.

The results of the study demonstrate the importance of screening children with benign focal epilepsy for psychological and other cognitive problems, Dr. Indulkar stressed. “Unfortunately, pediatric patients are not sufficiently screened for these problems; the nocturnal seizures are often missed, unless the child generalizes; and most institutions lack a good neuropsychiatry division to assess for learning difficulties. Subtle learning difficulties often go undetected.”

The investigators reviewed consecutive routine EEGs from 1995 through 2004 for pediatric patients with benign focal epileptiform discharges and identified 117 whose seizures were consistent with BECTS. These features included typical brief hemifacial seizures associated with speech arrest, drooling, and preservation of consciousness or gurgling or grunting noises with loss of consciousness and terminating in vomiting; or with nocturnal secondarily generalized seizures. They collected data on general demographics and neurologic, behavioral, and psychiatric disorders and used descriptive data and the Fisher's exact test for analysis.

Of the 117 patients included in the final analysis, 51 were girls and 66 were boys, and the mean age at initial diagnosis of EEG abnormality was 6.8 years (6.2 years in girls and 7.0 years in boys), said Dr. Indulkar, a neurology resident at the Cleveland Clinic.

The prevalence of co-existing psychiatric problems, including anxiety, schizophrenia, obsessive compulsive disorder, and depression in the study population was 9.4%, she reported, noting that this rate is substantially higher than the estimated 1%–4% seen in the general pediatric population, she said.

ADHD was observed in 11% of the seizure population, compared with an estimated prevalence rate of 3%–7% among school-aged children in the United States.

Additionally, developmental delay, including pervasive developmental disorder, language disorder, and autism, was found in 10.2% of the seizure population, and tics were noted in 5.1% of the population.

“Interestingly, we also found a high incidence of children with migraine and headaches in the study population,” Dr. Indulkar said.

Both psychiatric illness and developmental disorders were more common among boys in the study population than girls, she said.

The presence of epileptiform disturbances among children who have epilepsies of varying severity and learning, and other central nervous system-related comorbidities has led investigators to postulate that there is a link between the benign and more serious epilepsy syndromes.

However, “children with typical [BECTS] do not necessarily have abnormal EEGs in sleep, but they still may have learning difficulties, so the mechanism [for the CNS-related comorbidities] remains elusive,” Dr. Indulkar said in an interview.

She and her associates did not consider the influence of antiseizure medications on children in this study, according to Dr. Indulkar. “Not all children with BECTS are treated, as most seizures are rare, occur nocturnally, and are self-limited, so it's unlikely that medications alone could explain the cognitive problems.”

Major Finding: The prevalence of co-existing psychiatric problems was 9.4% among patients with epilepsy compared with the estimated 1%–4% prevalence of psychiatric problems seen in the general pediatric population.

Data Source: The investigators reviewed consecutive routine EEGs from 1995 through 2004 for pediatric patients with benign focal epileptiform discharges and identified 117 whose seizures were consistent with BECTS. They then compared comorbidity rates among those children with the general age-matched population.

Disclosures: The investigator reported no conflicts of interest with respect to her presentation and said that no specific funding was used to conduct the study.

BOSTON — An increased incidence of psychiatric and developmental comorbidities in children with a common form of childhood epilepsy might support the hypothesis that the benign epilepsies of childhood and epilepsy syndromes exist on a continuum, according to a retrospective study of EEGs.

In the study, children with benign focal epilepsy with centro-temporal spikes (BECTS)—the most common childhood epilepsy syndrome—had a higher incidence of psychiatric illnesses, attention-deficit/hyperactivity disorder (ADHD), and developmental delay than estimates from the general population, Dr. Shalaka Indulkar reported in a poster presentation at the annual meeting of the American Epilepsy Society.

The results of the study demonstrate the importance of screening children with benign focal epilepsy for psychological and other cognitive problems, Dr. Indulkar stressed. “Unfortunately, pediatric patients are not sufficiently screened for these problems; the nocturnal seizures are often missed, unless the child generalizes; and most institutions lack a good neuropsychiatry division to assess for learning difficulties. Subtle learning difficulties often go undetected.”

The investigators reviewed consecutive routine EEGs from 1995 through 2004 for pediatric patients with benign focal epileptiform discharges and identified 117 whose seizures were consistent with BECTS. These features included typical brief hemifacial seizures associated with speech arrest, drooling, and preservation of consciousness or gurgling or grunting noises with loss of consciousness and terminating in vomiting; or with nocturnal secondarily generalized seizures. They collected data on general demographics and neurologic, behavioral, and psychiatric disorders and used descriptive data and the Fisher's exact test for analysis.

Of the 117 patients included in the final analysis, 51 were girls and 66 were boys, and the mean age at initial diagnosis of EEG abnormality was 6.8 years (6.2 years in girls and 7.0 years in boys), said Dr. Indulkar, a neurology resident at the Cleveland Clinic.

The prevalence of co-existing psychiatric problems, including anxiety, schizophrenia, obsessive compulsive disorder, and depression in the study population was 9.4%, she reported, noting that this rate is substantially higher than the estimated 1%–4% seen in the general pediatric population, she said.

ADHD was observed in 11% of the seizure population, compared with an estimated prevalence rate of 3%–7% among school-aged children in the United States.

Additionally, developmental delay, including pervasive developmental disorder, language disorder, and autism, was found in 10.2% of the seizure population, and tics were noted in 5.1% of the population.

“Interestingly, we also found a high incidence of children with migraine and headaches in the study population,” Dr. Indulkar said.

Both psychiatric illness and developmental disorders were more common among boys in the study population than girls, she said.

The presence of epileptiform disturbances among children who have epilepsies of varying severity and learning, and other central nervous system-related comorbidities has led investigators to postulate that there is a link between the benign and more serious epilepsy syndromes.

However, “children with typical [BECTS] do not necessarily have abnormal EEGs in sleep, but they still may have learning difficulties, so the mechanism [for the CNS-related comorbidities] remains elusive,” Dr. Indulkar said in an interview.

She and her associates did not consider the influence of antiseizure medications on children in this study, according to Dr. Indulkar. “Not all children with BECTS are treated, as most seizures are rare, occur nocturnally, and are self-limited, so it's unlikely that medications alone could explain the cognitive problems.”

Major Finding: The prevalence of co-existing psychiatric problems was 9.4% among patients with epilepsy compared with the estimated 1%–4% prevalence of psychiatric problems seen in the general pediatric population.

Data Source: The investigators reviewed consecutive routine EEGs from 1995 through 2004 for pediatric patients with benign focal epileptiform discharges and identified 117 whose seizures were consistent with BECTS. They then compared comorbidity rates among those children with the general age-matched population.

Disclosures: The investigator reported no conflicts of interest with respect to her presentation and said that no specific funding was used to conduct the study.

BOSTON — An increased incidence of psychiatric and developmental comorbidities in children with a common form of childhood epilepsy might support the hypothesis that the benign epilepsies of childhood and epilepsy syndromes exist on a continuum, according to a retrospective study of EEGs.

In the study, children with benign focal epilepsy with centro-temporal spikes (BECTS)—the most common childhood epilepsy syndrome—had a higher incidence of psychiatric illnesses, attention-deficit/hyperactivity disorder (ADHD), and developmental delay than estimates from the general population, Dr. Shalaka Indulkar reported in a poster presentation at the annual meeting of the American Epilepsy Society.

The results of the study demonstrate the importance of screening children with benign focal epilepsy for psychological and other cognitive problems, Dr. Indulkar stressed. “Unfortunately, pediatric patients are not sufficiently screened for these problems; the nocturnal seizures are often missed, unless the child generalizes; and most institutions lack a good neuropsychiatry division to assess for learning difficulties. Subtle learning difficulties often go undetected.”

The investigators reviewed consecutive routine EEGs from 1995 through 2004 for pediatric patients with benign focal epileptiform discharges and identified 117 whose seizures were consistent with BECTS. These features included typical brief hemifacial seizures associated with speech arrest, drooling, and preservation of consciousness or gurgling or grunting noises with loss of consciousness and terminating in vomiting; or with nocturnal secondarily generalized seizures. They collected data on general demographics and neurologic, behavioral, and psychiatric disorders and used descriptive data and the Fisher's exact test for analysis.

Of the 117 patients included in the final analysis, 51 were girls and 66 were boys, and the mean age at initial diagnosis of EEG abnormality was 6.8 years (6.2 years in girls and 7.0 years in boys), said Dr. Indulkar, a neurology resident at the Cleveland Clinic.

The prevalence of co-existing psychiatric problems, including anxiety, schizophrenia, obsessive compulsive disorder, and depression in the study population was 9.4%, she reported, noting that this rate is substantially higher than the estimated 1%–4% seen in the general pediatric population, she said.

ADHD was observed in 11% of the seizure population, compared with an estimated prevalence rate of 3%–7% among school-aged children in the United States.

Additionally, developmental delay, including pervasive developmental disorder, language disorder, and autism, was found in 10.2% of the seizure population, and tics were noted in 5.1% of the population.

“Interestingly, we also found a high incidence of children with migraine and headaches in the study population,” Dr. Indulkar said.

Both psychiatric illness and developmental disorders were more common among boys in the study population than girls, she said.

The presence of epileptiform disturbances among children who have epilepsies of varying severity and learning, and other central nervous system-related comorbidities has led investigators to postulate that there is a link between the benign and more serious epilepsy syndromes.

However, “children with typical [BECTS] do not necessarily have abnormal EEGs in sleep, but they still may have learning difficulties, so the mechanism [for the CNS-related comorbidities] remains elusive,” Dr. Indulkar said in an interview.

She and her associates did not consider the influence of antiseizure medications on children in this study, according to Dr. Indulkar. “Not all children with BECTS are treated, as most seizures are rare, occur nocturnally, and are self-limited, so it's unlikely that medications alone could explain the cognitive problems.”

The monoclonal antibody tocilizumab has received approval by the U.S. Food and Drug Administration for the treatment of moderate to severely active rheumatoid arthritis in adult patients who have failed one or more tumor necrosis factor blockers, according to an announcement made last month by the drug's manufacturer, Roche Holding AG.

Tocilizumab (Actemra) is the first interleukin-6 (IL-6) receptor inhibitor to be approved for the treatment of rheumatoid arthritis, and it can be used alone or in combination with methotrexate or other disease modifying anti-rheumatic drugs (DMARDs), according to the statement. The drug was co-developed by Chugai Pharmaceuticals and its parent company Roche.

The approval comes on the heels of an extensive clinical development program comprising five phase III trials as well as a resubmission of documents, including a proposal for a risk evaluation and mitigation strategy. The pivotal clinical trials include RADIATE (Research on Actemra Determining Efficacy After Anti-TNF Failures), OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders), TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy), AMBITION (Actemra Versus Methotrexate Double-Blind Investigative Trial in Monotherapy), and LITHE (Tocilizumab Safety and the Prevention of Structural Joint Damage).

In the RADIATE trial, 30% of patients who received tocilizumab in combination with methotrexate achieved disease remission compared with 1.6% of patients receiving methotrexate alone. Lead investigator Dr. Paul Emery, professor of rheumatology at the University of Leeds, England, and colleagues wrote that the findings were especially promising for that subset of rheumatoid arthritis patients who have failed to achieve adequate symptom relief with anti–tumor necrosis factor agents (Ann. Rheum. Dis. 2008;67:1516–23).

The results from the OPTION trial showed that 59% of the patients with rheumatoid arthritis who had incomplete responses to methotrexate achieved an ACR20 response following treatment with tocilizumab 8 mg/kg compared with 26% of patients treated with placebo, and 27% of the patients on tocilizumab achieved remission compared with 0.8% in the placebo group (Lancet 2008;371:987–97).

Similarly, in the TOWARD trial, 61% of patients who received tocilizumab 8 mg/kg achieved an ACR20 response at 24 weeks compared with 25% of patients treated with placebo plus DMARDs, and approximately 38% of tocilizumab-treated patients met ACR50 criteria for symptom improvement, compared with 9% of patients receiving placebo (Arthritis Rheum. 2008;58:2968–80).

The AMBITION study, in which 70% of patients who received 8 mg/kg achieved an ACR20 response at 24 weeks, was the first to show that treatment with a single biologic agent was superior to methotrexate alone for the treatment of rheumatoid arthritis at 6 months, according to a press release issued by Roche when the phase III results were released in 2008 at the annual Congress of the European League Against Rheumatism

Findings from LITHE, presented by lead investigator Dr. Roy M. Fleischmann of the University of Texas Southwestern Medical Center in Dallas at the 2009 annual meeting of the American College of Rheumatology showed that, over a 2-year period, there was no radiographic progression or joint damage in 75% of rheumatoid arthritis patients taking tocilizumab 4 mg/kg plus methotrexate and 85% of those taking tocilizumab 8 mg/kg and methotrexate compared with 66% of patients taking methotrexate alone.

Among the serious tocilizumab-related adverse events that have been reported in the clinical trials are infections that lead to hospitalization or death, including tuberculosis, and bacterial, invasive fungal, viral, and other infections; gastrointestinal perforations; hypersensitivity reactions; and cellulitis, according to the press release.

In March 2009, Roche's Chugai Pharmaceuticals reported that, among nearly 5,000 rheumatoid arthritis patients in Japan who had been treated with tocilizumab between April 2008 and February 2009, 15 deaths occurred and the possibility of a link to the drug could not be denied, although the exact causes of the deaths were unknown, according to a press release from the company.

The monoclonal antibody tocilizumab has received approval by the U.S. Food and Drug Administration for the treatment of moderate to severely active rheumatoid arthritis in adult patients who have failed one or more tumor necrosis factor blockers, according to an announcement made last month by the drug's manufacturer, Roche Holding AG.

Tocilizumab (Actemra) is the first interleukin-6 (IL-6) receptor inhibitor to be approved for the treatment of rheumatoid arthritis, and it can be used alone or in combination with methotrexate or other disease modifying anti-rheumatic drugs (DMARDs), according to the statement. The drug was co-developed by Chugai Pharmaceuticals and its parent company Roche.

The approval comes on the heels of an extensive clinical development program comprising five phase III trials as well as a resubmission of documents, including a proposal for a risk evaluation and mitigation strategy. The pivotal clinical trials include RADIATE (Research on Actemra Determining Efficacy After Anti-TNF Failures), OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders), TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy), AMBITION (Actemra Versus Methotrexate Double-Blind Investigative Trial in Monotherapy), and LITHE (Tocilizumab Safety and the Prevention of Structural Joint Damage).

In the RADIATE trial, 30% of patients who received tocilizumab in combination with methotrexate achieved disease remission compared with 1.6% of patients receiving methotrexate alone. Lead investigator Dr. Paul Emery, professor of rheumatology at the University of Leeds, England, and colleagues wrote that the findings were especially promising for that subset of rheumatoid arthritis patients who have failed to achieve adequate symptom relief with anti–tumor necrosis factor agents (Ann. Rheum. Dis. 2008;67:1516–23).

The results from the OPTION trial showed that 59% of the patients with rheumatoid arthritis who had incomplete responses to methotrexate achieved an ACR20 response following treatment with tocilizumab 8 mg/kg compared with 26% of patients treated with placebo, and 27% of the patients on tocilizumab achieved remission compared with 0.8% in the placebo group (Lancet 2008;371:987–97).

Similarly, in the TOWARD trial, 61% of patients who received tocilizumab 8 mg/kg achieved an ACR20 response at 24 weeks compared with 25% of patients treated with placebo plus DMARDs, and approximately 38% of tocilizumab-treated patients met ACR50 criteria for symptom improvement, compared with 9% of patients receiving placebo (Arthritis Rheum. 2008;58:2968–80).

The AMBITION study, in which 70% of patients who received 8 mg/kg achieved an ACR20 response at 24 weeks, was the first to show that treatment with a single biologic agent was superior to methotrexate alone for the treatment of rheumatoid arthritis at 6 months, according to a press release issued by Roche when the phase III results were released in 2008 at the annual Congress of the European League Against Rheumatism

Findings from LITHE, presented by lead investigator Dr. Roy M. Fleischmann of the University of Texas Southwestern Medical Center in Dallas at the 2009 annual meeting of the American College of Rheumatology showed that, over a 2-year period, there was no radiographic progression or joint damage in 75% of rheumatoid arthritis patients taking tocilizumab 4 mg/kg plus methotrexate and 85% of those taking tocilizumab 8 mg/kg and methotrexate compared with 66% of patients taking methotrexate alone.

Among the serious tocilizumab-related adverse events that have been reported in the clinical trials are infections that lead to hospitalization or death, including tuberculosis, and bacterial, invasive fungal, viral, and other infections; gastrointestinal perforations; hypersensitivity reactions; and cellulitis, according to the press release.

In March 2009, Roche's Chugai Pharmaceuticals reported that, among nearly 5,000 rheumatoid arthritis patients in Japan who had been treated with tocilizumab between April 2008 and February 2009, 15 deaths occurred and the possibility of a link to the drug could not be denied, although the exact causes of the deaths were unknown, according to a press release from the company.

The monoclonal antibody tocilizumab has received approval by the U.S. Food and Drug Administration for the treatment of moderate to severely active rheumatoid arthritis in adult patients who have failed one or more tumor necrosis factor blockers, according to an announcement made last month by the drug's manufacturer, Roche Holding AG.

Tocilizumab (Actemra) is the first interleukin-6 (IL-6) receptor inhibitor to be approved for the treatment of rheumatoid arthritis, and it can be used alone or in combination with methotrexate or other disease modifying anti-rheumatic drugs (DMARDs), according to the statement. The drug was co-developed by Chugai Pharmaceuticals and its parent company Roche.

The approval comes on the heels of an extensive clinical development program comprising five phase III trials as well as a resubmission of documents, including a proposal for a risk evaluation and mitigation strategy. The pivotal clinical trials include RADIATE (Research on Actemra Determining Efficacy After Anti-TNF Failures), OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders), TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy), AMBITION (Actemra Versus Methotrexate Double-Blind Investigative Trial in Monotherapy), and LITHE (Tocilizumab Safety and the Prevention of Structural Joint Damage).

In the RADIATE trial, 30% of patients who received tocilizumab in combination with methotrexate achieved disease remission compared with 1.6% of patients receiving methotrexate alone. Lead investigator Dr. Paul Emery, professor of rheumatology at the University of Leeds, England, and colleagues wrote that the findings were especially promising for that subset of rheumatoid arthritis patients who have failed to achieve adequate symptom relief with anti–tumor necrosis factor agents (Ann. Rheum. Dis. 2008;67:1516–23).

The results from the OPTION trial showed that 59% of the patients with rheumatoid arthritis who had incomplete responses to methotrexate achieved an ACR20 response following treatment with tocilizumab 8 mg/kg compared with 26% of patients treated with placebo, and 27% of the patients on tocilizumab achieved remission compared with 0.8% in the placebo group (Lancet 2008;371:987–97).

Similarly, in the TOWARD trial, 61% of patients who received tocilizumab 8 mg/kg achieved an ACR20 response at 24 weeks compared with 25% of patients treated with placebo plus DMARDs, and approximately 38% of tocilizumab-treated patients met ACR50 criteria for symptom improvement, compared with 9% of patients receiving placebo (Arthritis Rheum. 2008;58:2968–80).

The AMBITION study, in which 70% of patients who received 8 mg/kg achieved an ACR20 response at 24 weeks, was the first to show that treatment with a single biologic agent was superior to methotrexate alone for the treatment of rheumatoid arthritis at 6 months, according to a press release issued by Roche when the phase III results were released in 2008 at the annual Congress of the European League Against Rheumatism

Findings from LITHE, presented by lead investigator Dr. Roy M. Fleischmann of the University of Texas Southwestern Medical Center in Dallas at the 2009 annual meeting of the American College of Rheumatology showed that, over a 2-year period, there was no radiographic progression or joint damage in 75% of rheumatoid arthritis patients taking tocilizumab 4 mg/kg plus methotrexate and 85% of those taking tocilizumab 8 mg/kg and methotrexate compared with 66% of patients taking methotrexate alone.

Among the serious tocilizumab-related adverse events that have been reported in the clinical trials are infections that lead to hospitalization or death, including tuberculosis, and bacterial, invasive fungal, viral, and other infections; gastrointestinal perforations; hypersensitivity reactions; and cellulitis, according to the press release.

In March 2009, Roche's Chugai Pharmaceuticals reported that, among nearly 5,000 rheumatoid arthritis patients in Japan who had been treated with tocilizumab between April 2008 and February 2009, 15 deaths occurred and the possibility of a link to the drug could not be denied, although the exact causes of the deaths were unknown, according to a press release from the company.

Revised recommendations for human papillomavirus vaccination—including a permissive recommendation for young men—and for measles, mumps, rubella immunization are part of the newly issued 2010 immunization schedule from the Advisory Committee on Immunization Practices at the Centers for Disease Control and Prevention.

The new schedule also includes updated indications and schedule information for hepatitis A and B vaccination, as well as clarifications about meningococcal and Haemophilus influenzae type B vaccination.

The 2010 Recommended Adult Immunization Schedule earned ACIP approval in October 2009 and reflects current recommendations for the licensed vaccines, according to the schedule's accompanying report (Ann. Intern. Med. 2010;152:36–9). The schedule is approved by the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, and the American College of Physicians.

The revised schedule includes the following changes:

▸ For human papillomavirus (HPV), a bivalent vaccine (HPV2) has been licensed for use in females. Therefore, either the bivalent or quadrivalent (HPV4) vaccination can be used for women between 19 and 26 years. In addition, HPV4 may be given to males aged 9 through 25 years “to reduce their likelihood of acquiring genital warts,” according to the revised schedule.

▸ For influenza vaccination, the term “seasonal” has been added to distinguish between seasonal and pandemic influenza vaccines.

▸ For measles, mumps, rubella (MMR) vaccination, most adults born after 1957 do not require repeat vaccination if they have documentation of having received at least one dose of the vaccine. Women without documentation of rubella vaccination should receive a dose of the MMR vaccine. Health care workers, college students, international travelers, and individuals who have been exposed to measles or mumps in an outbreak setting should receive two doses of MMR.

▸ For hepatitis A, vaccination is recommended for unvaccinated individuals who anticipate close personal contact with an international adoptee from a country with intermediate or high endemicity to hepatitis A. The first dose should be administered at least 2 weeks before the adoptee arrives.

▸ For the three-dose hepatitis B vaccine, the second dose should be administered 1 month after the first dose, and the third dose should be administered at least 2 months after the second. If using the combined hepatitis A and B vaccine, three doses should be administered at 0, 1, and 6 months.

▸ For meningococcal vaccination, the conjugate vaccine (MCV4) is preferred for adults age 55 years or younger, while the polysaccharide vaccine (MPSV4) is recommended for adults older than 55 years. Revaccination with MCV4 after 5 years is recommended for individuals who continue to be at risk for infection, such as adults with anatomic or functional asplenia.

▸ For Haemophilus influenzae type B (Hib) vaccination, there is no recommendation for individuals older than age 5 years. One dose of the vaccine is not contraindicated in certain high-risk patients who have not received the vaccine previously, including those patients with sickle cell disease, leukemia, HIV infection, or splenectomy.

Although vaccines are among the most effective strategies for preventing individual illness and protecting public health, “deaths from vaccine-preventable illnesses still occur in the United States,” noted Dr. Robert H. Hopkins Jr. and Dr. Keyur S. Vyas of the University of Arkansas for Medical Sciences, Little Rock, in an accompanying editorial (Ann. Intern. Med. 2010;152:59–60).

Clinicians must overcome patients' perception of vaccines as necessary only for children and travelers, added Dr. Hopkins and Dr. Vyas. “Our challenge is to change this perception and to make immunizations integral to each encounter for physicians who care for adults in primary and specialty care settings.”

The complete 2010 Adult Immunization Schedule will be available in English and Spanish at www.cdc.gov/vaccines/recs/schedules/adult-schedule.htm

Members of ACIP disclosed relationships with Med-Immune, Sanofi Pasteur, Novartis, and Wyeth. According to the report, members with conflicts are not permitted to vote if the conflict involves the vaccine or agent being considered.

Dr. Hopkins and Dr. Vyas reported no potential conflicts of interest.

The term “seasonal” has been added to distinguish between seasonal and pandemic influenza vaccines.

Source Joyce Frieden/Elsevier Global Medical News

Revised recommendations for human papillomavirus vaccination—including a permissive recommendation for young men—and for measles, mumps, rubella immunization are part of the newly issued 2010 immunization schedule from the Advisory Committee on Immunization Practices at the Centers for Disease Control and Prevention.

The new schedule also includes updated indications and schedule information for hepatitis A and B vaccination, as well as clarifications about meningococcal and Haemophilus influenzae type B vaccination.

The 2010 Recommended Adult Immunization Schedule earned ACIP approval in October 2009 and reflects current recommendations for the licensed vaccines, according to the schedule's accompanying report (Ann. Intern. Med. 2010;152:36–9). The schedule is approved by the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, and the American College of Physicians.

The revised schedule includes the following changes:

▸ For human papillomavirus (HPV), a bivalent vaccine (HPV2) has been licensed for use in females. Therefore, either the bivalent or quadrivalent (HPV4) vaccination can be used for women between 19 and 26 years. In addition, HPV4 may be given to males aged 9 through 25 years “to reduce their likelihood of acquiring genital warts,” according to the revised schedule.

▸ For influenza vaccination, the term “seasonal” has been added to distinguish between seasonal and pandemic influenza vaccines.

▸ For measles, mumps, rubella (MMR) vaccination, most adults born after 1957 do not require repeat vaccination if they have documentation of having received at least one dose of the vaccine. Women without documentation of rubella vaccination should receive a dose of the MMR vaccine. Health care workers, college students, international travelers, and individuals who have been exposed to measles or mumps in an outbreak setting should receive two doses of MMR.

▸ For hepatitis A, vaccination is recommended for unvaccinated individuals who anticipate close personal contact with an international adoptee from a country with intermediate or high endemicity to hepatitis A. The first dose should be administered at least 2 weeks before the adoptee arrives.

▸ For the three-dose hepatitis B vaccine, the second dose should be administered 1 month after the first dose, and the third dose should be administered at least 2 months after the second. If using the combined hepatitis A and B vaccine, three doses should be administered at 0, 1, and 6 months.

▸ For meningococcal vaccination, the conjugate vaccine (MCV4) is preferred for adults age 55 years or younger, while the polysaccharide vaccine (MPSV4) is recommended for adults older than 55 years. Revaccination with MCV4 after 5 years is recommended for individuals who continue to be at risk for infection, such as adults with anatomic or functional asplenia.

▸ For Haemophilus influenzae type B (Hib) vaccination, there is no recommendation for individuals older than age 5 years. One dose of the vaccine is not contraindicated in certain high-risk patients who have not received the vaccine previously, including those patients with sickle cell disease, leukemia, HIV infection, or splenectomy.

Although vaccines are among the most effective strategies for preventing individual illness and protecting public health, “deaths from vaccine-preventable illnesses still occur in the United States,” noted Dr. Robert H. Hopkins Jr. and Dr. Keyur S. Vyas of the University of Arkansas for Medical Sciences, Little Rock, in an accompanying editorial (Ann. Intern. Med. 2010;152:59–60).

Clinicians must overcome patients' perception of vaccines as necessary only for children and travelers, added Dr. Hopkins and Dr. Vyas. “Our challenge is to change this perception and to make immunizations integral to each encounter for physicians who care for adults in primary and specialty care settings.”

The complete 2010 Adult Immunization Schedule will be available in English and Spanish at www.cdc.gov/vaccines/recs/schedules/adult-schedule.htm

Members of ACIP disclosed relationships with Med-Immune, Sanofi Pasteur, Novartis, and Wyeth. According to the report, members with conflicts are not permitted to vote if the conflict involves the vaccine or agent being considered.

Dr. Hopkins and Dr. Vyas reported no potential conflicts of interest.

The term “seasonal” has been added to distinguish between seasonal and pandemic influenza vaccines.

Source Joyce Frieden/Elsevier Global Medical News

Revised recommendations for human papillomavirus vaccination—including a permissive recommendation for young men—and for measles, mumps, rubella immunization are part of the newly issued 2010 immunization schedule from the Advisory Committee on Immunization Practices at the Centers for Disease Control and Prevention.

The new schedule also includes updated indications and schedule information for hepatitis A and B vaccination, as well as clarifications about meningococcal and Haemophilus influenzae type B vaccination.

The 2010 Recommended Adult Immunization Schedule earned ACIP approval in October 2009 and reflects current recommendations for the licensed vaccines, according to the schedule's accompanying report (Ann. Intern. Med. 2010;152:36–9). The schedule is approved by the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, and the American College of Physicians.

The revised schedule includes the following changes:

▸ For human papillomavirus (HPV), a bivalent vaccine (HPV2) has been licensed for use in females. Therefore, either the bivalent or quadrivalent (HPV4) vaccination can be used for women between 19 and 26 years. In addition, HPV4 may be given to males aged 9 through 25 years “to reduce their likelihood of acquiring genital warts,” according to the revised schedule.

▸ For influenza vaccination, the term “seasonal” has been added to distinguish between seasonal and pandemic influenza vaccines.

▸ For measles, mumps, rubella (MMR) vaccination, most adults born after 1957 do not require repeat vaccination if they have documentation of having received at least one dose of the vaccine. Women without documentation of rubella vaccination should receive a dose of the MMR vaccine. Health care workers, college students, international travelers, and individuals who have been exposed to measles or mumps in an outbreak setting should receive two doses of MMR.

▸ For hepatitis A, vaccination is recommended for unvaccinated individuals who anticipate close personal contact with an international adoptee from a country with intermediate or high endemicity to hepatitis A. The first dose should be administered at least 2 weeks before the adoptee arrives.

▸ For the three-dose hepatitis B vaccine, the second dose should be administered 1 month after the first dose, and the third dose should be administered at least 2 months after the second. If using the combined hepatitis A and B vaccine, three doses should be administered at 0, 1, and 6 months.

▸ For meningococcal vaccination, the conjugate vaccine (MCV4) is preferred for adults age 55 years or younger, while the polysaccharide vaccine (MPSV4) is recommended for adults older than 55 years. Revaccination with MCV4 after 5 years is recommended for individuals who continue to be at risk for infection, such as adults with anatomic or functional asplenia.

▸ For Haemophilus influenzae type B (Hib) vaccination, there is no recommendation for individuals older than age 5 years. One dose of the vaccine is not contraindicated in certain high-risk patients who have not received the vaccine previously, including those patients with sickle cell disease, leukemia, HIV infection, or splenectomy.

Although vaccines are among the most effective strategies for preventing individual illness and protecting public health, “deaths from vaccine-preventable illnesses still occur in the United States,” noted Dr. Robert H. Hopkins Jr. and Dr. Keyur S. Vyas of the University of Arkansas for Medical Sciences, Little Rock, in an accompanying editorial (Ann. Intern. Med. 2010;152:59–60).

Clinicians must overcome patients' perception of vaccines as necessary only for children and travelers, added Dr. Hopkins and Dr. Vyas. “Our challenge is to change this perception and to make immunizations integral to each encounter for physicians who care for adults in primary and specialty care settings.”

The complete 2010 Adult Immunization Schedule will be available in English and Spanish at www.cdc.gov/vaccines/recs/schedules/adult-schedule.htm

Members of ACIP disclosed relationships with Med-Immune, Sanofi Pasteur, Novartis, and Wyeth. According to the report, members with conflicts are not permitted to vote if the conflict involves the vaccine or agent being considered.

Dr. Hopkins and Dr. Vyas reported no potential conflicts of interest.

The term “seasonal” has been added to distinguish between seasonal and pandemic influenza vaccines.

Source Joyce Frieden/Elsevier Global Medical News

Major Findings: Seizures declined by a mean of 29% during active stimulation with the device over the first 12 weeks, compared with a 14% reduction during sham activation.

Source of Data: Multicenter, randomized, sham-controlled clinical trial of 191 patients with medically intractable partial onset seizures.

Disclosures: Dr. Morrell is the chief medical officer of NeuroPace, which developed the system and funded the trial.

BOSTON – Patients with treatment-resistant epilepsy can significantly reduce their frequency of seizures with the use of an implantable device that detects preseizure electrical activity and preemptively aborts seizures.

In 191 patients with medically intractable partial onset seizures who were implanted with the neurostimulator, seizures declined by a mean of 29% during active stimulation with the device, compared with a 14% reduction during sham activation, Dr. Martha J. Morrell reported at the annual meeting of the American Epilepsy Society.

In the later, open-label phase of the study in which all of the patients received the active stimulation, nearly half of the 171 patients for whom 12 weeks of data were available experienced at least a 50% reduction in seizure frequency relative to baseline, said Dr. Morrell, clinical professor of neurology at Stanford (Calif.) University and chief medical officer of NeuroPace, developer of the Responsive NeuroStimulator System (RNS).

The cranially implanted RNS device differs from conventional, “open loop” brain stimulation technologies that involve the scheduled delivery of electrical stimulation to specific brain regions independent of brain activity.

“The RNS delivers stimulation in response to a detected event,” said Dr. Morrell, noting that the treatment is “individualized and dynamic” in that it uses computer technology to recognize and respond to patterns of brain activity specific to individual patients' seizure patterns.

The RNS comprises electrodes that are surgically implanted in epileptic regions of the brain and connected to the computerized, battery-powered neurostimulator, which is embedded in the patient's skull. The device, which continuously monitors the electrical activity of the patient's brain, is programmed by a neurologist to detect and disrupt significant electrical events. “The programming is done wirelessly via a laptop computer,” Dr. Morrell said. “It's highly modifiable in that the physician can view the patient's electrocorticographic activity in real time and change the [signal-detection] criteria at any time based on individual patient characteristics.”

Up to two leads, each containing four electrodes, can be connected to the neurostimulator, so the system can monitor and deliver responsive stimulation to two distinct epileptogenic zones independently, she noted.

Because the neurostimulation occurs in response to aberrant electrical activity in the brain, fewer electrical impulses are being delivered to the brain than would occur with continuous stimulation. This in turn diminishes the possibility of treatment-related adverse events.

In an initial feasibility study of 65 patients, the responsive neurostimulation system demonstrated excellent safety, tolerability, and preliminary evidence of efficacy, Dr. Morrell said. “There were no serious device-related adverse events, and stimulation-related symptoms experienced by several subjects were addressed by adjusting the stimulation settings.”

The preliminary efficacy evidence from that study showed that a minimum 50% reduction in seizure frequency was experienced by 43% of the patients with complex partial seizures and 35% of those with total disabling seizures (Neurotherapeutics 2008;5:68–74).

In the double-blind pivotal trial, the 191 patients were randomized to active or sham therapy. The patients were between 18 and 70 years of age (median age 35 years), and all had partial onset epilepsy localized to one or two foci and had failed at least two antiepileptic medications.

The patients were taking an average of three antiepileptic medications to attempt seizure control, and about 34% of the patients had been treated previously with vagus nerve stimulation, 33% had prior surgical resection, and 16% had been treated with both.

“These patients tended to be very ill. Most of them had epilepsy for more than 20 years, and many were having at least three seizures per 28-day period–often many more than that,” Dr. Morrell said.

Of the 191 patients implanted with the device, 50% had mesial temporal seizure onset, 42% had neocortical seizure onset, and 8% had both, Dr. Morrell said in a press briefing at the meeting.

The trial consisted of an initial, 12-week period prior to system implantation during which baseline seizure activity was collected, followed by a 12-week blinded period when participants were randomly assigned to have the responsive stimulation activated or left inactive, she said.

At each of the 31 trial sites, the patients and one neurologist were blinded to the stimulation status, while a separate neurologist programmed the devices in order to maintain the study blinding. The responsive stimulation was optimized in the treatment over the next four weeks, followed by 84 days of data collection. At the end of the blinded efficacy period, stimulation was activated for all of the study participants for two years post-implantation, Dr. Morrell said.

In addition to the statistically significant reduction in seizure frequency in the active therapy group relative to those in the sham therapy condition, there were no serious, unanticipated device-related adverse events during the trial, nor was there a difference between the two groups with respect to the rate of adverse events, including depression, memory impairment, and anxiety, Dr. Morrell reported.

The findings suggest that responsive neurostimulation might be a promising treatment option for individuals with seizures that are resistant to conventional antiepileptic therapy. Importantly, the apparent increase in the number of patients experiencing at least a 50% reduction in seizure frequency relative to baseline during the open-label phase of the study suggests the system might become more effective over time, she noted.

The RNS has not yet received Food and Drug Administration approval, but NeuroPace plans to submit a premarket approval application to the FDA in early 2010, Dr. Morrell said.

My Take

A New Kind of Stimulation

The development and use of stimulation devices for medically refractory epilepsy represents an altogether new approach for these patients when surgery is not possible and pharmacology is ineffective. Open loop devices that deliver electrical stimulation on a duty cycle include the vagal nerve stimulator (Cyberonics), which is FDA-approved for refractory partial epilepsy, and the thalamic deep brain stimulator (Medtronic), which is FDA-approved for Parkinson's disease and essential tremor and is currently seeking FDA approval for refractory partial epilepsy. The RNS is the first closed loop stimulator and is distinctly different from other investigational and FDA-approved devices used to treat patients with epilepsy. The fact that in this day and age one can successfully and safely detect seizures using an implantable device on a long-term basis may provide hope for future advancements. With time, device technology is likely to be refined and improved, both through technical advances and as additional data are gathered and further studies are completed. Clinical experience will also help define proper patient selection, expectations, and effectiveness.

DR. KATHERINE NOE and DR. JOSEPH DRAZKOWSKI are epilepsy specialists at the Mayo Clinic, Scottsdale, Ariz. They were both investigators in the RNS trial.

VITALS

Major Findings: Seizures declined by a mean of 29% during active stimulation with the device over the first 12 weeks, compared with a 14% reduction during sham activation.

Source of Data: Multicenter, randomized, sham-controlled clinical trial of 191 patients with medically intractable partial onset seizures.

Disclosures: Dr. Morrell is the chief medical officer of NeuroPace, which developed the system and funded the trial.

BOSTON – Patients with treatment-resistant epilepsy can significantly reduce their frequency of seizures with the use of an implantable device that detects preseizure electrical activity and preemptively aborts seizures.

In 191 patients with medically intractable partial onset seizures who were implanted with the neurostimulator, seizures declined by a mean of 29% during active stimulation with the device, compared with a 14% reduction during sham activation, Dr. Martha J. Morrell reported at the annual meeting of the American Epilepsy Society.

In the later, open-label phase of the study in which all of the patients received the active stimulation, nearly half of the 171 patients for whom 12 weeks of data were available experienced at least a 50% reduction in seizure frequency relative to baseline, said Dr. Morrell, clinical professor of neurology at Stanford (Calif.) University and chief medical officer of NeuroPace, developer of the Responsive NeuroStimulator System (RNS).

The cranially implanted RNS device differs from conventional, “open loop” brain stimulation technologies that involve the scheduled delivery of electrical stimulation to specific brain regions independent of brain activity.

“The RNS delivers stimulation in response to a detected event,” said Dr. Morrell, noting that the treatment is “individualized and dynamic” in that it uses computer technology to recognize and respond to patterns of brain activity specific to individual patients' seizure patterns.

The RNS comprises electrodes that are surgically implanted in epileptic regions of the brain and connected to the computerized, battery-powered neurostimulator, which is embedded in the patient's skull. The device, which continuously monitors the electrical activity of the patient's brain, is programmed by a neurologist to detect and disrupt significant electrical events. “The programming is done wirelessly via a laptop computer,” Dr. Morrell said. “It's highly modifiable in that the physician can view the patient's electrocorticographic activity in real time and change the [signal-detection] criteria at any time based on individual patient characteristics.”

Up to two leads, each containing four electrodes, can be connected to the neurostimulator, so the system can monitor and deliver responsive stimulation to two distinct epileptogenic zones independently, she noted.

Because the neurostimulation occurs in response to aberrant electrical activity in the brain, fewer electrical impulses are being delivered to the brain than would occur with continuous stimulation. This in turn diminishes the possibility of treatment-related adverse events.

In an initial feasibility study of 65 patients, the responsive neurostimulation system demonstrated excellent safety, tolerability, and preliminary evidence of efficacy, Dr. Morrell said. “There were no serious device-related adverse events, and stimulation-related symptoms experienced by several subjects were addressed by adjusting the stimulation settings.”

The preliminary efficacy evidence from that study showed that a minimum 50% reduction in seizure frequency was experienced by 43% of the patients with complex partial seizures and 35% of those with total disabling seizures (Neurotherapeutics 2008;5:68–74).

In the double-blind pivotal trial, the 191 patients were randomized to active or sham therapy. The patients were between 18 and 70 years of age (median age 35 years), and all had partial onset epilepsy localized to one or two foci and had failed at least two antiepileptic medications.

The patients were taking an average of three antiepileptic medications to attempt seizure control, and about 34% of the patients had been treated previously with vagus nerve stimulation, 33% had prior surgical resection, and 16% had been treated with both.

“These patients tended to be very ill. Most of them had epilepsy for more than 20 years, and many were having at least three seizures per 28-day period–often many more than that,” Dr. Morrell said.

Of the 191 patients implanted with the device, 50% had mesial temporal seizure onset, 42% had neocortical seizure onset, and 8% had both, Dr. Morrell said in a press briefing at the meeting.

The trial consisted of an initial, 12-week period prior to system implantation during which baseline seizure activity was collected, followed by a 12-week blinded period when participants were randomly assigned to have the responsive stimulation activated or left inactive, she said.

At each of the 31 trial sites, the patients and one neurologist were blinded to the stimulation status, while a separate neurologist programmed the devices in order to maintain the study blinding. The responsive stimulation was optimized in the treatment over the next four weeks, followed by 84 days of data collection. At the end of the blinded efficacy period, stimulation was activated for all of the study participants for two years post-implantation, Dr. Morrell said.

In addition to the statistically significant reduction in seizure frequency in the active therapy group relative to those in the sham therapy condition, there were no serious, unanticipated device-related adverse events during the trial, nor was there a difference between the two groups with respect to the rate of adverse events, including depression, memory impairment, and anxiety, Dr. Morrell reported.

The findings suggest that responsive neurostimulation might be a promising treatment option for individuals with seizures that are resistant to conventional antiepileptic therapy. Importantly, the apparent increase in the number of patients experiencing at least a 50% reduction in seizure frequency relative to baseline during the open-label phase of the study suggests the system might become more effective over time, she noted.

The RNS has not yet received Food and Drug Administration approval, but NeuroPace plans to submit a premarket approval application to the FDA in early 2010, Dr. Morrell said.

My Take

A New Kind of Stimulation

The development and use of stimulation devices for medically refractory epilepsy represents an altogether new approach for these patients when surgery is not possible and pharmacology is ineffective. Open loop devices that deliver electrical stimulation on a duty cycle include the vagal nerve stimulator (Cyberonics), which is FDA-approved for refractory partial epilepsy, and the thalamic deep brain stimulator (Medtronic), which is FDA-approved for Parkinson's disease and essential tremor and is currently seeking FDA approval for refractory partial epilepsy. The RNS is the first closed loop stimulator and is distinctly different from other investigational and FDA-approved devices used to treat patients with epilepsy. The fact that in this day and age one can successfully and safely detect seizures using an implantable device on a long-term basis may provide hope for future advancements. With time, device technology is likely to be refined and improved, both through technical advances and as additional data are gathered and further studies are completed. Clinical experience will also help define proper patient selection, expectations, and effectiveness.

DR. KATHERINE NOE and DR. JOSEPH DRAZKOWSKI are epilepsy specialists at the Mayo Clinic, Scottsdale, Ariz. They were both investigators in the RNS trial.

VITALS

Major Findings: Seizures declined by a mean of 29% during active stimulation with the device over the first 12 weeks, compared with a 14% reduction during sham activation.

Source of Data: Multicenter, randomized, sham-controlled clinical trial of 191 patients with medically intractable partial onset seizures.

Disclosures: Dr. Morrell is the chief medical officer of NeuroPace, which developed the system and funded the trial.

BOSTON – Patients with treatment-resistant epilepsy can significantly reduce their frequency of seizures with the use of an implantable device that detects preseizure electrical activity and preemptively aborts seizures.

In 191 patients with medically intractable partial onset seizures who were implanted with the neurostimulator, seizures declined by a mean of 29% during active stimulation with the device, compared with a 14% reduction during sham activation, Dr. Martha J. Morrell reported at the annual meeting of the American Epilepsy Society.

In the later, open-label phase of the study in which all of the patients received the active stimulation, nearly half of the 171 patients for whom 12 weeks of data were available experienced at least a 50% reduction in seizure frequency relative to baseline, said Dr. Morrell, clinical professor of neurology at Stanford (Calif.) University and chief medical officer of NeuroPace, developer of the Responsive NeuroStimulator System (RNS).

The cranially implanted RNS device differs from conventional, “open loop” brain stimulation technologies that involve the scheduled delivery of electrical stimulation to specific brain regions independent of brain activity.

“The RNS delivers stimulation in response to a detected event,” said Dr. Morrell, noting that the treatment is “individualized and dynamic” in that it uses computer technology to recognize and respond to patterns of brain activity specific to individual patients' seizure patterns.

The RNS comprises electrodes that are surgically implanted in epileptic regions of the brain and connected to the computerized, battery-powered neurostimulator, which is embedded in the patient's skull. The device, which continuously monitors the electrical activity of the patient's brain, is programmed by a neurologist to detect and disrupt significant electrical events. “The programming is done wirelessly via a laptop computer,” Dr. Morrell said. “It's highly modifiable in that the physician can view the patient's electrocorticographic activity in real time and change the [signal-detection] criteria at any time based on individual patient characteristics.”

Up to two leads, each containing four electrodes, can be connected to the neurostimulator, so the system can monitor and deliver responsive stimulation to two distinct epileptogenic zones independently, she noted.

Because the neurostimulation occurs in response to aberrant electrical activity in the brain, fewer electrical impulses are being delivered to the brain than would occur with continuous stimulation. This in turn diminishes the possibility of treatment-related adverse events.

In an initial feasibility study of 65 patients, the responsive neurostimulation system demonstrated excellent safety, tolerability, and preliminary evidence of efficacy, Dr. Morrell said. “There were no serious device-related adverse events, and stimulation-related symptoms experienced by several subjects were addressed by adjusting the stimulation settings.”

The preliminary efficacy evidence from that study showed that a minimum 50% reduction in seizure frequency was experienced by 43% of the patients with complex partial seizures and 35% of those with total disabling seizures (Neurotherapeutics 2008;5:68–74).

In the double-blind pivotal trial, the 191 patients were randomized to active or sham therapy. The patients were between 18 and 70 years of age (median age 35 years), and all had partial onset epilepsy localized to one or two foci and had failed at least two antiepileptic medications.

The patients were taking an average of three antiepileptic medications to attempt seizure control, and about 34% of the patients had been treated previously with vagus nerve stimulation, 33% had prior surgical resection, and 16% had been treated with both.

“These patients tended to be very ill. Most of them had epilepsy for more than 20 years, and many were having at least three seizures per 28-day period–often many more than that,” Dr. Morrell said.

Of the 191 patients implanted with the device, 50% had mesial temporal seizure onset, 42% had neocortical seizure onset, and 8% had both, Dr. Morrell said in a press briefing at the meeting.

The trial consisted of an initial, 12-week period prior to system implantation during which baseline seizure activity was collected, followed by a 12-week blinded period when participants were randomly assigned to have the responsive stimulation activated or left inactive, she said.

At each of the 31 trial sites, the patients and one neurologist were blinded to the stimulation status, while a separate neurologist programmed the devices in order to maintain the study blinding. The responsive stimulation was optimized in the treatment over the next four weeks, followed by 84 days of data collection. At the end of the blinded efficacy period, stimulation was activated for all of the study participants for two years post-implantation, Dr. Morrell said.

In addition to the statistically significant reduction in seizure frequency in the active therapy group relative to those in the sham therapy condition, there were no serious, unanticipated device-related adverse events during the trial, nor was there a difference between the two groups with respect to the rate of adverse events, including depression, memory impairment, and anxiety, Dr. Morrell reported.

The findings suggest that responsive neurostimulation might be a promising treatment option for individuals with seizures that are resistant to conventional antiepileptic therapy. Importantly, the apparent increase in the number of patients experiencing at least a 50% reduction in seizure frequency relative to baseline during the open-label phase of the study suggests the system might become more effective over time, she noted.

The RNS has not yet received Food and Drug Administration approval, but NeuroPace plans to submit a premarket approval application to the FDA in early 2010, Dr. Morrell said.

My Take

A New Kind of Stimulation

The development and use of stimulation devices for medically refractory epilepsy represents an altogether new approach for these patients when surgery is not possible and pharmacology is ineffective. Open loop devices that deliver electrical stimulation on a duty cycle include the vagal nerve stimulator (Cyberonics), which is FDA-approved for refractory partial epilepsy, and the thalamic deep brain stimulator (Medtronic), which is FDA-approved for Parkinson's disease and essential tremor and is currently seeking FDA approval for refractory partial epilepsy. The RNS is the first closed loop stimulator and is distinctly different from other investigational and FDA-approved devices used to treat patients with epilepsy. The fact that in this day and age one can successfully and safely detect seizures using an implantable device on a long-term basis may provide hope for future advancements. With time, device technology is likely to be refined and improved, both through technical advances and as additional data are gathered and further studies are completed. Clinical experience will also help define proper patient selection, expectations, and effectiveness.

DR. KATHERINE NOE and DR. JOSEPH DRAZKOWSKI are epilepsy specialists at the Mayo Clinic, Scottsdale, Ariz. They were both investigators in the RNS trial.

VITALS

BOSTON — Certain central nervous system-related comorbidities occur more often among people with self-reported epilepsy than in the general population, according to a large survey of U.S. households.

Individuals who reported ever having had epilepsy or a seizure disorder were more likely than those without a self-reported epilepsy diagnosis to have ever had depression, anxiety, bipolar disorder, attention-deficit/hyperactivity disorder, sleep disorder, or migraine, Ruth Ottman, Ph.D., reported at the annual meeting of the American Epilepsy Society.

Dr. Ottman, professor of epidemiology and neurology at Columbia University, New York, and her colleagues developed an 11-item screening survey that was mailed in 2008 to 340,000 households from two national panels selected to be representative of the U.S. population.

Of the 3,488 people who reported having ever had epilepsy or a seizure disorder, 61% were female, the mean age was 48 years, 35% had a seizure or convulsion within the previous 12 months, and 27% reported having had a febrile seizure or convulsion as a child. In the epilepsy cohort, 33% reported ever having depression, compared with 26% of controls without epilepsy. The epilepsy cohort was more likely to report a history of anxiety disorder (22% vs. 14%), bipolar disorder (14% vs. 7%), and ADHD (13% vs. 6%). The epilepsy cohort also was more likely to report sleep disorder (20% vs. 14%) and migraine (28% vs. 21%).

The survey did not collect information on specific medications, but “it is possible that some of the comorbidity in our study could be related to medications,” Dr. Ottman said in an interview. “However, for several of the comorbid disorders we described, other studies have found significantly increased occurrences even before the first seizure, suggesting that medications do not explain all of the comorbidity.” For example, “the prevalence of depression is higher in people with epilepsy than in people without it, even before the first seizure occurs, and this is also true for migraine.”

A possible explanation for the increased prevalence of certain CNS comorbidities might be a “shared pathogenic mechanism underlying epilepsy and the other disorders, possibly due to shared genetic susceptibilities or to common environmental risk factors,” Dr. Ottman said.

Clinicians should be aware of the potential for CNS-related comorbidities so they can consider medications effective in treating both epilepsy and certain comorbid disorders, she said. Comorbidities have been highlighted by the National Institute of Neurological Disorders and Stroke as a priority for epilepsy research, “and we hope our research will increase awareness of comorbidities.”

Disclosures: Study sponsored by Ortho-McNeil Janssen Scientific Affairs. Dr. Ottman reported no conflicts of interest.

BOSTON — Certain central nervous system-related comorbidities occur more often among people with self-reported epilepsy than in the general population, according to a large survey of U.S. households.

Individuals who reported ever having had epilepsy or a seizure disorder were more likely than those without a self-reported epilepsy diagnosis to have ever had depression, anxiety, bipolar disorder, attention-deficit/hyperactivity disorder, sleep disorder, or migraine, Ruth Ottman, Ph.D., reported at the annual meeting of the American Epilepsy Society.

Dr. Ottman, professor of epidemiology and neurology at Columbia University, New York, and her colleagues developed an 11-item screening survey that was mailed in 2008 to 340,000 households from two national panels selected to be representative of the U.S. population.

Of the 3,488 people who reported having ever had epilepsy or a seizure disorder, 61% were female, the mean age was 48 years, 35% had a seizure or convulsion within the previous 12 months, and 27% reported having had a febrile seizure or convulsion as a child. In the epilepsy cohort, 33% reported ever having depression, compared with 26% of controls without epilepsy. The epilepsy cohort was more likely to report a history of anxiety disorder (22% vs. 14%), bipolar disorder (14% vs. 7%), and ADHD (13% vs. 6%). The epilepsy cohort also was more likely to report sleep disorder (20% vs. 14%) and migraine (28% vs. 21%).

The survey did not collect information on specific medications, but “it is possible that some of the comorbidity in our study could be related to medications,” Dr. Ottman said in an interview. “However, for several of the comorbid disorders we described, other studies have found significantly increased occurrences even before the first seizure, suggesting that medications do not explain all of the comorbidity.” For example, “the prevalence of depression is higher in people with epilepsy than in people without it, even before the first seizure occurs, and this is also true for migraine.”

A possible explanation for the increased prevalence of certain CNS comorbidities might be a “shared pathogenic mechanism underlying epilepsy and the other disorders, possibly due to shared genetic susceptibilities or to common environmental risk factors,” Dr. Ottman said.

Clinicians should be aware of the potential for CNS-related comorbidities so they can consider medications effective in treating both epilepsy and certain comorbid disorders, she said. Comorbidities have been highlighted by the National Institute of Neurological Disorders and Stroke as a priority for epilepsy research, “and we hope our research will increase awareness of comorbidities.”

Disclosures: Study sponsored by Ortho-McNeil Janssen Scientific Affairs. Dr. Ottman reported no conflicts of interest.

BOSTON — Certain central nervous system-related comorbidities occur more often among people with self-reported epilepsy than in the general population, according to a large survey of U.S. households.

Individuals who reported ever having had epilepsy or a seizure disorder were more likely than those without a self-reported epilepsy diagnosis to have ever had depression, anxiety, bipolar disorder, attention-deficit/hyperactivity disorder, sleep disorder, or migraine, Ruth Ottman, Ph.D., reported at the annual meeting of the American Epilepsy Society.

Dr. Ottman, professor of epidemiology and neurology at Columbia University, New York, and her colleagues developed an 11-item screening survey that was mailed in 2008 to 340,000 households from two national panels selected to be representative of the U.S. population.

Of the 3,488 people who reported having ever had epilepsy or a seizure disorder, 61% were female, the mean age was 48 years, 35% had a seizure or convulsion within the previous 12 months, and 27% reported having had a febrile seizure or convulsion as a child. In the epilepsy cohort, 33% reported ever having depression, compared with 26% of controls without epilepsy. The epilepsy cohort was more likely to report a history of anxiety disorder (22% vs. 14%), bipolar disorder (14% vs. 7%), and ADHD (13% vs. 6%). The epilepsy cohort also was more likely to report sleep disorder (20% vs. 14%) and migraine (28% vs. 21%).

The survey did not collect information on specific medications, but “it is possible that some of the comorbidity in our study could be related to medications,” Dr. Ottman said in an interview. “However, for several of the comorbid disorders we described, other studies have found significantly increased occurrences even before the first seizure, suggesting that medications do not explain all of the comorbidity.” For example, “the prevalence of depression is higher in people with epilepsy than in people without it, even before the first seizure occurs, and this is also true for migraine.”

A possible explanation for the increased prevalence of certain CNS comorbidities might be a “shared pathogenic mechanism underlying epilepsy and the other disorders, possibly due to shared genetic susceptibilities or to common environmental risk factors,” Dr. Ottman said.

Clinicians should be aware of the potential for CNS-related comorbidities so they can consider medications effective in treating both epilepsy and certain comorbid disorders, she said. Comorbidities have been highlighted by the National Institute of Neurological Disorders and Stroke as a priority for epilepsy research, “and we hope our research will increase awareness of comorbidities.”

Disclosures: Study sponsored by Ortho-McNeil Janssen Scientific Affairs. Dr. Ottman reported no conflicts of interest.

Major Findings: After evidence-based recommendations were published, no significant trends were found suggesting earlier referral for epilepsy surgery evaluation.

Data Source: Retrospective, single-center comparison.

Disclosures: The investigators reported no relevant conflicts of interest.

BOSTON — The 2003 publication of evidence-based recommendations for referring patients with temporal lobe epilepsy for surgical evaluation has not led to an increase in timely referrals for appropriate candidates, according to a study of referral patterns.

Researchers at the Seizure Disorder Center of the David Geffen School of Medicine at the University of California, Los Angeles, compared data for patients seen in the center's epilepsy monitoring unit (EMU) before and after the American Academy of Neurology issued a practice parameter recommending referral for epilepsy surgery evaluation for patients who failed appropriate trials of first-line antiepileptic drugs (Neurology 2003;60:538-47).

Among 435 patients seen at the center during 1995-1998 and 712 patients seen during 2005-2008, those with brain tumors, previous EMU evaluations, or previous neurosurgery were excluded. This left 83 patients in the earlier period and 102 in the later period, Dr. Jerome Engel Jr. said at the annual meeting of the American Epilepsy Society.

No significant differences were found between the groups with respect to age at diagnosis, duration of epilepsy, or age at EMU evaluation, Dr. Engel reported. The mean age of onset was 17 years for the earlier group and 18.4 years for the latter group, the mean duration of epilepsy was 17.1 vs. 18.6 years, and the mean age at EMU evaluation was 34.1 vs. 37 years.

The findings confirm that the failure to refer patients with drug-resistant epilepsy continues to be a major problem, despite the availability of class I evidence for the effectiveness of surgery and evidence-based recommendations. As a result, patients who are surgical candidates—those whose seizures persist after appropriate trials of two antiepileptic drug regimens—continue to suffer debilitating seizures long after they might have if they had been referred to a surgical center according to the evidence-based guidelines, said Dr. Engel, director of the Seizure Disorder Center.

The UCLA investigators are conducting a critical review of factors that prevent the translation of recommendations for surgical referral in epilepsy to clinical practice.

Major Findings: After evidence-based recommendations were published, no significant trends were found suggesting earlier referral for epilepsy surgery evaluation.

Data Source: Retrospective, single-center comparison.

Disclosures: The investigators reported no relevant conflicts of interest.

BOSTON — The 2003 publication of evidence-based recommendations for referring patients with temporal lobe epilepsy for surgical evaluation has not led to an increase in timely referrals for appropriate candidates, according to a study of referral patterns.

Researchers at the Seizure Disorder Center of the David Geffen School of Medicine at the University of California, Los Angeles, compared data for patients seen in the center's epilepsy monitoring unit (EMU) before and after the American Academy of Neurology issued a practice parameter recommending referral for epilepsy surgery evaluation for patients who failed appropriate trials of first-line antiepileptic drugs (Neurology 2003;60:538-47).

Among 435 patients seen at the center during 1995-1998 and 712 patients seen during 2005-2008, those with brain tumors, previous EMU evaluations, or previous neurosurgery were excluded. This left 83 patients in the earlier period and 102 in the later period, Dr. Jerome Engel Jr. said at the annual meeting of the American Epilepsy Society.

No significant differences were found between the groups with respect to age at diagnosis, duration of epilepsy, or age at EMU evaluation, Dr. Engel reported. The mean age of onset was 17 years for the earlier group and 18.4 years for the latter group, the mean duration of epilepsy was 17.1 vs. 18.6 years, and the mean age at EMU evaluation was 34.1 vs. 37 years.

The findings confirm that the failure to refer patients with drug-resistant epilepsy continues to be a major problem, despite the availability of class I evidence for the effectiveness of surgery and evidence-based recommendations. As a result, patients who are surgical candidates—those whose seizures persist after appropriate trials of two antiepileptic drug regimens—continue to suffer debilitating seizures long after they might have if they had been referred to a surgical center according to the evidence-based guidelines, said Dr. Engel, director of the Seizure Disorder Center.

The UCLA investigators are conducting a critical review of factors that prevent the translation of recommendations for surgical referral in epilepsy to clinical practice.

Major Findings: After evidence-based recommendations were published, no significant trends were found suggesting earlier referral for epilepsy surgery evaluation.

Data Source: Retrospective, single-center comparison.

Disclosures: The investigators reported no relevant conflicts of interest.

BOSTON — The 2003 publication of evidence-based recommendations for referring patients with temporal lobe epilepsy for surgical evaluation has not led to an increase in timely referrals for appropriate candidates, according to a study of referral patterns.

Researchers at the Seizure Disorder Center of the David Geffen School of Medicine at the University of California, Los Angeles, compared data for patients seen in the center's epilepsy monitoring unit (EMU) before and after the American Academy of Neurology issued a practice parameter recommending referral for epilepsy surgery evaluation for patients who failed appropriate trials of first-line antiepileptic drugs (Neurology 2003;60:538-47).

Among 435 patients seen at the center during 1995-1998 and 712 patients seen during 2005-2008, those with brain tumors, previous EMU evaluations, or previous neurosurgery were excluded. This left 83 patients in the earlier period and 102 in the later period, Dr. Jerome Engel Jr. said at the annual meeting of the American Epilepsy Society.

No significant differences were found between the groups with respect to age at diagnosis, duration of epilepsy, or age at EMU evaluation, Dr. Engel reported. The mean age of onset was 17 years for the earlier group and 18.4 years for the latter group, the mean duration of epilepsy was 17.1 vs. 18.6 years, and the mean age at EMU evaluation was 34.1 vs. 37 years.

The findings confirm that the failure to refer patients with drug-resistant epilepsy continues to be a major problem, despite the availability of class I evidence for the effectiveness of surgery and evidence-based recommendations. As a result, patients who are surgical candidates—those whose seizures persist after appropriate trials of two antiepileptic drug regimens—continue to suffer debilitating seizures long after they might have if they had been referred to a surgical center according to the evidence-based guidelines, said Dr. Engel, director of the Seizure Disorder Center.

The UCLA investigators are conducting a critical review of factors that prevent the translation of recommendations for surgical referral in epilepsy to clinical practice.