Sherry Boschert

HONOLULU – The first approved oral medication for multiple sclerosis causes transient reductions in heart rate and atrioventricular conduction and a sustained increase in blood pressure, according to investigators who analyzed pooled data from two phase III trials.

The cohorts from the two phase III clinical trials of fingolimod (Gilenya) for relapsing-remitting muscular sclerosis involved 854 patients treated with the currently approved dosage of fingolimod (0.5 mg/day), 849 patients on a higher dosage (1.25 mg/day), 418 patients on placebo, and 431 patients treated with weekly intramuscular injections of 30 mcg interferon beta-1a (Avonex) for 1-2 years.

The investigators measured vital signs hourly for 6 hours after starting treatment and at quarterly follow-up visits. Patients underwent an ECG before the first dose, 6 hours after treatment initiation, and if they developed symptoms during those 6 hours, as well as at selected follow-up visits. The studies did not use continuous ECG monitoring because they were designed to mimic treatment initiation in a neurologist’s office.

Heart rates hit a nadir approximately 4-5 hours after starting fingolimod, and then began to increase, Dr. John DiMarco reported at the annual meeting of the American Academy of Neurology. By 2 weeks after starting therapy, heart rates in the fingolimod groups were almost back to baseline, and thereafter were similar to baseline heart rates in the placebo group. As expected, some tachycardia was seen on interferon therapy.

In the first 6 hours of treatment, the lowest measured heart rate was below 35 beats per minute (bpm) in one patient on fingolimod 1.25 mg/day and one patient on interferon. Heart rates fell to as low as 35-39 bpm in six patients on fingolimod 1.25 mg/day, reported Dr. DiMarco, a cardiologist and professor of medicine at the University of Virginia, Charlottesville.

A heart rate nadir of 40-44 bpm was seen in approximately 1% of the low-dose fingolimod group, 3% of the high-dose fingolimod group, 0.2% of the placebo group, and no patients on interferon. A nadir of 45-54 bpm was measured in 18% on low-dose fingolimod, 29% on high-dose fingolimod, 6% on placebo, and 3% on interferon.

The lowest heart rate was 55-64 bpm in 49% on low-dose fingolimod, 50% on high-dose fingolimod, 37% on placebo, and 33% on interferon. Heart rates never fell below 65 bpm in 32% on low-dose fingolimod, 18% on high-dose fingolimod, 56% on placebo, and 64% on interferon.

Patients could be discharged at the 6-hour follow-up if any slowing in heart rate had started to return toward baseline, the heart rate was at least 55 bpm or greater than 80% of the baseline rate, and the patient had no symptoms related to bradycardia and no new, clinically relevant abnormality on ECG.

Observation beyond the 6-hour period was required in 12% on low-dose fingolimod, 18% on high-dose fingolimod, 3% on placebo, and 1% on interferon. Clinicians chose to hospitalize 2% of patients on fingolimod 0.5 mg/day, 3% of patients on 1.25 mg/day, 0.5% of patients on interferon, and none on placebo.

"Most of these hospitalizations and even the prolonged observations were driven by the study criteria and not by symptoms," Dr. DiMarco noted.

Symptoms of bradycardia were seen in 0.5% of patients on 0.5 mg/day fingolimod, 1% of patients on 1.25 mg/day, and no patients in the other groups. All symptoms were described as mild or moderate in severity.

Conduction abnormalities also were more common within 6 hours of taking low-dose fingolimod (7%) or high-dose fingolimod (13%), compared with placebo or interferon (4% each). First-degree atrioventricular (AV) block was seen in 5% on low-dose fingolimod, 10% on high-dose fingolimod, 2% on placebo, and 3% on interferon. A Wenckebach second-degree AV block was seen in 0.2% on low-dose fingolimod, 0.7% on high-dose fingolimod, and no patients in the other groups. Two patients (0.2%) in the high-dose fingolimod group developed 2:1 second-degree AV block.

One patient in the low-dose fingolimod group and three in the high-dose fingolimod group were treated for heart rate or conduction abnormalities, although two of these patients were asymptomatic. Fingolimod was discontinued after the first dose in 1% of the high-dose group. In the others, the AV conduction changes attenuated with continued therapy and returned to baseline levels by 1 month.

"Most episodes of bradycardia could be managed just with observation. Active intervention was rarely required," Dr. DiMarco said.

The rise in blood pressure on fingolimod was small, but sustained and statistically significant, starting within 2-6 months of treatment initiation. Systolic and diastolic blood pressure increases averaged 1-2 mm Hg on 0.5 mg/day fingolimod and 1-3 mm Hg on 1.25 mg/day fingolimod, compared with the placebo group.

"The significance of these findings is uncertain," he said.

Rates of hypertension adverse events were higher in the fingolimod groups – 4% on the lower dose and 5% on the higher dose – compared with the placebo group (3%) or the interferon group (2%). The proportions of patients who needed antihypertensive therapy, however, were similar between groups: 5% on low-dose fingolimod, 6% on high-dose fingolimod, 6% on placebo, and 4% on interferon.

Patients who were treated responded to standard antihypertensive therapy.

Data for the analysis came from the Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis (FREEDOMS) trial and from the Trial Assessing Injectable Interferon vs. FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS). Both were international, multicenter, randomized double-blind trials.

Both trials excluded patients with moderate to severe cardiovascular disease. At baseline, 3%-4% in each treatment group had a cardiovascular disorder and 5%-7% had hypertension.

The current analysis was funded by Novartis, which markets fingolimod. Dr. DiMarco disclosed financial relationships with Novartis, Medtronic, St. Jude Medical, Astellas, Sanofi-Aventis Pharmaceuticals, and Boston Scientific. His associates in the study have been employees of Novartis, have held stock in the company, or disclosed other financial relationships with Novartis and other pharmaceutical companies.

HONOLULU – The first approved oral medication for multiple sclerosis causes transient reductions in heart rate and atrioventricular conduction and a sustained increase in blood pressure, according to investigators who analyzed pooled data from two phase III trials.

The cohorts from the two phase III clinical trials of fingolimod (Gilenya) for relapsing-remitting muscular sclerosis involved 854 patients treated with the currently approved dosage of fingolimod (0.5 mg/day), 849 patients on a higher dosage (1.25 mg/day), 418 patients on placebo, and 431 patients treated with weekly intramuscular injections of 30 mcg interferon beta-1a (Avonex) for 1-2 years.

The investigators measured vital signs hourly for 6 hours after starting treatment and at quarterly follow-up visits. Patients underwent an ECG before the first dose, 6 hours after treatment initiation, and if they developed symptoms during those 6 hours, as well as at selected follow-up visits. The studies did not use continuous ECG monitoring because they were designed to mimic treatment initiation in a neurologist’s office.

Heart rates hit a nadir approximately 4-5 hours after starting fingolimod, and then began to increase, Dr. John DiMarco reported at the annual meeting of the American Academy of Neurology. By 2 weeks after starting therapy, heart rates in the fingolimod groups were almost back to baseline, and thereafter were similar to baseline heart rates in the placebo group. As expected, some tachycardia was seen on interferon therapy.

In the first 6 hours of treatment, the lowest measured heart rate was below 35 beats per minute (bpm) in one patient on fingolimod 1.25 mg/day and one patient on interferon. Heart rates fell to as low as 35-39 bpm in six patients on fingolimod 1.25 mg/day, reported Dr. DiMarco, a cardiologist and professor of medicine at the University of Virginia, Charlottesville.

A heart rate nadir of 40-44 bpm was seen in approximately 1% of the low-dose fingolimod group, 3% of the high-dose fingolimod group, 0.2% of the placebo group, and no patients on interferon. A nadir of 45-54 bpm was measured in 18% on low-dose fingolimod, 29% on high-dose fingolimod, 6% on placebo, and 3% on interferon.

The lowest heart rate was 55-64 bpm in 49% on low-dose fingolimod, 50% on high-dose fingolimod, 37% on placebo, and 33% on interferon. Heart rates never fell below 65 bpm in 32% on low-dose fingolimod, 18% on high-dose fingolimod, 56% on placebo, and 64% on interferon.

Patients could be discharged at the 6-hour follow-up if any slowing in heart rate had started to return toward baseline, the heart rate was at least 55 bpm or greater than 80% of the baseline rate, and the patient had no symptoms related to bradycardia and no new, clinically relevant abnormality on ECG.

Observation beyond the 6-hour period was required in 12% on low-dose fingolimod, 18% on high-dose fingolimod, 3% on placebo, and 1% on interferon. Clinicians chose to hospitalize 2% of patients on fingolimod 0.5 mg/day, 3% of patients on 1.25 mg/day, 0.5% of patients on interferon, and none on placebo.

"Most of these hospitalizations and even the prolonged observations were driven by the study criteria and not by symptoms," Dr. DiMarco noted.

Symptoms of bradycardia were seen in 0.5% of patients on 0.5 mg/day fingolimod, 1% of patients on 1.25 mg/day, and no patients in the other groups. All symptoms were described as mild or moderate in severity.

Conduction abnormalities also were more common within 6 hours of taking low-dose fingolimod (7%) or high-dose fingolimod (13%), compared with placebo or interferon (4% each). First-degree atrioventricular (AV) block was seen in 5% on low-dose fingolimod, 10% on high-dose fingolimod, 2% on placebo, and 3% on interferon. A Wenckebach second-degree AV block was seen in 0.2% on low-dose fingolimod, 0.7% on high-dose fingolimod, and no patients in the other groups. Two patients (0.2%) in the high-dose fingolimod group developed 2:1 second-degree AV block.

One patient in the low-dose fingolimod group and three in the high-dose fingolimod group were treated for heart rate or conduction abnormalities, although two of these patients were asymptomatic. Fingolimod was discontinued after the first dose in 1% of the high-dose group. In the others, the AV conduction changes attenuated with continued therapy and returned to baseline levels by 1 month.

"Most episodes of bradycardia could be managed just with observation. Active intervention was rarely required," Dr. DiMarco said.

The rise in blood pressure on fingolimod was small, but sustained and statistically significant, starting within 2-6 months of treatment initiation. Systolic and diastolic blood pressure increases averaged 1-2 mm Hg on 0.5 mg/day fingolimod and 1-3 mm Hg on 1.25 mg/day fingolimod, compared with the placebo group.

"The significance of these findings is uncertain," he said.

Rates of hypertension adverse events were higher in the fingolimod groups – 4% on the lower dose and 5% on the higher dose – compared with the placebo group (3%) or the interferon group (2%). The proportions of patients who needed antihypertensive therapy, however, were similar between groups: 5% on low-dose fingolimod, 6% on high-dose fingolimod, 6% on placebo, and 4% on interferon.

Patients who were treated responded to standard antihypertensive therapy.

Data for the analysis came from the Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis (FREEDOMS) trial and from the Trial Assessing Injectable Interferon vs. FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS). Both were international, multicenter, randomized double-blind trials.

Both trials excluded patients with moderate to severe cardiovascular disease. At baseline, 3%-4% in each treatment group had a cardiovascular disorder and 5%-7% had hypertension.

The current analysis was funded by Novartis, which markets fingolimod. Dr. DiMarco disclosed financial relationships with Novartis, Medtronic, St. Jude Medical, Astellas, Sanofi-Aventis Pharmaceuticals, and Boston Scientific. His associates in the study have been employees of Novartis, have held stock in the company, or disclosed other financial relationships with Novartis and other pharmaceutical companies.

HONOLULU – The first approved oral medication for multiple sclerosis causes transient reductions in heart rate and atrioventricular conduction and a sustained increase in blood pressure, according to investigators who analyzed pooled data from two phase III trials.

The cohorts from the two phase III clinical trials of fingolimod (Gilenya) for relapsing-remitting muscular sclerosis involved 854 patients treated with the currently approved dosage of fingolimod (0.5 mg/day), 849 patients on a higher dosage (1.25 mg/day), 418 patients on placebo, and 431 patients treated with weekly intramuscular injections of 30 mcg interferon beta-1a (Avonex) for 1-2 years.

The investigators measured vital signs hourly for 6 hours after starting treatment and at quarterly follow-up visits. Patients underwent an ECG before the first dose, 6 hours after treatment initiation, and if they developed symptoms during those 6 hours, as well as at selected follow-up visits. The studies did not use continuous ECG monitoring because they were designed to mimic treatment initiation in a neurologist’s office.

Heart rates hit a nadir approximately 4-5 hours after starting fingolimod, and then began to increase, Dr. John DiMarco reported at the annual meeting of the American Academy of Neurology. By 2 weeks after starting therapy, heart rates in the fingolimod groups were almost back to baseline, and thereafter were similar to baseline heart rates in the placebo group. As expected, some tachycardia was seen on interferon therapy.

In the first 6 hours of treatment, the lowest measured heart rate was below 35 beats per minute (bpm) in one patient on fingolimod 1.25 mg/day and one patient on interferon. Heart rates fell to as low as 35-39 bpm in six patients on fingolimod 1.25 mg/day, reported Dr. DiMarco, a cardiologist and professor of medicine at the University of Virginia, Charlottesville.

A heart rate nadir of 40-44 bpm was seen in approximately 1% of the low-dose fingolimod group, 3% of the high-dose fingolimod group, 0.2% of the placebo group, and no patients on interferon. A nadir of 45-54 bpm was measured in 18% on low-dose fingolimod, 29% on high-dose fingolimod, 6% on placebo, and 3% on interferon.

The lowest heart rate was 55-64 bpm in 49% on low-dose fingolimod, 50% on high-dose fingolimod, 37% on placebo, and 33% on interferon. Heart rates never fell below 65 bpm in 32% on low-dose fingolimod, 18% on high-dose fingolimod, 56% on placebo, and 64% on interferon.

Patients could be discharged at the 6-hour follow-up if any slowing in heart rate had started to return toward baseline, the heart rate was at least 55 bpm or greater than 80% of the baseline rate, and the patient had no symptoms related to bradycardia and no new, clinically relevant abnormality on ECG.

Observation beyond the 6-hour period was required in 12% on low-dose fingolimod, 18% on high-dose fingolimod, 3% on placebo, and 1% on interferon. Clinicians chose to hospitalize 2% of patients on fingolimod 0.5 mg/day, 3% of patients on 1.25 mg/day, 0.5% of patients on interferon, and none on placebo.

"Most of these hospitalizations and even the prolonged observations were driven by the study criteria and not by symptoms," Dr. DiMarco noted.

Symptoms of bradycardia were seen in 0.5% of patients on 0.5 mg/day fingolimod, 1% of patients on 1.25 mg/day, and no patients in the other groups. All symptoms were described as mild or moderate in severity.

Conduction abnormalities also were more common within 6 hours of taking low-dose fingolimod (7%) or high-dose fingolimod (13%), compared with placebo or interferon (4% each). First-degree atrioventricular (AV) block was seen in 5% on low-dose fingolimod, 10% on high-dose fingolimod, 2% on placebo, and 3% on interferon. A Wenckebach second-degree AV block was seen in 0.2% on low-dose fingolimod, 0.7% on high-dose fingolimod, and no patients in the other groups. Two patients (0.2%) in the high-dose fingolimod group developed 2:1 second-degree AV block.

One patient in the low-dose fingolimod group and three in the high-dose fingolimod group were treated for heart rate or conduction abnormalities, although two of these patients were asymptomatic. Fingolimod was discontinued after the first dose in 1% of the high-dose group. In the others, the AV conduction changes attenuated with continued therapy and returned to baseline levels by 1 month.

"Most episodes of bradycardia could be managed just with observation. Active intervention was rarely required," Dr. DiMarco said.

The rise in blood pressure on fingolimod was small, but sustained and statistically significant, starting within 2-6 months of treatment initiation. Systolic and diastolic blood pressure increases averaged 1-2 mm Hg on 0.5 mg/day fingolimod and 1-3 mm Hg on 1.25 mg/day fingolimod, compared with the placebo group.

"The significance of these findings is uncertain," he said.

Rates of hypertension adverse events were higher in the fingolimod groups – 4% on the lower dose and 5% on the higher dose – compared with the placebo group (3%) or the interferon group (2%). The proportions of patients who needed antihypertensive therapy, however, were similar between groups: 5% on low-dose fingolimod, 6% on high-dose fingolimod, 6% on placebo, and 4% on interferon.

Patients who were treated responded to standard antihypertensive therapy.

Data for the analysis came from the Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis (FREEDOMS) trial and from the Trial Assessing Injectable Interferon vs. FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS). Both were international, multicenter, randomized double-blind trials.

Both trials excluded patients with moderate to severe cardiovascular disease. At baseline, 3%-4% in each treatment group had a cardiovascular disorder and 5%-7% had hypertension.

The current analysis was funded by Novartis, which markets fingolimod. Dr. DiMarco disclosed financial relationships with Novartis, Medtronic, St. Jude Medical, Astellas, Sanofi-Aventis Pharmaceuticals, and Boston Scientific. His associates in the study have been employees of Novartis, have held stock in the company, or disclosed other financial relationships with Novartis and other pharmaceutical companies.

HONOLULU – The first approved oral medication for multiple sclerosis causes transient reductions in heart rate and atrioventricular conduction and a sustained increase in blood pressure, according to investigators who analyzed pooled data from two phase III trials.

The cohorts from the two phase III clinical trials of fingolimod (Gilenya) for relapsing-remitting muscular sclerosis involved 854 patients treated with the currently approved dosage of fingolimod (0.5 mg/day), 849 patients on a higher dosage (1.25 mg/day), 418 patients on placebo, and 431 patients treated with weekly intramuscular injections of 30 mcg interferon beta-1a (Avonex) for 1-2 years.

The investigators measured vital signs hourly for 6 hours after starting treatment and at quarterly follow-up visits. Patients underwent an ECG before the first dose, 6 hours after treatment initiation, and if they developed symptoms during those 6 hours, as well as at selected follow-up visits. The studies did not use continuous ECG monitoring because they were designed to mimic treatment initiation in a neurologist’s office.

Heart rates hit a nadir approximately 4-5 hours after starting fingolimod, and then began to increase, Dr. John DiMarco reported at the annual meeting of the American Academy of Neurology. By 2 weeks after starting therapy, heart rates in the fingolimod groups were almost back to baseline, and thereafter were similar to baseline heart rates in the placebo group. As expected, some tachycardia was seen on interferon therapy.

In the first 6 hours of treatment, the lowest measured heart rate was below 35 beats per minute (bpm) in one patient on fingolimod 1.25 mg/day and one patient on interferon. Heart rates fell to as low as 35-39 bpm in six patients on fingolimod 1.25 mg/day, reported Dr. DiMarco, a cardiologist and professor of medicine at the University of Virginia, Charlottesville.

A heart rate nadir of 40-44 bpm was seen in approximately 1% of the low-dose fingolimod group, 3% of the high-dose fingolimod group, 0.2% of the placebo group, and no patients on interferon. A nadir of 45-54 bpm was measured in 18% on low-dose fingolimod, 29% on high-dose fingolimod, 6% on placebo, and 3% on interferon.

The lowest heart rate was 55-64 bpm in 49% on low-dose fingolimod, 50% on high-dose fingolimod, 37% on placebo, and 33% on interferon. Heart rates never fell below 65 bpm in 32% on low-dose fingolimod, 18% on high-dose fingolimod, 56% on placebo, and 64% on interferon.

Patients could be discharged at the 6-hour follow-up if any slowing in heart rate had started to return toward baseline, the heart rate was at least 55 bpm or greater than 80% of the baseline rate, and the patient had no symptoms related to bradycardia and no new, clinically relevant abnormality on ECG.

Observation beyond the 6-hour period was required in 12% on low-dose fingolimod, 18% on high-dose fingolimod, 3% on placebo, and 1% on interferon. Clinicians chose to hospitalize 2% of patients on fingolimod 0.5 mg/day, 3% of patients on 1.25 mg/day, 0.5% of patients on interferon, and none on placebo.

"Most of these hospitalizations and even the prolonged observations were driven by the study criteria and not by symptoms," Dr. DiMarco noted.

Symptoms of bradycardia were seen in 0.5% of patients on 0.5 mg/day fingolimod, 1% of patients on 1.25 mg/day, and no patients in the other groups. All symptoms were described as mild or moderate in severity.

Conduction abnormalities also were more common within 6 hours of taking low-dose fingolimod (7%) or high-dose fingolimod (13%), compared with placebo or interferon (4% each). First-degree atrioventricular (AV) block was seen in 5% on low-dose fingolimod, 10% on high-dose fingolimod, 2% on placebo, and 3% on interferon. A Wenckebach second-degree AV block was seen in 0.2% on low-dose fingolimod, 0.7% on high-dose fingolimod, and no patients in the other groups. Two patients (0.2%) in the high-dose fingolimod group developed 2:1 second-degree AV block.

One patient in the low-dose fingolimod group and three in the high-dose fingolimod group were treated for heart rate or conduction abnormalities, although two of these patients were asymptomatic. Fingolimod was discontinued after the first dose in 1% of the high-dose group. In the others, the AV conduction changes attenuated with continued therapy and returned to baseline levels by 1 month.

"Most episodes of bradycardia could be managed just with observation. Active intervention was rarely required," Dr. DiMarco said.

The rise in blood pressure on fingolimod was small, but sustained and statistically significant, starting within 2-6 months of treatment initiation. Systolic and diastolic blood pressure increases averaged 1-2 mm Hg on 0.5 mg/day fingolimod and 1-3 mm Hg on 1.25 mg/day fingolimod, compared with the placebo group.

"The significance of these findings is uncertain," he said.

Rates of hypertension adverse events were higher in the fingolimod groups – 4% on the lower dose and 5% on the higher dose – compared with the placebo group (3%) or the interferon group (2%). The proportions of patients who needed antihypertensive therapy, however, were similar between groups: 5% on low-dose fingolimod, 6% on high-dose fingolimod, 6% on placebo, and 4% on interferon.

Patients who were treated responded to standard antihypertensive therapy.

Data for the analysis came from the Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis (FREEDOMS) trial and from the Trial Assessing Injectable Interferon vs. FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS). Both were international, multicenter, randomized double-blind trials.

Both trials excluded patients with moderate to severe cardiovascular disease. At baseline, 3%-4% in each treatment group had a cardiovascular disorder and 5%-7% had hypertension.

The current analysis was funded by Novartis, which markets fingolimod. Dr. DiMarco disclosed financial relationships with Novartis, Medtronic, St. Jude Medical, Astellas, Sanofi-Aventis Pharmaceuticals, and Boston Scientific. His associates in the study have been employees of Novartis, have held stock in the company, or disclosed other financial relationships with Novartis and other pharmaceutical companies.

HONOLULU – The first approved oral medication for multiple sclerosis causes transient reductions in heart rate and atrioventricular conduction and a sustained increase in blood pressure, according to investigators who analyzed pooled data from two phase III trials.

The cohorts from the two phase III clinical trials of fingolimod (Gilenya) for relapsing-remitting muscular sclerosis involved 854 patients treated with the currently approved dosage of fingolimod (0.5 mg/day), 849 patients on a higher dosage (1.25 mg/day), 418 patients on placebo, and 431 patients treated with weekly intramuscular injections of 30 mcg interferon beta-1a (Avonex) for 1-2 years.

The investigators measured vital signs hourly for 6 hours after starting treatment and at quarterly follow-up visits. Patients underwent an ECG before the first dose, 6 hours after treatment initiation, and if they developed symptoms during those 6 hours, as well as at selected follow-up visits. The studies did not use continuous ECG monitoring because they were designed to mimic treatment initiation in a neurologist’s office.

Heart rates hit a nadir approximately 4-5 hours after starting fingolimod, and then began to increase, Dr. John DiMarco reported at the annual meeting of the American Academy of Neurology. By 2 weeks after starting therapy, heart rates in the fingolimod groups were almost back to baseline, and thereafter were similar to baseline heart rates in the placebo group. As expected, some tachycardia was seen on interferon therapy.

In the first 6 hours of treatment, the lowest measured heart rate was below 35 beats per minute (bpm) in one patient on fingolimod 1.25 mg/day and one patient on interferon. Heart rates fell to as low as 35-39 bpm in six patients on fingolimod 1.25 mg/day, reported Dr. DiMarco, a cardiologist and professor of medicine at the University of Virginia, Charlottesville.

A heart rate nadir of 40-44 bpm was seen in approximately 1% of the low-dose fingolimod group, 3% of the high-dose fingolimod group, 0.2% of the placebo group, and no patients on interferon. A nadir of 45-54 bpm was measured in 18% on low-dose fingolimod, 29% on high-dose fingolimod, 6% on placebo, and 3% on interferon.

The lowest heart rate was 55-64 bpm in 49% on low-dose fingolimod, 50% on high-dose fingolimod, 37% on placebo, and 33% on interferon. Heart rates never fell below 65 bpm in 32% on low-dose fingolimod, 18% on high-dose fingolimod, 56% on placebo, and 64% on interferon.

Patients could be discharged at the 6-hour follow-up if any slowing in heart rate had started to return toward baseline, the heart rate was at least 55 bpm or greater than 80% of the baseline rate, and the patient had no symptoms related to bradycardia and no new, clinically relevant abnormality on ECG.

Observation beyond the 6-hour period was required in 12% on low-dose fingolimod, 18% on high-dose fingolimod, 3% on placebo, and 1% on interferon. Clinicians chose to hospitalize 2% of patients on fingolimod 0.5 mg/day, 3% of patients on 1.25 mg/day, 0.5% of patients on interferon, and none on placebo.

"Most of these hospitalizations and even the prolonged observations were driven by the study criteria and not by symptoms," Dr. DiMarco noted.

Symptoms of bradycardia were seen in 0.5% of patients on 0.5 mg/day fingolimod, 1% of patients on 1.25 mg/day, and no patients in the other groups. All symptoms were described as mild or moderate in severity.

Conduction abnormalities also were more common within 6 hours of taking low-dose fingolimod (7%) or high-dose fingolimod (13%), compared with placebo or interferon (4% each). First-degree atrioventricular (AV) block was seen in 5% on low-dose fingolimod, 10% on high-dose fingolimod, 2% on placebo, and 3% on interferon. A Wenckebach second-degree AV block was seen in 0.2% on low-dose fingolimod, 0.7% on high-dose fingolimod, and no patients in the other groups. Two patients (0.2%) in the high-dose fingolimod group developed 2:1 second-degree AV block.

One patient in the low-dose fingolimod group and three in the high-dose fingolimod group were treated for heart rate or conduction abnormalities, although two of these patients were asymptomatic. Fingolimod was discontinued after the first dose in 1% of the high-dose group. In the others, the AV conduction changes attenuated with continued therapy and returned to baseline levels by 1 month.

"Most episodes of bradycardia could be managed just with observation. Active intervention was rarely required," Dr. DiMarco said.

The rise in blood pressure on fingolimod was small, but sustained and statistically significant, starting within 2-6 months of treatment initiation. Systolic and diastolic blood pressure increases averaged 1-2 mm Hg on 0.5 mg/day fingolimod and 1-3 mm Hg on 1.25 mg/day fingolimod, compared with the placebo group.

"The significance of these findings is uncertain," he said.

Rates of hypertension adverse events were higher in the fingolimod groups – 4% on the lower dose and 5% on the higher dose – compared with the placebo group (3%) or the interferon group (2%). The proportions of patients who needed antihypertensive therapy, however, were similar between groups: 5% on low-dose fingolimod, 6% on high-dose fingolimod, 6% on placebo, and 4% on interferon.

Patients who were treated responded to standard antihypertensive therapy.

Data for the analysis came from the Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis (FREEDOMS) trial and from the Trial Assessing Injectable Interferon vs. FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS). Both were international, multicenter, randomized double-blind trials.

Both trials excluded patients with moderate to severe cardiovascular disease. At baseline, 3%-4% in each treatment group had a cardiovascular disorder and 5%-7% had hypertension.

The current analysis was funded by Novartis, which markets fingolimod. Dr. DiMarco disclosed financial relationships with Novartis, Medtronic, St. Jude Medical, Astellas, Sanofi-Aventis Pharmaceuticals, and Boston Scientific. His associates in the study have been employees of Novartis, have held stock in the company, or disclosed other financial relationships with Novartis and other pharmaceutical companies.

HONOLULU – The first approved oral medication for multiple sclerosis causes transient reductions in heart rate and atrioventricular conduction and a sustained increase in blood pressure, according to investigators who analyzed pooled data from two phase III trials.

The cohorts from the two phase III clinical trials of fingolimod (Gilenya) for relapsing-remitting muscular sclerosis involved 854 patients treated with the currently approved dosage of fingolimod (0.5 mg/day), 849 patients on a higher dosage (1.25 mg/day), 418 patients on placebo, and 431 patients treated with weekly intramuscular injections of 30 mcg interferon beta-1a (Avonex) for 1-2 years.

The investigators measured vital signs hourly for 6 hours after starting treatment and at quarterly follow-up visits. Patients underwent an ECG before the first dose, 6 hours after treatment initiation, and if they developed symptoms during those 6 hours, as well as at selected follow-up visits. The studies did not use continuous ECG monitoring because they were designed to mimic treatment initiation in a neurologist’s office.

Heart rates hit a nadir approximately 4-5 hours after starting fingolimod, and then began to increase, Dr. John DiMarco reported at the annual meeting of the American Academy of Neurology. By 2 weeks after starting therapy, heart rates in the fingolimod groups were almost back to baseline, and thereafter were similar to baseline heart rates in the placebo group. As expected, some tachycardia was seen on interferon therapy.

In the first 6 hours of treatment, the lowest measured heart rate was below 35 beats per minute (bpm) in one patient on fingolimod 1.25 mg/day and one patient on interferon. Heart rates fell to as low as 35-39 bpm in six patients on fingolimod 1.25 mg/day, reported Dr. DiMarco, a cardiologist and professor of medicine at the University of Virginia, Charlottesville.

A heart rate nadir of 40-44 bpm was seen in approximately 1% of the low-dose fingolimod group, 3% of the high-dose fingolimod group, 0.2% of the placebo group, and no patients on interferon. A nadir of 45-54 bpm was measured in 18% on low-dose fingolimod, 29% on high-dose fingolimod, 6% on placebo, and 3% on interferon.

The lowest heart rate was 55-64 bpm in 49% on low-dose fingolimod, 50% on high-dose fingolimod, 37% on placebo, and 33% on interferon. Heart rates never fell below 65 bpm in 32% on low-dose fingolimod, 18% on high-dose fingolimod, 56% on placebo, and 64% on interferon.

Patients could be discharged at the 6-hour follow-up if any slowing in heart rate had started to return toward baseline, the heart rate was at least 55 bpm or greater than 80% of the baseline rate, and the patient had no symptoms related to bradycardia and no new, clinically relevant abnormality on ECG.

Observation beyond the 6-hour period was required in 12% on low-dose fingolimod, 18% on high-dose fingolimod, 3% on placebo, and 1% on interferon. Clinicians chose to hospitalize 2% of patients on fingolimod 0.5 mg/day, 3% of patients on 1.25 mg/day, 0.5% of patients on interferon, and none on placebo.

"Most of these hospitalizations and even the prolonged observations were driven by the study criteria and not by symptoms," Dr. DiMarco noted.

Symptoms of bradycardia were seen in 0.5% of patients on 0.5 mg/day fingolimod, 1% of patients on 1.25 mg/day, and no patients in the other groups. All symptoms were described as mild or moderate in severity.

Conduction abnormalities also were more common within 6 hours of taking low-dose fingolimod (7%) or high-dose fingolimod (13%), compared with placebo or interferon (4% each). First-degree atrioventricular (AV) block was seen in 5% on low-dose fingolimod, 10% on high-dose fingolimod, 2% on placebo, and 3% on interferon. A Wenckebach second-degree AV block was seen in 0.2% on low-dose fingolimod, 0.7% on high-dose fingolimod, and no patients in the other groups. Two patients (0.2%) in the high-dose fingolimod group developed 2:1 second-degree AV block.

One patient in the low-dose fingolimod group and three in the high-dose fingolimod group were treated for heart rate or conduction abnormalities, although two of these patients were asymptomatic. Fingolimod was discontinued after the first dose in 1% of the high-dose group. In the others, the AV conduction changes attenuated with continued therapy and returned to baseline levels by 1 month.

"Most episodes of bradycardia could be managed just with observation. Active intervention was rarely required," Dr. DiMarco said.

The rise in blood pressure on fingolimod was small, but sustained and statistically significant, starting within 2-6 months of treatment initiation. Systolic and diastolic blood pressure increases averaged 1-2 mm Hg on 0.5 mg/day fingolimod and 1-3 mm Hg on 1.25 mg/day fingolimod, compared with the placebo group.

"The significance of these findings is uncertain," he said.

Rates of hypertension adverse events were higher in the fingolimod groups – 4% on the lower dose and 5% on the higher dose – compared with the placebo group (3%) or the interferon group (2%). The proportions of patients who needed antihypertensive therapy, however, were similar between groups: 5% on low-dose fingolimod, 6% on high-dose fingolimod, 6% on placebo, and 4% on interferon.

Patients who were treated responded to standard antihypertensive therapy.

Data for the analysis came from the Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis (FREEDOMS) trial and from the Trial Assessing Injectable Interferon vs. FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS). Both were international, multicenter, randomized double-blind trials.

Both trials excluded patients with moderate to severe cardiovascular disease. At baseline, 3%-4% in each treatment group had a cardiovascular disorder and 5%-7% had hypertension.

The current analysis was funded by Novartis, which markets fingolimod. Dr. DiMarco disclosed financial relationships with Novartis, Medtronic, St. Jude Medical, Astellas, Sanofi-Aventis Pharmaceuticals, and Boston Scientific. His associates in the study have been employees of Novartis, have held stock in the company, or disclosed other financial relationships with Novartis and other pharmaceutical companies.

HONOLULU – The first approved oral medication for multiple sclerosis causes transient reductions in heart rate and atrioventricular conduction and a sustained increase in blood pressure, according to investigators who analyzed pooled data from two phase III trials.

The cohorts from the two phase III clinical trials of fingolimod (Gilenya) for relapsing-remitting muscular sclerosis involved 854 patients treated with the currently approved dosage of fingolimod (0.5 mg/day), 849 patients on a higher dosage (1.25 mg/day), 418 patients on placebo, and 431 patients treated with weekly intramuscular injections of 30 mcg interferon beta-1a (Avonex) for 1-2 years.

The investigators measured vital signs hourly for 6 hours after starting treatment and at quarterly follow-up visits. Patients underwent an ECG before the first dose, 6 hours after treatment initiation, and if they developed symptoms during those 6 hours, as well as at selected follow-up visits. The studies did not use continuous ECG monitoring because they were designed to mimic treatment initiation in a neurologist’s office.

Heart rates hit a nadir approximately 4-5 hours after starting fingolimod, and then began to increase, Dr. John DiMarco reported at the annual meeting of the American Academy of Neurology. By 2 weeks after starting therapy, heart rates in the fingolimod groups were almost back to baseline, and thereafter were similar to baseline heart rates in the placebo group. As expected, some tachycardia was seen on interferon therapy.

In the first 6 hours of treatment, the lowest measured heart rate was below 35 beats per minute (bpm) in one patient on fingolimod 1.25 mg/day and one patient on interferon. Heart rates fell to as low as 35-39 bpm in six patients on fingolimod 1.25 mg/day, reported Dr. DiMarco, a cardiologist and professor of medicine at the University of Virginia, Charlottesville.

A heart rate nadir of 40-44 bpm was seen in approximately 1% of the low-dose fingolimod group, 3% of the high-dose fingolimod group, 0.2% of the placebo group, and no patients on interferon. A nadir of 45-54 bpm was measured in 18% on low-dose fingolimod, 29% on high-dose fingolimod, 6% on placebo, and 3% on interferon.

The lowest heart rate was 55-64 bpm in 49% on low-dose fingolimod, 50% on high-dose fingolimod, 37% on placebo, and 33% on interferon. Heart rates never fell below 65 bpm in 32% on low-dose fingolimod, 18% on high-dose fingolimod, 56% on placebo, and 64% on interferon.

Patients could be discharged at the 6-hour follow-up if any slowing in heart rate had started to return toward baseline, the heart rate was at least 55 bpm or greater than 80% of the baseline rate, and the patient had no symptoms related to bradycardia and no new, clinically relevant abnormality on ECG.

Observation beyond the 6-hour period was required in 12% on low-dose fingolimod, 18% on high-dose fingolimod, 3% on placebo, and 1% on interferon. Clinicians chose to hospitalize 2% of patients on fingolimod 0.5 mg/day, 3% of patients on 1.25 mg/day, 0.5% of patients on interferon, and none on placebo.

"Most of these hospitalizations and even the prolonged observations were driven by the study criteria and not by symptoms," Dr. DiMarco noted.

Symptoms of bradycardia were seen in 0.5% of patients on 0.5 mg/day fingolimod, 1% of patients on 1.25 mg/day, and no patients in the other groups. All symptoms were described as mild or moderate in severity.

Conduction abnormalities also were more common within 6 hours of taking low-dose fingolimod (7%) or high-dose fingolimod (13%), compared with placebo or interferon (4% each). First-degree atrioventricular (AV) block was seen in 5% on low-dose fingolimod, 10% on high-dose fingolimod, 2% on placebo, and 3% on interferon. A Wenckebach second-degree AV block was seen in 0.2% on low-dose fingolimod, 0.7% on high-dose fingolimod, and no patients in the other groups. Two patients (0.2%) in the high-dose fingolimod group developed 2:1 second-degree AV block.

One patient in the low-dose fingolimod group and three in the high-dose fingolimod group were treated for heart rate or conduction abnormalities, although two of these patients were asymptomatic. Fingolimod was discontinued after the first dose in 1% of the high-dose group. In the others, the AV conduction changes attenuated with continued therapy and returned to baseline levels by 1 month.

"Most episodes of bradycardia could be managed just with observation. Active intervention was rarely required," Dr. DiMarco said.

The rise in blood pressure on fingolimod was small, but sustained and statistically significant, starting within 2-6 months of treatment initiation. Systolic and diastolic blood pressure increases averaged 1-2 mm Hg on 0.5 mg/day fingolimod and 1-3 mm Hg on 1.25 mg/day fingolimod, compared with the placebo group.

"The significance of these findings is uncertain," he said.

Rates of hypertension adverse events were higher in the fingolimod groups – 4% on the lower dose and 5% on the higher dose – compared with the placebo group (3%) or the interferon group (2%). The proportions of patients who needed antihypertensive therapy, however, were similar between groups: 5% on low-dose fingolimod, 6% on high-dose fingolimod, 6% on placebo, and 4% on interferon.

Patients who were treated responded to standard antihypertensive therapy.

Data for the analysis came from the Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis (FREEDOMS) trial and from the Trial Assessing Injectable Interferon vs. FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS). Both were international, multicenter, randomized double-blind trials.

Both trials excluded patients with moderate to severe cardiovascular disease. At baseline, 3%-4% in each treatment group had a cardiovascular disorder and 5%-7% had hypertension.

The current analysis was funded by Novartis, which markets fingolimod. Dr. DiMarco disclosed financial relationships with Novartis, Medtronic, St. Jude Medical, Astellas, Sanofi-Aventis Pharmaceuticals, and Boston Scientific. His associates in the study have been employees of Novartis, have held stock in the company, or disclosed other financial relationships with Novartis and other pharmaceutical companies.

HONOLULU – The first approved oral medication for multiple sclerosis causes transient reductions in heart rate and atrioventricular conduction and a sustained increase in blood pressure, according to investigators who analyzed pooled data from two phase III trials.

The cohorts from the two phase III clinical trials of fingolimod (Gilenya) for relapsing-remitting muscular sclerosis involved 854 patients treated with the currently approved dosage of fingolimod (0.5 mg/day), 849 patients on a higher dosage (1.25 mg/day), 418 patients on placebo, and 431 patients treated with weekly intramuscular injections of 30 mcg interferon beta-1a (Avonex) for 1-2 years.

The investigators measured vital signs hourly for 6 hours after starting treatment and at quarterly follow-up visits. Patients underwent an ECG before the first dose, 6 hours after treatment initiation, and if they developed symptoms during those 6 hours, as well as at selected follow-up visits. The studies did not use continuous ECG monitoring because they were designed to mimic treatment initiation in a neurologist’s office.

Heart rates hit a nadir approximately 4-5 hours after starting fingolimod, and then began to increase, Dr. John DiMarco reported at the annual meeting of the American Academy of Neurology. By 2 weeks after starting therapy, heart rates in the fingolimod groups were almost back to baseline, and thereafter were similar to baseline heart rates in the placebo group. As expected, some tachycardia was seen on interferon therapy.

In the first 6 hours of treatment, the lowest measured heart rate was below 35 beats per minute (bpm) in one patient on fingolimod 1.25 mg/day and one patient on interferon. Heart rates fell to as low as 35-39 bpm in six patients on fingolimod 1.25 mg/day, reported Dr. DiMarco, a cardiologist and professor of medicine at the University of Virginia, Charlottesville.

A heart rate nadir of 40-44 bpm was seen in approximately 1% of the low-dose fingolimod group, 3% of the high-dose fingolimod group, 0.2% of the placebo group, and no patients on interferon. A nadir of 45-54 bpm was measured in 18% on low-dose fingolimod, 29% on high-dose fingolimod, 6% on placebo, and 3% on interferon.

The lowest heart rate was 55-64 bpm in 49% on low-dose fingolimod, 50% on high-dose fingolimod, 37% on placebo, and 33% on interferon. Heart rates never fell below 65 bpm in 32% on low-dose fingolimod, 18% on high-dose fingolimod, 56% on placebo, and 64% on interferon.

Patients could be discharged at the 6-hour follow-up if any slowing in heart rate had started to return toward baseline, the heart rate was at least 55 bpm or greater than 80% of the baseline rate, and the patient had no symptoms related to bradycardia and no new, clinically relevant abnormality on ECG.

Observation beyond the 6-hour period was required in 12% on low-dose fingolimod, 18% on high-dose fingolimod, 3% on placebo, and 1% on interferon. Clinicians chose to hospitalize 2% of patients on fingolimod 0.5 mg/day, 3% of patients on 1.25 mg/day, 0.5% of patients on interferon, and none on placebo.

"Most of these hospitalizations and even the prolonged observations were driven by the study criteria and not by symptoms," Dr. DiMarco noted.

Symptoms of bradycardia were seen in 0.5% of patients on 0.5 mg/day fingolimod, 1% of patients on 1.25 mg/day, and no patients in the other groups. All symptoms were described as mild or moderate in severity.

Conduction abnormalities also were more common within 6 hours of taking low-dose fingolimod (7%) or high-dose fingolimod (13%), compared with placebo or interferon (4% each). First-degree atrioventricular (AV) block was seen in 5% on low-dose fingolimod, 10% on high-dose fingolimod, 2% on placebo, and 3% on interferon. A Wenckebach second-degree AV block was seen in 0.2% on low-dose fingolimod, 0.7% on high-dose fingolimod, and no patients in the other groups. Two patients (0.2%) in the high-dose fingolimod group developed 2:1 second-degree AV block.

One patient in the low-dose fingolimod group and three in the high-dose fingolimod group were treated for heart rate or conduction abnormalities, although two of these patients were asymptomatic. Fingolimod was discontinued after the first dose in 1% of the high-dose group. In the others, the AV conduction changes attenuated with continued therapy and returned to baseline levels by 1 month.

"Most episodes of bradycardia could be managed just with observation. Active intervention was rarely required," Dr. DiMarco said.

The rise in blood pressure on fingolimod was small, but sustained and statistically significant, starting within 2-6 months of treatment initiation. Systolic and diastolic blood pressure increases averaged 1-2 mm Hg on 0.5 mg/day fingolimod and 1-3 mm Hg on 1.25 mg/day fingolimod, compared with the placebo group.

"The significance of these findings is uncertain," he said.

Rates of hypertension adverse events were higher in the fingolimod groups – 4% on the lower dose and 5% on the higher dose – compared with the placebo group (3%) or the interferon group (2%). The proportions of patients who needed antihypertensive therapy, however, were similar between groups: 5% on low-dose fingolimod, 6% on high-dose fingolimod, 6% on placebo, and 4% on interferon.

Patients who were treated responded to standard antihypertensive therapy.

Data for the analysis came from the Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis (FREEDOMS) trial and from the Trial Assessing Injectable Interferon vs. FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS). Both were international, multicenter, randomized double-blind trials.

Both trials excluded patients with moderate to severe cardiovascular disease. At baseline, 3%-4% in each treatment group had a cardiovascular disorder and 5%-7% had hypertension.

The current analysis was funded by Novartis, which markets fingolimod. Dr. DiMarco disclosed financial relationships with Novartis, Medtronic, St. Jude Medical, Astellas, Sanofi-Aventis Pharmaceuticals, and Boston Scientific. His associates in the study have been employees of Novartis, have held stock in the company, or disclosed other financial relationships with Novartis and other pharmaceutical companies.

HONOLULU – The first approved oral medication for multiple sclerosis causes transient reductions in heart rate and atrioventricular conduction and a sustained increase in blood pressure, according to investigators who analyzed pooled data from two phase III trials.

The cohorts from the two phase III clinical trials of fingolimod (Gilenya) for relapsing-remitting muscular sclerosis involved 854 patients treated with the currently approved dosage of fingolimod (0.5 mg/day), 849 patients on a higher dosage (1.25 mg/day), 418 patients on placebo, and 431 patients treated with weekly intramuscular injections of 30 mcg interferon beta-1a (Avonex) for 1-2 years.

The investigators measured vital signs hourly for 6 hours after starting treatment and at quarterly follow-up visits. Patients underwent an ECG before the first dose, 6 hours after treatment initiation, and if they developed symptoms during those 6 hours, as well as at selected follow-up visits. The studies did not use continuous ECG monitoring because they were designed to mimic treatment initiation in a neurologist’s office.

Heart rates hit a nadir approximately 4-5 hours after starting fingolimod, and then began to increase, Dr. John DiMarco reported at the annual meeting of the American Academy of Neurology. By 2 weeks after starting therapy, heart rates in the fingolimod groups were almost back to baseline, and thereafter were similar to baseline heart rates in the placebo group. As expected, some tachycardia was seen on interferon therapy.

In the first 6 hours of treatment, the lowest measured heart rate was below 35 beats per minute (bpm) in one patient on fingolimod 1.25 mg/day and one patient on interferon. Heart rates fell to as low as 35-39 bpm in six patients on fingolimod 1.25 mg/day, reported Dr. DiMarco, a cardiologist and professor of medicine at the University of Virginia, Charlottesville.

A heart rate nadir of 40-44 bpm was seen in approximately 1% of the low-dose fingolimod group, 3% of the high-dose fingolimod group, 0.2% of the placebo group, and no patients on interferon. A nadir of 45-54 bpm was measured in 18% on low-dose fingolimod, 29% on high-dose fingolimod, 6% on placebo, and 3% on interferon.

The lowest heart rate was 55-64 bpm in 49% on low-dose fingolimod, 50% on high-dose fingolimod, 37% on placebo, and 33% on interferon. Heart rates never fell below 65 bpm in 32% on low-dose fingolimod, 18% on high-dose fingolimod, 56% on placebo, and 64% on interferon.

Patients could be discharged at the 6-hour follow-up if any slowing in heart rate had started to return toward baseline, the heart rate was at least 55 bpm or greater than 80% of the baseline rate, and the patient had no symptoms related to bradycardia and no new, clinically relevant abnormality on ECG.

Observation beyond the 6-hour period was required in 12% on low-dose fingolimod, 18% on high-dose fingolimod, 3% on placebo, and 1% on interferon. Clinicians chose to hospitalize 2% of patients on fingolimod 0.5 mg/day, 3% of patients on 1.25 mg/day, 0.5% of patients on interferon, and none on placebo.

"Most of these hospitalizations and even the prolonged observations were driven by the study criteria and not by symptoms," Dr. DiMarco noted.

Symptoms of bradycardia were seen in 0.5% of patients on 0.5 mg/day fingolimod, 1% of patients on 1.25 mg/day, and no patients in the other groups. All symptoms were described as mild or moderate in severity.

Conduction abnormalities also were more common within 6 hours of taking low-dose fingolimod (7%) or high-dose fingolimod (13%), compared with placebo or interferon (4% each). First-degree atrioventricular (AV) block was seen in 5% on low-dose fingolimod, 10% on high-dose fingolimod, 2% on placebo, and 3% on interferon. A Wenckebach second-degree AV block was seen in 0.2% on low-dose fingolimod, 0.7% on high-dose fingolimod, and no patients in the other groups. Two patients (0.2%) in the high-dose fingolimod group developed 2:1 second-degree AV block.

One patient in the low-dose fingolimod group and three in the high-dose fingolimod group were treated for heart rate or conduction abnormalities, although two of these patients were asymptomatic. Fingolimod was discontinued after the first dose in 1% of the high-dose group. In the others, the AV conduction changes attenuated with continued therapy and returned to baseline levels by 1 month.

"Most episodes of bradycardia could be managed just with observation. Active intervention was rarely required," Dr. DiMarco said.

The rise in blood pressure on fingolimod was small, but sustained and statistically significant, starting within 2-6 months of treatment initiation. Systolic and diastolic blood pressure increases averaged 1-2 mm Hg on 0.5 mg/day fingolimod and 1-3 mm Hg on 1.25 mg/day fingolimod, compared with the placebo group.

"The significance of these findings is uncertain," he said.

Rates of hypertension adverse events were higher in the fingolimod groups – 4% on the lower dose and 5% on the higher dose – compared with the placebo group (3%) or the interferon group (2%). The proportions of patients who needed antihypertensive therapy, however, were similar between groups: 5% on low-dose fingolimod, 6% on high-dose fingolimod, 6% on placebo, and 4% on interferon.

Patients who were treated responded to standard antihypertensive therapy.

Data for the analysis came from the Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis (FREEDOMS) trial and from the Trial Assessing Injectable Interferon vs. FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS). Both were international, multicenter, randomized double-blind trials.

Both trials excluded patients with moderate to severe cardiovascular disease. At baseline, 3%-4% in each treatment group had a cardiovascular disorder and 5%-7% had hypertension.

The current analysis was funded by Novartis, which markets fingolimod. Dr. DiMarco disclosed financial relationships with Novartis, Medtronic, St. Jude Medical, Astellas, Sanofi-Aventis Pharmaceuticals, and Boston Scientific. His associates in the study have been employees of Novartis, have held stock in the company, or disclosed other financial relationships with Novartis and other pharmaceutical companies.

HONOLULU – Nutritional assessments of 210 consecutive patients with Parkinson’s disease found malnutrition, weight loss, dysphagia, constipation, and other reasons for dietary treatment in high proportions of patients.

The assessments of patients who were admitted to the Parkinson Institute at Istituti Clinici di Perfezionamento, Milan, showed that 75% were taking levodopa (average dose 509 mg/day). The investigators prescribed a low-protein lunch to these patients and advised them to take their medications 30 minutes before meals to improve levodopa absorption, Dr. Michela Barichella and her associates reported in a poster presentation at the annual meeting of the American Academy of Neurology.

Postprandial motor blocks caused by protein’s interference with levodopa absorption occurred in 32% of the patients. They were prescribed low-protein products, according to Dr. Barichella, a neurologist at the institute.

The patients’ mean body mass index was 27 kg/m². By using the Malnutrition Universal Screening Tool, Dr. Barichella and her colleagues found moderate to severe malnutrition in 10%, and 4% of patients reported losing more than 10% of their weight in the previous 6 months. The investigators prescribed high-calorie, low-protein oral supplements to patients with malnourishment or rapid weight loss.

Constipation in 59% of the patients was treated with soluble fiber supplements.

For the 28% of patients with fluids-related dysphagia, the investigators prescribed fluid thickeners. Another 11% who had general dysphagia were told to follow a semisolid dietary regimen.

Complete nutritional status assessments are recommended as part of a multidisciplinary approach to Parkinson’s disease, the investigators noted. Validated diagnostic scales are available for early diagnosis and monitoring of dysphagia and constipation.

The findings suggest that dysphagia for solids and liquids is a common, dangerous, and often undetected condition in patients with Parkinson’s disease that can be managed by dietary measures, the investigators concluded.

Dr. Barichella and her associates reported having no relevant conflicts of interest.

HONOLULU – Nutritional assessments of 210 consecutive patients with Parkinson’s disease found malnutrition, weight loss, dysphagia, constipation, and other reasons for dietary treatment in high proportions of patients.

The assessments of patients who were admitted to the Parkinson Institute at Istituti Clinici di Perfezionamento, Milan, showed that 75% were taking levodopa (average dose 509 mg/day). The investigators prescribed a low-protein lunch to these patients and advised them to take their medications 30 minutes before meals to improve levodopa absorption, Dr. Michela Barichella and her associates reported in a poster presentation at the annual meeting of the American Academy of Neurology.

Postprandial motor blocks caused by protein’s interference with levodopa absorption occurred in 32% of the patients. They were prescribed low-protein products, according to Dr. Barichella, a neurologist at the institute.

The patients’ mean body mass index was 27 kg/m². By using the Malnutrition Universal Screening Tool, Dr. Barichella and her colleagues found moderate to severe malnutrition in 10%, and 4% of patients reported losing more than 10% of their weight in the previous 6 months. The investigators prescribed high-calorie, low-protein oral supplements to patients with malnourishment or rapid weight loss.

Constipation in 59% of the patients was treated with soluble fiber supplements.

For the 28% of patients with fluids-related dysphagia, the investigators prescribed fluid thickeners. Another 11% who had general dysphagia were told to follow a semisolid dietary regimen.

Complete nutritional status assessments are recommended as part of a multidisciplinary approach to Parkinson’s disease, the investigators noted. Validated diagnostic scales are available for early diagnosis and monitoring of dysphagia and constipation.

The findings suggest that dysphagia for solids and liquids is a common, dangerous, and often undetected condition in patients with Parkinson’s disease that can be managed by dietary measures, the investigators concluded.

Dr. Barichella and her associates reported having no relevant conflicts of interest.

HONOLULU – Nutritional assessments of 210 consecutive patients with Parkinson’s disease found malnutrition, weight loss, dysphagia, constipation, and other reasons for dietary treatment in high proportions of patients.

The assessments of patients who were admitted to the Parkinson Institute at Istituti Clinici di Perfezionamento, Milan, showed that 75% were taking levodopa (average dose 509 mg/day). The investigators prescribed a low-protein lunch to these patients and advised them to take their medications 30 minutes before meals to improve levodopa absorption, Dr. Michela Barichella and her associates reported in a poster presentation at the annual meeting of the American Academy of Neurology.

Postprandial motor blocks caused by protein’s interference with levodopa absorption occurred in 32% of the patients. They were prescribed low-protein products, according to Dr. Barichella, a neurologist at the institute.

The patients’ mean body mass index was 27 kg/m². By using the Malnutrition Universal Screening Tool, Dr. Barichella and her colleagues found moderate to severe malnutrition in 10%, and 4% of patients reported losing more than 10% of their weight in the previous 6 months. The investigators prescribed high-calorie, low-protein oral supplements to patients with malnourishment or rapid weight loss.

Constipation in 59% of the patients was treated with soluble fiber supplements.

For the 28% of patients with fluids-related dysphagia, the investigators prescribed fluid thickeners. Another 11% who had general dysphagia were told to follow a semisolid dietary regimen.

Complete nutritional status assessments are recommended as part of a multidisciplinary approach to Parkinson’s disease, the investigators noted. Validated diagnostic scales are available for early diagnosis and monitoring of dysphagia and constipation.

The findings suggest that dysphagia for solids and liquids is a common, dangerous, and often undetected condition in patients with Parkinson’s disease that can be managed by dietary measures, the investigators concluded.

Dr. Barichella and her associates reported having no relevant conflicts of interest.

HONOLULU – Nutritional assessments of 210 consecutive patients with Parkinson’s disease found malnutrition, weight loss, dysphagia, constipation, and other reasons for dietary treatment in high proportions of patients.

The assessments of patients who were admitted to the Parkinson Institute at Istituti Clinici di Perfezionamento, Milan, showed that 75% were taking levodopa (average dose 509 mg/day). The investigators prescribed a low-protein lunch to these patients and advised them to take their medications 30 minutes before meals to improve levodopa absorption, Dr. Michela Barichella and her associates reported in a poster presentation at the annual meeting of the American Academy of Neurology.

Postprandial motor blocks caused by protein’s interference with levodopa absorption occurred in 32% of the patients. They were prescribed low-protein products, according to Dr. Barichella, a neurologist at the institute.

The patients’ mean body mass index was 27 kg/m². By using the Malnutrition Universal Screening Tool, Dr. Barichella and her colleagues found moderate to severe malnutrition in 10%, and 4% of patients reported losing more than 10% of their weight in the previous 6 months. The investigators prescribed high-calorie, low-protein oral supplements to patients with malnourishment or rapid weight loss.

Constipation in 59% of the patients was treated with soluble fiber supplements.

For the 28% of patients with fluids-related dysphagia, the investigators prescribed fluid thickeners. Another 11% who had general dysphagia were told to follow a semisolid dietary regimen.

Complete nutritional status assessments are recommended as part of a multidisciplinary approach to Parkinson’s disease, the investigators noted. Validated diagnostic scales are available for early diagnosis and monitoring of dysphagia and constipation.

The findings suggest that dysphagia for solids and liquids is a common, dangerous, and often undetected condition in patients with Parkinson’s disease that can be managed by dietary measures, the investigators concluded.

Dr. Barichella and her associates reported having no relevant conflicts of interest.

HONOLULU – Nutritional assessments of 210 consecutive patients with Parkinson’s disease found malnutrition, weight loss, dysphagia, constipation, and other reasons for dietary treatment in high proportions of patients.

The assessments of patients who were admitted to the Parkinson Institute at Istituti Clinici di Perfezionamento, Milan, showed that 75% were taking levodopa (average dose 509 mg/day). The investigators prescribed a low-protein lunch to these patients and advised them to take their medications 30 minutes before meals to improve levodopa absorption, Dr. Michela Barichella and her associates reported in a poster presentation at the annual meeting of the American Academy of Neurology.

Postprandial motor blocks caused by protein’s interference with levodopa absorption occurred in 32% of the patients. They were prescribed low-protein products, according to Dr. Barichella, a neurologist at the institute.

The patients’ mean body mass index was 27 kg/m². By using the Malnutrition Universal Screening Tool, Dr. Barichella and her colleagues found moderate to severe malnutrition in 10%, and 4% of patients reported losing more than 10% of their weight in the previous 6 months. The investigators prescribed high-calorie, low-protein oral supplements to patients with malnourishment or rapid weight loss.

Constipation in 59% of the patients was treated with soluble fiber supplements.

For the 28% of patients with fluids-related dysphagia, the investigators prescribed fluid thickeners. Another 11% who had general dysphagia were told to follow a semisolid dietary regimen.

Complete nutritional status assessments are recommended as part of a multidisciplinary approach to Parkinson’s disease, the investigators noted. Validated diagnostic scales are available for early diagnosis and monitoring of dysphagia and constipation.

The findings suggest that dysphagia for solids and liquids is a common, dangerous, and often undetected condition in patients with Parkinson’s disease that can be managed by dietary measures, the investigators concluded.

Dr. Barichella and her associates reported having no relevant conflicts of interest.

HONOLULU – Nutritional assessments of 210 consecutive patients with Parkinson’s disease found malnutrition, weight loss, dysphagia, constipation, and other reasons for dietary treatment in high proportions of patients.

The assessments of patients who were admitted to the Parkinson Institute at Istituti Clinici di Perfezionamento, Milan, showed that 75% were taking levodopa (average dose 509 mg/day). The investigators prescribed a low-protein lunch to these patients and advised them to take their medications 30 minutes before meals to improve levodopa absorption, Dr. Michela Barichella and her associates reported in a poster presentation at the annual meeting of the American Academy of Neurology.

Postprandial motor blocks caused by protein’s interference with levodopa absorption occurred in 32% of the patients. They were prescribed low-protein products, according to Dr. Barichella, a neurologist at the institute.

The patients’ mean body mass index was 27 kg/m². By using the Malnutrition Universal Screening Tool, Dr. Barichella and her colleagues found moderate to severe malnutrition in 10%, and 4% of patients reported losing more than 10% of their weight in the previous 6 months. The investigators prescribed high-calorie, low-protein oral supplements to patients with malnourishment or rapid weight loss.

Constipation in 59% of the patients was treated with soluble fiber supplements.

For the 28% of patients with fluids-related dysphagia, the investigators prescribed fluid thickeners. Another 11% who had general dysphagia were told to follow a semisolid dietary regimen.

Complete nutritional status assessments are recommended as part of a multidisciplinary approach to Parkinson’s disease, the investigators noted. Validated diagnostic scales are available for early diagnosis and monitoring of dysphagia and constipation.

The findings suggest that dysphagia for solids and liquids is a common, dangerous, and often undetected condition in patients with Parkinson’s disease that can be managed by dietary measures, the investigators concluded.

Dr. Barichella and her associates reported having no relevant conflicts of interest.

HONOLULU – Nutritional assessments of 210 consecutive patients with Parkinson’s disease found malnutrition, weight loss, dysphagia, constipation, and other reasons for dietary treatment in high proportions of patients.

The assessments of patients who were admitted to the Parkinson Institute at Istituti Clinici di Perfezionamento, Milan, showed that 75% were taking levodopa (average dose 509 mg/day). The investigators prescribed a low-protein lunch to these patients and advised them to take their medications 30 minutes before meals to improve levodopa absorption, Dr. Michela Barichella and her associates reported in a poster presentation at the annual meeting of the American Academy of Neurology.

Postprandial motor blocks caused by protein’s interference with levodopa absorption occurred in 32% of the patients. They were prescribed low-protein products, according to Dr. Barichella, a neurologist at the institute.

The patients’ mean body mass index was 27 kg/m². By using the Malnutrition Universal Screening Tool, Dr. Barichella and her colleagues found moderate to severe malnutrition in 10%, and 4% of patients reported losing more than 10% of their weight in the previous 6 months. The investigators prescribed high-calorie, low-protein oral supplements to patients with malnourishment or rapid weight loss.

Constipation in 59% of the patients was treated with soluble fiber supplements.

For the 28% of patients with fluids-related dysphagia, the investigators prescribed fluid thickeners. Another 11% who had general dysphagia were told to follow a semisolid dietary regimen.

Complete nutritional status assessments are recommended as part of a multidisciplinary approach to Parkinson’s disease, the investigators noted. Validated diagnostic scales are available for early diagnosis and monitoring of dysphagia and constipation.

The findings suggest that dysphagia for solids and liquids is a common, dangerous, and often undetected condition in patients with Parkinson’s disease that can be managed by dietary measures, the investigators concluded.

Dr. Barichella and her associates reported having no relevant conflicts of interest.

HONOLULU – Nutritional assessments of 210 consecutive patients with Parkinson’s disease found malnutrition, weight loss, dysphagia, constipation, and other reasons for dietary treatment in high proportions of patients.

The assessments of patients who were admitted to the Parkinson Institute at Istituti Clinici di Perfezionamento, Milan, showed that 75% were taking levodopa (average dose 509 mg/day). The investigators prescribed a low-protein lunch to these patients and advised them to take their medications 30 minutes before meals to improve levodopa absorption, Dr. Michela Barichella and her associates reported in a poster presentation at the annual meeting of the American Academy of Neurology.

Postprandial motor blocks caused by protein’s interference with levodopa absorption occurred in 32% of the patients. They were prescribed low-protein products, according to Dr. Barichella, a neurologist at the institute.

The patients’ mean body mass index was 27 kg/m². By using the Malnutrition Universal Screening Tool, Dr. Barichella and her colleagues found moderate to severe malnutrition in 10%, and 4% of patients reported losing more than 10% of their weight in the previous 6 months. The investigators prescribed high-calorie, low-protein oral supplements to patients with malnourishment or rapid weight loss.

Constipation in 59% of the patients was treated with soluble fiber supplements.

For the 28% of patients with fluids-related dysphagia, the investigators prescribed fluid thickeners. Another 11% who had general dysphagia were told to follow a semisolid dietary regimen.

Complete nutritional status assessments are recommended as part of a multidisciplinary approach to Parkinson’s disease, the investigators noted. Validated diagnostic scales are available for early diagnosis and monitoring of dysphagia and constipation.

The findings suggest that dysphagia for solids and liquids is a common, dangerous, and often undetected condition in patients with Parkinson’s disease that can be managed by dietary measures, the investigators concluded.

Dr. Barichella and her associates reported having no relevant conflicts of interest.

HONOLULU – Nutritional assessments of 210 consecutive patients with Parkinson’s disease found malnutrition, weight loss, dysphagia, constipation, and other reasons for dietary treatment in high proportions of patients.

The assessments of patients who were admitted to the Parkinson Institute at Istituti Clinici di Perfezionamento, Milan, showed that 75% were taking levodopa (average dose 509 mg/day). The investigators prescribed a low-protein lunch to these patients and advised them to take their medications 30 minutes before meals to improve levodopa absorption, Dr. Michela Barichella and her associates reported in a poster presentation at the annual meeting of the American Academy of Neurology.

Postprandial motor blocks caused by protein’s interference with levodopa absorption occurred in 32% of the patients. They were prescribed low-protein products, according to Dr. Barichella, a neurologist at the institute.

The patients’ mean body mass index was 27 kg/m². By using the Malnutrition Universal Screening Tool, Dr. Barichella and her colleagues found moderate to severe malnutrition in 10%, and 4% of patients reported losing more than 10% of their weight in the previous 6 months. The investigators prescribed high-calorie, low-protein oral supplements to patients with malnourishment or rapid weight loss.

Constipation in 59% of the patients was treated with soluble fiber supplements.

For the 28% of patients with fluids-related dysphagia, the investigators prescribed fluid thickeners. Another 11% who had general dysphagia were told to follow a semisolid dietary regimen.

Complete nutritional status assessments are recommended as part of a multidisciplinary approach to Parkinson’s disease, the investigators noted. Validated diagnostic scales are available for early diagnosis and monitoring of dysphagia and constipation.

The findings suggest that dysphagia for solids and liquids is a common, dangerous, and often undetected condition in patients with Parkinson’s disease that can be managed by dietary measures, the investigators concluded.

Dr. Barichella and her associates reported having no relevant conflicts of interest.

HONOLULU – Results of five diverse studies on the risk of progressive multifocal leukoencephalopathy when using natalizumab to treat multiple sclerosis could change the way clinicians decide how to manage these patients.

In one of five presentations about natalizumab (Tysabri) that were given during one session at the annual meeting of the American Academy of Neurology, researchers confirmed that the presence of anti-JC virus (JCV) antibodies always precedes development of progressive multifocal leukoencephalopathy (PML). As a part of their study, the investigators developed a new assay to identify antibody-negative patients who could be at lower risk for PML when taking natalizumab. Another study looked at using serum natalizumab concentrations to predict the risk of PML.

A separate study found that earlier diagnosis of PML after symptom onset was associated with increased survival. A case presentation of PML presenting only with subacute amotivational syndrome raised questions about the need for more frequent brain MRIs. Another study confirmed that a history of taking an immunosuppressant medication at any point prior to taking natalizumab increased the risk for PML.

Antibodies Precede PML

In samples taken from four large clinical treatment trials, approximately 55% of patients with multiple sclerosis had anti-JCV antibodies, Dr. Meena Subramanyam said. (JCV infection is necessary for the development of PML.) In comparison, anti-JCV antibodies were detected in the blood of 100% of 25 patients who later were diagnosed with PML and from 100% of 39 patients with samples taken at or around the time of PML diagnosis.

"This shows that the PML patients were exposed to the virus prior to natalizumab treatment," Dr. Subramanyam said. She and her associates hold stock in and are employees of Biogen Idec, which comarkets Tysabri with Elan Pharmaceuticals.

In 17 of the 25 patients with blood samples prior to PML diagnosis, additional samples were taken after starting natalizumab. Another 39 patients had samples taken at the time of PML diagnosis or soon after. All were positive for anti-JCV antibodies. Treatment of PML for 17-98 months did not affect anti-JCV antibody positivity, though overall antibody levels fell.

The investigators used a unique two-step enzyme-linked immunosorbent assay to detect antibodies. Biogen Idec and Elan Pharmaceuticals plan to make the assay commercially available in Europe in May 2011 and in the United States soon after that, Dr. Subramanyam said.

Large clinical studies are ongoing to test the utility of anti-JCV antibody status for stratifying the risk of PML in patients given natalizumab for multiple sclerosis.

Serum Concentration Predicts Risk

The risk for PML increases after 2 years or more of natalizumab use, previous data show. A new study of biochemical samples from 207 patients on natalizumab for multiple sclerosis found that plasma concentrations of the drug increase over time, peaking after 20 months of therapy, reported Dr. John F. Foley of the Rocky Mountain Multiple Sclerosis Clinic, Salt Lake City, and his associates.

For comparison, they looked at data from two phase III trials of natalizumab, in which they also found longitudinal increases in mean natalizumab concentrations.

In the current study, samples taken in each 28- to 30-day infusion interval showed a mean 56% increase in drug concentrations over 45 months. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) trial, serum concentrations increased 70% over 30 months. In the Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis (SENTINEL) trial, drug concentrations increased 99% over 30 months.

Theoretically, if elevated natalizumab concentrations are found to be associated with elevated risk for PML, it may be possible to make kinetic manipulations by changing dosing or adjusting infusion intervals to lower the risk for PML, Dr. Foley said. Studies are ongoing to explore this hypothesis.

Higher Survival With Early Diagnosis

Postmarketing data since November 2004 show that 78,800 patients worldwide have taken natalizumab and 102 of these patients developed PML. A study of the first 79 cases of PML found that 63 (80%) were alive in December 2010. Follow-up visits with these survivors ranged from 1 to 29 months since PML diagnosis. In the 16 patients who died, the time from diagnosis to death ranged from 1 to 11 months, reported Dr. Patrick Vermersch of the University of Lille (France) and his associates.

In all cases, natalizumab was stopped when signs or symptoms suggesting PML appeared, and most patients were treated by plasma exchange or immunoadsorption to rapidly remove the drug from circulation.

Compared with the patients who died, survivors were younger when diagnosed with PML, had a shorter time from symptom onset to diagnosis of PML, and had more localized disease on brain MRI. The likelihood of survival was not affected by the duration of natalizumab use or prior use of immunosuppressive therapy.

The median age at diagnosis of PML was 43 years in survivors and 53 years in those who died. The mean time from PML symptom onset to diagnosis was 34 days in survivors and 54 days in those who died. Among 70 patients with brain MRIs, 29 of the survivors (54%) had unilobar PML extensions, compared with 2 (12%) of those who died.

Among the 38 survivors with at least 6 months of follow-up since PML diagnosis, 5 (13%) had mild disability as rated on the Karnofsky Performance Scale, 19 (50%) had moderate disability, and 14 (37%) had severe disability.

The findings suggest that earlier diagnosis through enhanced clinical vigilance and optimal management of PML might improve outcomes, Dr. Vermersch said.

Data on the first 35 confirmed cases of PML will be published in the May issues of the journal Neurology.

PML Presentation Can Be Subtle

PML usually presents as an aggressive disease with symptoms of visual, motor, language, neurobehavioral, and cognitive changes. Seizures also can occur. Dr. Kristen Babinski of New York University and her associates presented a case of PML that presented in a 26-year-old man being treated for multiple sclerosis whose only symptom of PML was subacute amotivational syndrome.

After his 42nd infusion of natalizumab, a brain MRI showed not only signals typical of multiple sclerosis but new abnormalities in the left frontal white matter. The patient’s brother reported that the patient had become depressed, unmotivated, nihilistic, hopeless, and cynical. An ultrasensitive quantitative polymerase chain reaction (PCR) analysis found JCV DNA in the patient’s cerebrospinal fluid. Findings on MR spectroscopy supported a PML diagnosis.

He stopped taking natalizumab and received treatment for PML. Seven months later, brain imaging shows no signs of PML and his cognitive function and mood have improved, Dr. Babinski said. The patient is being treated for multiple sclerosis with daily glatiramer acetate (Copaxone) injections, monthly infusions of IV immunoglobulin, and monthly methylprednisolone infusions, with 4-aminopyridine (Ampyra), mirtazapine (Remeron), and clonazepam for management of symptoms.

The case suggests that recommended yearly brain MRIs in patients on natalizumab are not frequent enough and that ultrasensitive quantitative PCR and MR spectroscopy may be useful to diagnose PML, Dr. Babinski said. Her institution now performs brain MRI every 6 months in these patients, she said.

Immunosuppressant History Is Relevant

A study of postmarketing data from 2,943 patients taking natalizumab for multiple sclerosis in Canada, Europe, and Australia identified no unknown safety concerns and confirmed that the risk for PML increases with longer use of natalizumab and with any prior use of immunosuppressive therapy.

The risk for PML was 0% in patients untreated for multiple sclerosis before starting natalizumab, 0.1% in patients who had taken one or more disease-modifying drugs, and 0.5% in patients previously treated with an immunosuppressive therapy for multiple sclerosis, reported Dr. Helmut Butzkueven of the University of Melbourne and his associates.

Mean annualized relapse rates on natalizumab therapy were lowest in the therapy-naive patients (0.17) and highest in patients with a history of immunosuppressive therapy (0.36) or those who had switched between glatiramer acetate and interferon therapy (0.29). The risk of serious adverse events was 0.3% in the therapy-naive group, 0.9% in patients on one or more disease-modifying drugs when starting natalizumab, and 1.3% in those with a history of immunosuppressive therapy.

The Food and Drug Administration recently updated the natalizumab (Tysabri) label to include new information about the risk for progressive multifocal leukoencephalopathy (PML) associated with use of the drug. Tysabri is approved to treat multiple sclerosis and Crohn’s disease.

The previous label had warned that using an immunosuppressive medication at the same time as Tysabri may increase the risk of developing PML. The label now includes a warning that taking an immunosuppressive drug at any point prior to taking Tysabri increases the risk for PML. The immunosuppressive drugs include mitoxantrone (Novantrone), azathioprine (Imuran), methotrexate, cyclophosphamide (Cytoxan), or mycophenolate (CellCept).

The updated label also includes a new table listing rates of PML by the number of Tysabri infusions.

Biogen Idec and Elan Pharmaceuticals, which comarket Tysabri, funded most of the studies. Except for Dr. Babinski, each of the presenters and some of their coinvestigators disclosed financial associations with Biogen Idec and other pharmaceutical companies.

HONOLULU – Results of five diverse studies on the risk of progressive multifocal leukoencephalopathy when using natalizumab to treat multiple sclerosis could change the way clinicians decide how to manage these patients.

In one of five presentations about natalizumab (Tysabri) that were given during one session at the annual meeting of the American Academy of Neurology, researchers confirmed that the presence of anti-JC virus (JCV) antibodies always precedes development of progressive multifocal leukoencephalopathy (PML). As a part of their study, the investigators developed a new assay to identify antibody-negative patients who could be at lower risk for PML when taking natalizumab. Another study looked at using serum natalizumab concentrations to predict the risk of PML.

A separate study found that earlier diagnosis of PML after symptom onset was associated with increased survival. A case presentation of PML presenting only with subacute amotivational syndrome raised questions about the need for more frequent brain MRIs. Another study confirmed that a history of taking an immunosuppressant medication at any point prior to taking natalizumab increased the risk for PML.

Antibodies Precede PML

In samples taken from four large clinical treatment trials, approximately 55% of patients with multiple sclerosis had anti-JCV antibodies, Dr. Meena Subramanyam said. (JCV infection is necessary for the development of PML.) In comparison, anti-JCV antibodies were detected in the blood of 100% of 25 patients who later were diagnosed with PML and from 100% of 39 patients with samples taken at or around the time of PML diagnosis.

"This shows that the PML patients were exposed to the virus prior to natalizumab treatment," Dr. Subramanyam said. She and her associates hold stock in and are employees of Biogen Idec, which comarkets Tysabri with Elan Pharmaceuticals.

In 17 of the 25 patients with blood samples prior to PML diagnosis, additional samples were taken after starting natalizumab. Another 39 patients had samples taken at the time of PML diagnosis or soon after. All were positive for anti-JCV antibodies. Treatment of PML for 17-98 months did not affect anti-JCV antibody positivity, though overall antibody levels fell.

The investigators used a unique two-step enzyme-linked immunosorbent assay to detect antibodies. Biogen Idec and Elan Pharmaceuticals plan to make the assay commercially available in Europe in May 2011 and in the United States soon after that, Dr. Subramanyam said.

Large clinical studies are ongoing to test the utility of anti-JCV antibody status for stratifying the risk of PML in patients given natalizumab for multiple sclerosis.

Serum Concentration Predicts Risk

The risk for PML increases after 2 years or more of natalizumab use, previous data show. A new study of biochemical samples from 207 patients on natalizumab for multiple sclerosis found that plasma concentrations of the drug increase over time, peaking after 20 months of therapy, reported Dr. John F. Foley of the Rocky Mountain Multiple Sclerosis Clinic, Salt Lake City, and his associates.

For comparison, they looked at data from two phase III trials of natalizumab, in which they also found longitudinal increases in mean natalizumab concentrations.

In the current study, samples taken in each 28- to 30-day infusion interval showed a mean 56% increase in drug concentrations over 45 months. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) trial, serum concentrations increased 70% over 30 months. In the Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis (SENTINEL) trial, drug concentrations increased 99% over 30 months.

Theoretically, if elevated natalizumab concentrations are found to be associated with elevated risk for PML, it may be possible to make kinetic manipulations by changing dosing or adjusting infusion intervals to lower the risk for PML, Dr. Foley said. Studies are ongoing to explore this hypothesis.

Higher Survival With Early Diagnosis

Postmarketing data since November 2004 show that 78,800 patients worldwide have taken natalizumab and 102 of these patients developed PML. A study of the first 79 cases of PML found that 63 (80%) were alive in December 2010. Follow-up visits with these survivors ranged from 1 to 29 months since PML diagnosis. In the 16 patients who died, the time from diagnosis to death ranged from 1 to 11 months, reported Dr. Patrick Vermersch of the University of Lille (France) and his associates.

In all cases, natalizumab was stopped when signs or symptoms suggesting PML appeared, and most patients were treated by plasma exchange or immunoadsorption to rapidly remove the drug from circulation.

Compared with the patients who died, survivors were younger when diagnosed with PML, had a shorter time from symptom onset to diagnosis of PML, and had more localized disease on brain MRI. The likelihood of survival was not affected by the duration of natalizumab use or prior use of immunosuppressive therapy.

The median age at diagnosis of PML was 43 years in survivors and 53 years in those who died. The mean time from PML symptom onset to diagnosis was 34 days in survivors and 54 days in those who died. Among 70 patients with brain MRIs, 29 of the survivors (54%) had unilobar PML extensions, compared with 2 (12%) of those who died.

Among the 38 survivors with at least 6 months of follow-up since PML diagnosis, 5 (13%) had mild disability as rated on the Karnofsky Performance Scale, 19 (50%) had moderate disability, and 14 (37%) had severe disability.

The findings suggest that earlier diagnosis through enhanced clinical vigilance and optimal management of PML might improve outcomes, Dr. Vermersch said.

Data on the first 35 confirmed cases of PML will be published in the May issues of the journal Neurology.

PML Presentation Can Be Subtle

PML usually presents as an aggressive disease with symptoms of visual, motor, language, neurobehavioral, and cognitive changes. Seizures also can occur. Dr. Kristen Babinski of New York University and her associates presented a case of PML that presented in a 26-year-old man being treated for multiple sclerosis whose only symptom of PML was subacute amotivational syndrome.

After his 42nd infusion of natalizumab, a brain MRI showed not only signals typical of multiple sclerosis but new abnormalities in the left frontal white matter. The patient’s brother reported that the patient had become depressed, unmotivated, nihilistic, hopeless, and cynical. An ultrasensitive quantitative polymerase chain reaction (PCR) analysis found JCV DNA in the patient’s cerebrospinal fluid. Findings on MR spectroscopy supported a PML diagnosis.

He stopped taking natalizumab and received treatment for PML. Seven months later, brain imaging shows no signs of PML and his cognitive function and mood have improved, Dr. Babinski said. The patient is being treated for multiple sclerosis with daily glatiramer acetate (Copaxone) injections, monthly infusions of IV immunoglobulin, and monthly methylprednisolone infusions, with 4-aminopyridine (Ampyra), mirtazapine (Remeron), and clonazepam for management of symptoms.

The case suggests that recommended yearly brain MRIs in patients on natalizumab are not frequent enough and that ultrasensitive quantitative PCR and MR spectroscopy may be useful to diagnose PML, Dr. Babinski said. Her institution now performs brain MRI every 6 months in these patients, she said.

Immunosuppressant History Is Relevant

A study of postmarketing data from 2,943 patients taking natalizumab for multiple sclerosis in Canada, Europe, and Australia identified no unknown safety concerns and confirmed that the risk for PML increases with longer use of natalizumab and with any prior use of immunosuppressive therapy.

The risk for PML was 0% in patients untreated for multiple sclerosis before starting natalizumab, 0.1% in patients who had taken one or more disease-modifying drugs, and 0.5% in patients previously treated with an immunosuppressive therapy for multiple sclerosis, reported Dr. Helmut Butzkueven of the University of Melbourne and his associates.

Mean annualized relapse rates on natalizumab therapy were lowest in the therapy-naive patients (0.17) and highest in patients with a history of immunosuppressive therapy (0.36) or those who had switched between glatiramer acetate and interferon therapy (0.29). The risk of serious adverse events was 0.3% in the therapy-naive group, 0.9% in patients on one or more disease-modifying drugs when starting natalizumab, and 1.3% in those with a history of immunosuppressive therapy.

The Food and Drug Administration recently updated the natalizumab (Tysabri) label to include new information about the risk for progressive multifocal leukoencephalopathy (PML) associated with use of the drug. Tysabri is approved to treat multiple sclerosis and Crohn’s disease.

The previous label had warned that using an immunosuppressive medication at the same time as Tysabri may increase the risk of developing PML. The label now includes a warning that taking an immunosuppressive drug at any point prior to taking Tysabri increases the risk for PML. The immunosuppressive drugs include mitoxantrone (Novantrone), azathioprine (Imuran), methotrexate, cyclophosphamide (Cytoxan), or mycophenolate (CellCept).

The updated label also includes a new table listing rates of PML by the number of Tysabri infusions.

Biogen Idec and Elan Pharmaceuticals, which comarket Tysabri, funded most of the studies. Except for Dr. Babinski, each of the presenters and some of their coinvestigators disclosed financial associations with Biogen Idec and other pharmaceutical companies.

HONOLULU – Results of five diverse studies on the risk of progressive multifocal leukoencephalopathy when using natalizumab to treat multiple sclerosis could change the way clinicians decide how to manage these patients.

In one of five presentations about natalizumab (Tysabri) that were given during one session at the annual meeting of the American Academy of Neurology, researchers confirmed that the presence of anti-JC virus (JCV) antibodies always precedes development of progressive multifocal leukoencephalopathy (PML). As a part of their study, the investigators developed a new assay to identify antibody-negative patients who could be at lower risk for PML when taking natalizumab. Another study looked at using serum natalizumab concentrations to predict the risk of PML.

A separate study found that earlier diagnosis of PML after symptom onset was associated with increased survival. A case presentation of PML presenting only with subacute amotivational syndrome raised questions about the need for more frequent brain MRIs. Another study confirmed that a history of taking an immunosuppressant medication at any point prior to taking natalizumab increased the risk for PML.

Antibodies Precede PML

In samples taken from four large clinical treatment trials, approximately 55% of patients with multiple sclerosis had anti-JCV antibodies, Dr. Meena Subramanyam said. (JCV infection is necessary for the development of PML.) In comparison, anti-JCV antibodies were detected in the blood of 100% of 25 patients who later were diagnosed with PML and from 100% of 39 patients with samples taken at or around the time of PML diagnosis.

"This shows that the PML patients were exposed to the virus prior to natalizumab treatment," Dr. Subramanyam said. She and her associates hold stock in and are employees of Biogen Idec, which comarkets Tysabri with Elan Pharmaceuticals.

In 17 of the 25 patients with blood samples prior to PML diagnosis, additional samples were taken after starting natalizumab. Another 39 patients had samples taken at the time of PML diagnosis or soon after. All were positive for anti-JCV antibodies. Treatment of PML for 17-98 months did not affect anti-JCV antibody positivity, though overall antibody levels fell.

The investigators used a unique two-step enzyme-linked immunosorbent assay to detect antibodies. Biogen Idec and Elan Pharmaceuticals plan to make the assay commercially available in Europe in May 2011 and in the United States soon after that, Dr. Subramanyam said.

Large clinical studies are ongoing to test the utility of anti-JCV antibody status for stratifying the risk of PML in patients given natalizumab for multiple sclerosis.

Serum Concentration Predicts Risk

The risk for PML increases after 2 years or more of natalizumab use, previous data show. A new study of biochemical samples from 207 patients on natalizumab for multiple sclerosis found that plasma concentrations of the drug increase over time, peaking after 20 months of therapy, reported Dr. John F. Foley of the Rocky Mountain Multiple Sclerosis Clinic, Salt Lake City, and his associates.

For comparison, they looked at data from two phase III trials of natalizumab, in which they also found longitudinal increases in mean natalizumab concentrations.

In the current study, samples taken in each 28- to 30-day infusion interval showed a mean 56% increase in drug concentrations over 45 months. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) trial, serum concentrations increased 70% over 30 months. In the Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis (SENTINEL) trial, drug concentrations increased 99% over 30 months.

Theoretically, if elevated natalizumab concentrations are found to be associated with elevated risk for PML, it may be possible to make kinetic manipulations by changing dosing or adjusting infusion intervals to lower the risk for PML, Dr. Foley said. Studies are ongoing to explore this hypothesis.

Higher Survival With Early Diagnosis

Postmarketing data since November 2004 show that 78,800 patients worldwide have taken natalizumab and 102 of these patients developed PML. A study of the first 79 cases of PML found that 63 (80%) were alive in December 2010. Follow-up visits with these survivors ranged from 1 to 29 months since PML diagnosis. In the 16 patients who died, the time from diagnosis to death ranged from 1 to 11 months, reported Dr. Patrick Vermersch of the University of Lille (France) and his associates.

In all cases, natalizumab was stopped when signs or symptoms suggesting PML appeared, and most patients were treated by plasma exchange or immunoadsorption to rapidly remove the drug from circulation.

Compared with the patients who died, survivors were younger when diagnosed with PML, had a shorter time from symptom onset to diagnosis of PML, and had more localized disease on brain MRI. The likelihood of survival was not affected by the duration of natalizumab use or prior use of immunosuppressive therapy.

The median age at diagnosis of PML was 43 years in survivors and 53 years in those who died. The mean time from PML symptom onset to diagnosis was 34 days in survivors and 54 days in those who died. Among 70 patients with brain MRIs, 29 of the survivors (54%) had unilobar PML extensions, compared with 2 (12%) of those who died.

Among the 38 survivors with at least 6 months of follow-up since PML diagnosis, 5 (13%) had mild disability as rated on the Karnofsky Performance Scale, 19 (50%) had moderate disability, and 14 (37%) had severe disability.

The findings suggest that earlier diagnosis through enhanced clinical vigilance and optimal management of PML might improve outcomes, Dr. Vermersch said.

Data on the first 35 confirmed cases of PML will be published in the May issues of the journal Neurology.

PML Presentation Can Be Subtle

PML usually presents as an aggressive disease with symptoms of visual, motor, language, neurobehavioral, and cognitive changes. Seizures also can occur. Dr. Kristen Babinski of New York University and her associates presented a case of PML that presented in a 26-year-old man being treated for multiple sclerosis whose only symptom of PML was subacute amotivational syndrome.

After his 42nd infusion of natalizumab, a brain MRI showed not only signals typical of multiple sclerosis but new abnormalities in the left frontal white matter. The patient’s brother reported that the patient had become depressed, unmotivated, nihilistic, hopeless, and cynical. An ultrasensitive quantitative polymerase chain reaction (PCR) analysis found JCV DNA in the patient’s cerebrospinal fluid. Findings on MR spectroscopy supported a PML diagnosis.

He stopped taking natalizumab and received treatment for PML. Seven months later, brain imaging shows no signs of PML and his cognitive function and mood have improved, Dr. Babinski said. The patient is being treated for multiple sclerosis with daily glatiramer acetate (Copaxone) injections, monthly infusions of IV immunoglobulin, and monthly methylprednisolone infusions, with 4-aminopyridine (Ampyra), mirtazapine (Remeron), and clonazepam for management of symptoms.

The case suggests that recommended yearly brain MRIs in patients on natalizumab are not frequent enough and that ultrasensitive quantitative PCR and MR spectroscopy may be useful to diagnose PML, Dr. Babinski said. Her institution now performs brain MRI every 6 months in these patients, she said.

Immunosuppressant History Is Relevant

A study of postmarketing data from 2,943 patients taking natalizumab for multiple sclerosis in Canada, Europe, and Australia identified no unknown safety concerns and confirmed that the risk for PML increases with longer use of natalizumab and with any prior use of immunosuppressive therapy.

The risk for PML was 0% in patients untreated for multiple sclerosis before starting natalizumab, 0.1% in patients who had taken one or more disease-modifying drugs, and 0.5% in patients previously treated with an immunosuppressive therapy for multiple sclerosis, reported Dr. Helmut Butzkueven of the University of Melbourne and his associates.

Mean annualized relapse rates on natalizumab therapy were lowest in the therapy-naive patients (0.17) and highest in patients with a history of immunosuppressive therapy (0.36) or those who had switched between glatiramer acetate and interferon therapy (0.29). The risk of serious adverse events was 0.3% in the therapy-naive group, 0.9% in patients on one or more disease-modifying drugs when starting natalizumab, and 1.3% in those with a history of immunosuppressive therapy.

The Food and Drug Administration recently updated the natalizumab (Tysabri) label to include new information about the risk for progressive multifocal leukoencephalopathy (PML) associated with use of the drug. Tysabri is approved to treat multiple sclerosis and Crohn’s disease.

The previous label had warned that using an immunosuppressive medication at the same time as Tysabri may increase the risk of developing PML. The label now includes a warning that taking an immunosuppressive drug at any point prior to taking Tysabri increases the risk for PML. The immunosuppressive drugs include mitoxantrone (Novantrone), azathioprine (Imuran), methotrexate, cyclophosphamide (Cytoxan), or mycophenolate (CellCept).

The updated label also includes a new table listing rates of PML by the number of Tysabri infusions.

Biogen Idec and Elan Pharmaceuticals, which comarket Tysabri, funded most of the studies. Except for Dr. Babinski, each of the presenters and some of their coinvestigators disclosed financial associations with Biogen Idec and other pharmaceutical companies.

HONOLULU – Results of five diverse studies on the risk of progressive multifocal leukoencephalopathy when using natalizumab to treat multiple sclerosis could change the way clinicians decide how to manage these patients.

In one of five presentations about natalizumab (Tysabri) that were given during one session at the annual meeting of the American Academy of Neurology, researchers confirmed that the presence of anti-JC virus (JCV) antibodies always precedes development of progressive multifocal leukoencephalopathy (PML). As a part of their study, the investigators developed a new assay to identify antibody-negative patients who could be at lower risk for PML when taking natalizumab. Another study looked at using serum natalizumab concentrations to predict the risk of PML.

A separate study found that earlier diagnosis of PML after symptom onset was associated with increased survival. A case presentation of PML presenting only with subacute amotivational syndrome raised questions about the need for more frequent brain MRIs. Another study confirmed that a history of taking an immunosuppressant medication at any point prior to taking natalizumab increased the risk for PML.

Antibodies Precede PML

In samples taken from four large clinical treatment trials, approximately 55% of patients with multiple sclerosis had anti-JCV antibodies, Dr. Meena Subramanyam said. (JCV infection is necessary for the development of PML.) In comparison, anti-JCV antibodies were detected in the blood of 100% of 25 patients who later were diagnosed with PML and from 100% of 39 patients with samples taken at or around the time of PML diagnosis.

"This shows that the PML patients were exposed to the virus prior to natalizumab treatment," Dr. Subramanyam said. She and her associates hold stock in and are employees of Biogen Idec, which comarkets Tysabri with Elan Pharmaceuticals.

In 17 of the 25 patients with blood samples prior to PML diagnosis, additional samples were taken after starting natalizumab. Another 39 patients had samples taken at the time of PML diagnosis or soon after. All were positive for anti-JCV antibodies. Treatment of PML for 17-98 months did not affect anti-JCV antibody positivity, though overall antibody levels fell.

The investigators used a unique two-step enzyme-linked immunosorbent assay to detect antibodies. Biogen Idec and Elan Pharmaceuticals plan to make the assay commercially available in Europe in May 2011 and in the United States soon after that, Dr. Subramanyam said.

Large clinical studies are ongoing to test the utility of anti-JCV antibody status for stratifying the risk of PML in patients given natalizumab for multiple sclerosis.

Serum Concentration Predicts Risk

The risk for PML increases after 2 years or more of natalizumab use, previous data show. A new study of biochemical samples from 207 patients on natalizumab for multiple sclerosis found that plasma concentrations of the drug increase over time, peaking after 20 months of therapy, reported Dr. John F. Foley of the Rocky Mountain Multiple Sclerosis Clinic, Salt Lake City, and his associates.

For comparison, they looked at data from two phase III trials of natalizumab, in which they also found longitudinal increases in mean natalizumab concentrations.

In the current study, samples taken in each 28- to 30-day infusion interval showed a mean 56% increase in drug concentrations over 45 months. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) trial, serum concentrations increased 70% over 30 months. In the Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis (SENTINEL) trial, drug concentrations increased 99% over 30 months.

Theoretically, if elevated natalizumab concentrations are found to be associated with elevated risk for PML, it may be possible to make kinetic manipulations by changing dosing or adjusting infusion intervals to lower the risk for PML, Dr. Foley said. Studies are ongoing to explore this hypothesis.

Higher Survival With Early Diagnosis

Postmarketing data since November 2004 show that 78,800 patients worldwide have taken natalizumab and 102 of these patients developed PML. A study of the first 79 cases of PML found that 63 (80%) were alive in December 2010. Follow-up visits with these survivors ranged from 1 to 29 months since PML diagnosis. In the 16 patients who died, the time from diagnosis to death ranged from 1 to 11 months, reported Dr. Patrick Vermersch of the University of Lille (France) and his associates.

In all cases, natalizumab was stopped when signs or symptoms suggesting PML appeared, and most patients were treated by plasma exchange or immunoadsorption to rapidly remove the drug from circulation.

Compared with the patients who died, survivors were younger when diagnosed with PML, had a shorter time from symptom onset to diagnosis of PML, and had more localized disease on brain MRI. The likelihood of survival was not affected by the duration of natalizumab use or prior use of immunosuppressive therapy.

The median age at diagnosis of PML was 43 years in survivors and 53 years in those who died. The mean time from PML symptom onset to diagnosis was 34 days in survivors and 54 days in those who died. Among 70 patients with brain MRIs, 29 of the survivors (54%) had unilobar PML extensions, compared with 2 (12%) of those who died.

Among the 38 survivors with at least 6 months of follow-up since PML diagnosis, 5 (13%) had mild disability as rated on the Karnofsky Performance Scale, 19 (50%) had moderate disability, and 14 (37%) had severe disability.

The findings suggest that earlier diagnosis through enhanced clinical vigilance and optimal management of PML might improve outcomes, Dr. Vermersch said.

Data on the first 35 confirmed cases of PML will be published in the May issues of the journal Neurology.

PML Presentation Can Be Subtle

PML usually presents as an aggressive disease with symptoms of visual, motor, language, neurobehavioral, and cognitive changes. Seizures also can occur. Dr. Kristen Babinski of New York University and her associates presented a case of PML that presented in a 26-year-old man being treated for multiple sclerosis whose only symptom of PML was subacute amotivational syndrome.

After his 42nd infusion of natalizumab, a brain MRI showed not only signals typical of multiple sclerosis but new abnormalities in the left frontal white matter. The patient’s brother reported that the patient had become depressed, unmotivated, nihilistic, hopeless, and cynical. An ultrasensitive quantitative polymerase chain reaction (PCR) analysis found JCV DNA in the patient’s cerebrospinal fluid. Findings on MR spectroscopy supported a PML diagnosis.

He stopped taking natalizumab and received treatment for PML. Seven months later, brain imaging shows no signs of PML and his cognitive function and mood have improved, Dr. Babinski said. The patient is being treated for multiple sclerosis with daily glatiramer acetate (Copaxone) injections, monthly infusions of IV immunoglobulin, and monthly methylprednisolone infusions, with 4-aminopyridine (Ampyra), mirtazapine (Remeron), and clonazepam for management of symptoms.

The case suggests that recommended yearly brain MRIs in patients on natalizumab are not frequent enough and that ultrasensitive quantitative PCR and MR spectroscopy may be useful to diagnose PML, Dr. Babinski said. Her institution now performs brain MRI every 6 months in these patients, she said.

Immunosuppressant History Is Relevant

A study of postmarketing data from 2,943 patients taking natalizumab for multiple sclerosis in Canada, Europe, and Australia identified no unknown safety concerns and confirmed that the risk for PML increases with longer use of natalizumab and with any prior use of immunosuppressive therapy.

The risk for PML was 0% in patients untreated for multiple sclerosis before starting natalizumab, 0.1% in patients who had taken one or more disease-modifying drugs, and 0.5% in patients previously treated with an immunosuppressive therapy for multiple sclerosis, reported Dr. Helmut Butzkueven of the University of Melbourne and his associates.

Mean annualized relapse rates on natalizumab therapy were lowest in the therapy-naive patients (0.17) and highest in patients with a history of immunosuppressive therapy (0.36) or those who had switched between glatiramer acetate and interferon therapy (0.29). The risk of serious adverse events was 0.3% in the therapy-naive group, 0.9% in patients on one or more disease-modifying drugs when starting natalizumab, and 1.3% in those with a history of immunosuppressive therapy.

The Food and Drug Administration recently updated the natalizumab (Tysabri) label to include new information about the risk for progressive multifocal leukoencephalopathy (PML) associated with use of the drug. Tysabri is approved to treat multiple sclerosis and Crohn’s disease.

The previous label had warned that using an immunosuppressive medication at the same time as Tysabri may increase the risk of developing PML. The label now includes a warning that taking an immunosuppressive drug at any point prior to taking Tysabri increases the risk for PML. The immunosuppressive drugs include mitoxantrone (Novantrone), azathioprine (Imuran), methotrexate, cyclophosphamide (Cytoxan), or mycophenolate (CellCept).

The updated label also includes a new table listing rates of PML by the number of Tysabri infusions.

Biogen Idec and Elan Pharmaceuticals, which comarket Tysabri, funded most of the studies. Except for Dr. Babinski, each of the presenters and some of their coinvestigators disclosed financial associations with Biogen Idec and other pharmaceutical companies.

HONOLULU – Results of five diverse studies on the risk of progressive multifocal leukoencephalopathy when using natalizumab to treat multiple sclerosis could change the way clinicians decide how to manage these patients.

In one of five presentations about natalizumab (Tysabri) that were given during one session at the annual meeting of the American Academy of Neurology, researchers confirmed that the presence of anti-JC virus (JCV) antibodies always precedes development of progressive multifocal leukoencephalopathy (PML). As a part of their study, the investigators developed a new assay to identify antibody-negative patients who could be at lower risk for PML when taking natalizumab. Another study looked at using serum natalizumab concentrations to predict the risk of PML.

A separate study found that earlier diagnosis of PML after symptom onset was associated with increased survival. A case presentation of PML presenting only with subacute amotivational syndrome raised questions about the need for more frequent brain MRIs. Another study confirmed that a history of taking an immunosuppressant medication at any point prior to taking natalizumab increased the risk for PML.

Antibodies Precede PML

In samples taken from four large clinical treatment trials, approximately 55% of patients with multiple sclerosis had anti-JCV antibodies, Dr. Meena Subramanyam said. (JCV infection is necessary for the development of PML.) In comparison, anti-JCV antibodies were detected in the blood of 100% of 25 patients who later were diagnosed with PML and from 100% of 39 patients with samples taken at or around the time of PML diagnosis.

"This shows that the PML patients were exposed to the virus prior to natalizumab treatment," Dr. Subramanyam said. She and her associates hold stock in and are employees of Biogen Idec, which comarkets Tysabri with Elan Pharmaceuticals.

In 17 of the 25 patients with blood samples prior to PML diagnosis, additional samples were taken after starting natalizumab. Another 39 patients had samples taken at the time of PML diagnosis or soon after. All were positive for anti-JCV antibodies. Treatment of PML for 17-98 months did not affect anti-JCV antibody positivity, though overall antibody levels fell.

The investigators used a unique two-step enzyme-linked immunosorbent assay to detect antibodies. Biogen Idec and Elan Pharmaceuticals plan to make the assay commercially available in Europe in May 2011 and in the United States soon after that, Dr. Subramanyam said.

Large clinical studies are ongoing to test the utility of anti-JCV antibody status for stratifying the risk of PML in patients given natalizumab for multiple sclerosis.

Serum Concentration Predicts Risk

The risk for PML increases after 2 years or more of natalizumab use, previous data show. A new study of biochemical samples from 207 patients on natalizumab for multiple sclerosis found that plasma concentrations of the drug increase over time, peaking after 20 months of therapy, reported Dr. John F. Foley of the Rocky Mountain Multiple Sclerosis Clinic, Salt Lake City, and his associates.

For comparison, they looked at data from two phase III trials of natalizumab, in which they also found longitudinal increases in mean natalizumab concentrations.

In the current study, samples taken in each 28- to 30-day infusion interval showed a mean 56% increase in drug concentrations over 45 months. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) trial, serum concentrations increased 70% over 30 months. In the Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis (SENTINEL) trial, drug concentrations increased 99% over 30 months.

Theoretically, if elevated natalizumab concentrations are found to be associated with elevated risk for PML, it may be possible to make kinetic manipulations by changing dosing or adjusting infusion intervals to lower the risk for PML, Dr. Foley said. Studies are ongoing to explore this hypothesis.

Higher Survival With Early Diagnosis

Postmarketing data since November 2004 show that 78,800 patients worldwide have taken natalizumab and 102 of these patients developed PML. A study of the first 79 cases of PML found that 63 (80%) were alive in December 2010. Follow-up visits with these survivors ranged from 1 to 29 months since PML diagnosis. In the 16 patients who died, the time from diagnosis to death ranged from 1 to 11 months, reported Dr. Patrick Vermersch of the University of Lille (France) and his associates.

In all cases, natalizumab was stopped when signs or symptoms suggesting PML appeared, and most patients were treated by plasma exchange or immunoadsorption to rapidly remove the drug from circulation.

Compared with the patients who died, survivors were younger when diagnosed with PML, had a shorter time from symptom onset to diagnosis of PML, and had more localized disease on brain MRI. The likelihood of survival was not affected by the duration of natalizumab use or prior use of immunosuppressive therapy.

The median age at diagnosis of PML was 43 years in survivors and 53 years in those who died. The mean time from PML symptom onset to diagnosis was 34 days in survivors and 54 days in those who died. Among 70 patients with brain MRIs, 29 of the survivors (54%) had unilobar PML extensions, compared with 2 (12%) of those who died.

Among the 38 survivors with at least 6 months of follow-up since PML diagnosis, 5 (13%) had mild disability as rated on the Karnofsky Performance Scale, 19 (50%) had moderate disability, and 14 (37%) had severe disability.

The findings suggest that earlier diagnosis through enhanced clinical vigilance and optimal management of PML might improve outcomes, Dr. Vermersch said.

Data on the first 35 confirmed cases of PML will be published in the May issues of the journal Neurology.

PML Presentation Can Be Subtle

PML usually presents as an aggressive disease with symptoms of visual, motor, language, neurobehavioral, and cognitive changes. Seizures also can occur. Dr. Kristen Babinski of New York University and her associates presented a case of PML that presented in a 26-year-old man being treated for multiple sclerosis whose only symptom of PML was subacute amotivational syndrome.

After his 42nd infusion of natalizumab, a brain MRI showed not only signals typical of multiple sclerosis but new abnormalities in the left frontal white matter. The patient’s brother reported that the patient had become depressed, unmotivated, nihilistic, hopeless, and cynical. An ultrasensitive quantitative polymerase chain reaction (PCR) analysis found JCV DNA in the patient’s cerebrospinal fluid. Findings on MR spectroscopy supported a PML diagnosis.

He stopped taking natalizumab and received treatment for PML. Seven months later, brain imaging shows no signs of PML and his cognitive function and mood have improved, Dr. Babinski said. The patient is being treated for multiple sclerosis with daily glatiramer acetate (Copaxone) injections, monthly infusions of IV immunoglobulin, and monthly methylprednisolone infusions, with 4-aminopyridine (Ampyra), mirtazapine (Remeron), and clonazepam for management of symptoms.

The case suggests that recommended yearly brain MRIs in patients on natalizumab are not frequent enough and that ultrasensitive quantitative PCR and MR spectroscopy may be useful to diagnose PML, Dr. Babinski said. Her institution now performs brain MRI every 6 months in these patients, she said.

Immunosuppressant History Is Relevant

A study of postmarketing data from 2,943 patients taking natalizumab for multiple sclerosis in Canada, Europe, and Australia identified no unknown safety concerns and confirmed that the risk for PML increases with longer use of natalizumab and with any prior use of immunosuppressive therapy.

The risk for PML was 0% in patients untreated for multiple sclerosis before starting natalizumab, 0.1% in patients who had taken one or more disease-modifying drugs, and 0.5% in patients previously treated with an immunosuppressive therapy for multiple sclerosis, reported Dr. Helmut Butzkueven of the University of Melbourne and his associates.

Mean annualized relapse rates on natalizumab therapy were lowest in the therapy-naive patients (0.17) and highest in patients with a history of immunosuppressive therapy (0.36) or those who had switched between glatiramer acetate and interferon therapy (0.29). The risk of serious adverse events was 0.3% in the therapy-naive group, 0.9% in patients on one or more disease-modifying drugs when starting natalizumab, and 1.3% in those with a history of immunosuppressive therapy.

The Food and Drug Administration recently updated the natalizumab (Tysabri) label to include new information about the risk for progressive multifocal leukoencephalopathy (PML) associated with use of the drug. Tysabri is approved to treat multiple sclerosis and Crohn’s disease.

The previous label had warned that using an immunosuppressive medication at the same time as Tysabri may increase the risk of developing PML. The label now includes a warning that taking an immunosuppressive drug at any point prior to taking Tysabri increases the risk for PML. The immunosuppressive drugs include mitoxantrone (Novantrone), azathioprine (Imuran), methotrexate, cyclophosphamide (Cytoxan), or mycophenolate (CellCept).

The updated label also includes a new table listing rates of PML by the number of Tysabri infusions.

Biogen Idec and Elan Pharmaceuticals, which comarket Tysabri, funded most of the studies. Except for Dr. Babinski, each of the presenters and some of their coinvestigators disclosed financial associations with Biogen Idec and other pharmaceutical companies.

HONOLULU – Results of five diverse studies on the risk of progressive multifocal leukoencephalopathy when using natalizumab to treat multiple sclerosis could change the way clinicians decide how to manage these patients.

In one of five presentations about natalizumab (Tysabri) that were given during one session at the annual meeting of the American Academy of Neurology, researchers confirmed that the presence of anti-JC virus (JCV) antibodies always precedes development of progressive multifocal leukoencephalopathy (PML). As a part of their study, the investigators developed a new assay to identify antibody-negative patients who could be at lower risk for PML when taking natalizumab. Another study looked at using serum natalizumab concentrations to predict the risk of PML.

A separate study found that earlier diagnosis of PML after symptom onset was associated with increased survival. A case presentation of PML presenting only with subacute amotivational syndrome raised questions about the need for more frequent brain MRIs. Another study confirmed that a history of taking an immunosuppressant medication at any point prior to taking natalizumab increased the risk for PML.

Antibodies Precede PML

In samples taken from four large clinical treatment trials, approximately 55% of patients with multiple sclerosis had anti-JCV antibodies, Dr. Meena Subramanyam said. (JCV infection is necessary for the development of PML.) In comparison, anti-JCV antibodies were detected in the blood of 100% of 25 patients who later were diagnosed with PML and from 100% of 39 patients with samples taken at or around the time of PML diagnosis.

"This shows that the PML patients were exposed to the virus prior to natalizumab treatment," Dr. Subramanyam said. She and her associates hold stock in and are employees of Biogen Idec, which comarkets Tysabri with Elan Pharmaceuticals.

In 17 of the 25 patients with blood samples prior to PML diagnosis, additional samples were taken after starting natalizumab. Another 39 patients had samples taken at the time of PML diagnosis or soon after. All were positive for anti-JCV antibodies. Treatment of PML for 17-98 months did not affect anti-JCV antibody positivity, though overall antibody levels fell.

The investigators used a unique two-step enzyme-linked immunosorbent assay to detect antibodies. Biogen Idec and Elan Pharmaceuticals plan to make the assay commercially available in Europe in May 2011 and in the United States soon after that, Dr. Subramanyam said.

Large clinical studies are ongoing to test the utility of anti-JCV antibody status for stratifying the risk of PML in patients given natalizumab for multiple sclerosis.

Serum Concentration Predicts Risk

The risk for PML increases after 2 years or more of natalizumab use, previous data show. A new study of biochemical samples from 207 patients on natalizumab for multiple sclerosis found that plasma concentrations of the drug increase over time, peaking after 20 months of therapy, reported Dr. John F. Foley of the Rocky Mountain Multiple Sclerosis Clinic, Salt Lake City, and his associates.

For comparison, they looked at data from two phase III trials of natalizumab, in which they also found longitudinal increases in mean natalizumab concentrations.

In the current study, samples taken in each 28- to 30-day infusion interval showed a mean 56% increase in drug concentrations over 45 months. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) trial, serum concentrations increased 70% over 30 months. In the Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis (SENTINEL) trial, drug concentrations increased 99% over 30 months.

Theoretically, if elevated natalizumab concentrations are found to be associated with elevated risk for PML, it may be possible to make kinetic manipulations by changing dosing or adjusting infusion intervals to lower the risk for PML, Dr. Foley said. Studies are ongoing to explore this hypothesis.

Higher Survival With Early Diagnosis

Postmarketing data since November 2004 show that 78,800 patients worldwide have taken natalizumab and 102 of these patients developed PML. A study of the first 79 cases of PML found that 63 (80%) were alive in December 2010. Follow-up visits with these survivors ranged from 1 to 29 months since PML diagnosis. In the 16 patients who died, the time from diagnosis to death ranged from 1 to 11 months, reported Dr. Patrick Vermersch of the University of Lille (France) and his associates.

In all cases, natalizumab was stopped when signs or symptoms suggesting PML appeared, and most patients were treated by plasma exchange or immunoadsorption to rapidly remove the drug from circulation.

Compared with the patients who died, survivors were younger when diagnosed with PML, had a shorter time from symptom onset to diagnosis of PML, and had more localized disease on brain MRI. The likelihood of survival was not affected by the duration of natalizumab use or prior use of immunosuppressive therapy.

The median age at diagnosis of PML was 43 years in survivors and 53 years in those who died. The mean time from PML symptom onset to diagnosis was 34 days in survivors and 54 days in those who died. Among 70 patients with brain MRIs, 29 of the survivors (54%) had unilobar PML extensions, compared with 2 (12%) of those who died.

Among the 38 survivors with at least 6 months of follow-up since PML diagnosis, 5 (13%) had mild disability as rated on the Karnofsky Performance Scale, 19 (50%) had moderate disability, and 14 (37%) had severe disability.

The findings suggest that earlier diagnosis through enhanced clinical vigilance and optimal management of PML might improve outcomes, Dr. Vermersch said.

Data on the first 35 confirmed cases of PML will be published in the May issues of the journal Neurology.

PML Presentation Can Be Subtle

PML usually presents as an aggressive disease with symptoms of visual, motor, language, neurobehavioral, and cognitive changes. Seizures also can occur. Dr. Kristen Babinski of New York University and her associates presented a case of PML that presented in a 26-year-old man being treated for multiple sclerosis whose only symptom of PML was subacute amotivational syndrome.

After his 42nd infusion of natalizumab, a brain MRI showed not only signals typical of multiple sclerosis but new abnormalities in the left frontal white matter. The patient’s brother reported that the patient had become depressed, unmotivated, nihilistic, hopeless, and cynical. An ultrasensitive quantitative polymerase chain reaction (PCR) analysis found JCV DNA in the patient’s cerebrospinal fluid. Findings on MR spectroscopy supported a PML diagnosis.

He stopped taking natalizumab and received treatment for PML. Seven months later, brain imaging shows no signs of PML and his cognitive function and mood have improved, Dr. Babinski said. The patient is being treated for multiple sclerosis with daily glatiramer acetate (Copaxone) injections, monthly infusions of IV immunoglobulin, and monthly methylprednisolone infusions, with 4-aminopyridine (Ampyra), mirtazapine (Remeron), and clonazepam for management of symptoms.

The case suggests that recommended yearly brain MRIs in patients on natalizumab are not frequent enough and that ultrasensitive quantitative PCR and MR spectroscopy may be useful to diagnose PML, Dr. Babinski said. Her institution now performs brain MRI every 6 months in these patients, she said.

Immunosuppressant History Is Relevant

A study of postmarketing data from 2,943 patients taking natalizumab for multiple sclerosis in Canada, Europe, and Australia identified no unknown safety concerns and confirmed that the risk for PML increases with longer use of natalizumab and with any prior use of immunosuppressive therapy.

The risk for PML was 0% in patients untreated for multiple sclerosis before starting natalizumab, 0.1% in patients who had taken one or more disease-modifying drugs, and 0.5% in patients previously treated with an immunosuppressive therapy for multiple sclerosis, reported Dr. Helmut Butzkueven of the University of Melbourne and his associates.

Mean annualized relapse rates on natalizumab therapy were lowest in the therapy-naive patients (0.17) and highest in patients with a history of immunosuppressive therapy (0.36) or those who had switched between glatiramer acetate and interferon therapy (0.29). The risk of serious adverse events was 0.3% in the therapy-naive group, 0.9% in patients on one or more disease-modifying drugs when starting natalizumab, and 1.3% in those with a history of immunosuppressive therapy.

The Food and Drug Administration recently updated the natalizumab (Tysabri) label to include new information about the risk for progressive multifocal leukoencephalopathy (PML) associated with use of the drug. Tysabri is approved to treat multiple sclerosis and Crohn’s disease.

The previous label had warned that using an immunosuppressive medication at the same time as Tysabri may increase the risk of developing PML. The label now includes a warning that taking an immunosuppressive drug at any point prior to taking Tysabri increases the risk for PML. The immunosuppressive drugs include mitoxantrone (Novantrone), azathioprine (Imuran), methotrexate, cyclophosphamide (Cytoxan), or mycophenolate (CellCept).

The updated label also includes a new table listing rates of PML by the number of Tysabri infusions.

Biogen Idec and Elan Pharmaceuticals, which comarket Tysabri, funded most of the studies. Except for Dr. Babinski, each of the presenters and some of their coinvestigators disclosed financial associations with Biogen Idec and other pharmaceutical companies.

HONOLULU – Results of five diverse studies on the risk of progressive multifocal leukoencephalopathy when using natalizumab to treat multiple sclerosis could change the way clinicians decide how to manage these patients.

In one of five presentations about natalizumab (Tysabri) that were given during one session at the annual meeting of the American Academy of Neurology, researchers confirmed that the presence of anti-JC virus (JCV) antibodies always precedes development of progressive multifocal leukoencephalopathy (PML). As a part of their study, the investigators developed a new assay to identify antibody-negative patients who could be at lower risk for PML when taking natalizumab. Another study looked at using serum natalizumab concentrations to predict the risk of PML.

A separate study found that earlier diagnosis of PML after symptom onset was associated with increased survival. A case presentation of PML presenting only with subacute amotivational syndrome raised questions about the need for more frequent brain MRIs. Another study confirmed that a history of taking an immunosuppressant medication at any point prior to taking natalizumab increased the risk for PML.

Antibodies Precede PML

In samples taken from four large clinical treatment trials, approximately 55% of patients with multiple sclerosis had anti-JCV antibodies, Dr. Meena Subramanyam said. (JCV infection is necessary for the development of PML.) In comparison, anti-JCV antibodies were detected in the blood of 100% of 25 patients who later were diagnosed with PML and from 100% of 39 patients with samples taken at or around the time of PML diagnosis.

"This shows that the PML patients were exposed to the virus prior to natalizumab treatment," Dr. Subramanyam said. She and her associates hold stock in and are employees of Biogen Idec, which comarkets Tysabri with Elan Pharmaceuticals.

In 17 of the 25 patients with blood samples prior to PML diagnosis, additional samples were taken after starting natalizumab. Another 39 patients had samples taken at the time of PML diagnosis or soon after. All were positive for anti-JCV antibodies. Treatment of PML for 17-98 months did not affect anti-JCV antibody positivity, though overall antibody levels fell.

The investigators used a unique two-step enzyme-linked immunosorbent assay to detect antibodies. Biogen Idec and Elan Pharmaceuticals plan to make the assay commercially available in Europe in May 2011 and in the United States soon after that, Dr. Subramanyam said.

Large clinical studies are ongoing to test the utility of anti-JCV antibody status for stratifying the risk of PML in patients given natalizumab for multiple sclerosis.

Serum Concentration Predicts Risk

The risk for PML increases after 2 years or more of natalizumab use, previous data show. A new study of biochemical samples from 207 patients on natalizumab for multiple sclerosis found that plasma concentrations of the drug increase over time, peaking after 20 months of therapy, reported Dr. John F. Foley of the Rocky Mountain Multiple Sclerosis Clinic, Salt Lake City, and his associates.

For comparison, they looked at data from two phase III trials of natalizumab, in which they also found longitudinal increases in mean natalizumab concentrations.

In the current study, samples taken in each 28- to 30-day infusion interval showed a mean 56% increase in drug concentrations over 45 months. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) trial, serum concentrations increased 70% over 30 months. In the Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis (SENTINEL) trial, drug concentrations increased 99% over 30 months.

Theoretically, if elevated natalizumab concentrations are found to be associated with elevated risk for PML, it may be possible to make kinetic manipulations by changing dosing or adjusting infusion intervals to lower the risk for PML, Dr. Foley said. Studies are ongoing to explore this hypothesis.

Higher Survival With Early Diagnosis

Postmarketing data since November 2004 show that 78,800 patients worldwide have taken natalizumab and 102 of these patients developed PML. A study of the first 79 cases of PML found that 63 (80%) were alive in December 2010. Follow-up visits with these survivors ranged from 1 to 29 months since PML diagnosis. In the 16 patients who died, the time from diagnosis to death ranged from 1 to 11 months, reported Dr. Patrick Vermersch of the University of Lille (France) and his associates.

In all cases, natalizumab was stopped when signs or symptoms suggesting PML appeared, and most patients were treated by plasma exchange or immunoadsorption to rapidly remove the drug from circulation.

Compared with the patients who died, survivors were younger when diagnosed with PML, had a shorter time from symptom onset to diagnosis of PML, and had more localized disease on brain MRI. The likelihood of survival was not affected by the duration of natalizumab use or prior use of immunosuppressive therapy.

The median age at diagnosis of PML was 43 years in survivors and 53 years in those who died. The mean time from PML symptom onset to diagnosis was 34 days in survivors and 54 days in those who died. Among 70 patients with brain MRIs, 29 of the survivors (54%) had unilobar PML extensions, compared with 2 (12%) of those who died.

Among the 38 survivors with at least 6 months of follow-up since PML diagnosis, 5 (13%) had mild disability as rated on the Karnofsky Performance Scale, 19 (50%) had moderate disability, and 14 (37%) had severe disability.

The findings suggest that earlier diagnosis through enhanced clinical vigilance and optimal management of PML might improve outcomes, Dr. Vermersch said.

Data on the first 35 confirmed cases of PML will be published in the May issues of the journal Neurology.

PML Presentation Can Be Subtle

PML usually presents as an aggressive disease with symptoms of visual, motor, language, neurobehavioral, and cognitive changes. Seizures also can occur. Dr. Kristen Babinski of New York University and her associates presented a case of PML that presented in a 26-year-old man being treated for multiple sclerosis whose only symptom of PML was subacute amotivational syndrome.

After his 42nd infusion of natalizumab, a brain MRI showed not only signals typical of multiple sclerosis but new abnormalities in the left frontal white matter. The patient’s brother reported that the patient had become depressed, unmotivated, nihilistic, hopeless, and cynical. An ultrasensitive quantitative polymerase chain reaction (PCR) analysis found JCV DNA in the patient’s cerebrospinal fluid. Findings on MR spectroscopy supported a PML diagnosis.

He stopped taking natalizumab and received treatment for PML. Seven months later, brain imaging shows no signs of PML and his cognitive function and mood have improved, Dr. Babinski said. The patient is being treated for multiple sclerosis with daily glatiramer acetate (Copaxone) injections, monthly infusions of IV immunoglobulin, and monthly methylprednisolone infusions, with 4-aminopyridine (Ampyra), mirtazapine (Remeron), and clonazepam for management of symptoms.

The case suggests that recommended yearly brain MRIs in patients on natalizumab are not frequent enough and that ultrasensitive quantitative PCR and MR spectroscopy may be useful to diagnose PML, Dr. Babinski said. Her institution now performs brain MRI every 6 months in these patients, she said.

Immunosuppressant History Is Relevant

A study of postmarketing data from 2,943 patients taking natalizumab for multiple sclerosis in Canada, Europe, and Australia identified no unknown safety concerns and confirmed that the risk for PML increases with longer use of natalizumab and with any prior use of immunosuppressive therapy.

The risk for PML was 0% in patients untreated for multiple sclerosis before starting natalizumab, 0.1% in patients who had taken one or more disease-modifying drugs, and 0.5% in patients previously treated with an immunosuppressive therapy for multiple sclerosis, reported Dr. Helmut Butzkueven of the University of Melbourne and his associates.

Mean annualized relapse rates on natalizumab therapy were lowest in the therapy-naive patients (0.17) and highest in patients with a history of immunosuppressive therapy (0.36) or those who had switched between glatiramer acetate and interferon therapy (0.29). The risk of serious adverse events was 0.3% in the therapy-naive group, 0.9% in patients on one or more disease-modifying drugs when starting natalizumab, and 1.3% in those with a history of immunosuppressive therapy.

The Food and Drug Administration recently updated the natalizumab (Tysabri) label to include new information about the risk for progressive multifocal leukoencephalopathy (PML) associated with use of the drug. Tysabri is approved to treat multiple sclerosis and Crohn’s disease.

The previous label had warned that using an immunosuppressive medication at the same time as Tysabri may increase the risk of developing PML. The label now includes a warning that taking an immunosuppressive drug at any point prior to taking Tysabri increases the risk for PML. The immunosuppressive drugs include mitoxantrone (Novantrone), azathioprine (Imuran), methotrexate, cyclophosphamide (Cytoxan), or mycophenolate (CellCept).

The updated label also includes a new table listing rates of PML by the number of Tysabri infusions.

Biogen Idec and Elan Pharmaceuticals, which comarket Tysabri, funded most of the studies. Except for Dr. Babinski, each of the presenters and some of their coinvestigators disclosed financial associations with Biogen Idec and other pharmaceutical companies.

HONOLULU – Results of five diverse studies on the risk of progressive multifocal leukoencephalopathy when using natalizumab to treat multiple sclerosis could change the way clinicians decide how to manage these patients.

In one of five presentations about natalizumab (Tysabri) that were given during one session at the annual meeting of the American Academy of Neurology, researchers confirmed that the presence of anti-JC virus (JCV) antibodies always precedes development of progressive multifocal leukoencephalopathy (PML). As a part of their study, the investigators developed a new assay to identify antibody-negative patients who could be at lower risk for PML when taking natalizumab. Another study looked at using serum natalizumab concentrations to predict the risk of PML.

A separate study found that earlier diagnosis of PML after symptom onset was associated with increased survival. A case presentation of PML presenting only with subacute amotivational syndrome raised questions about the need for more frequent brain MRIs. Another study confirmed that a history of taking an immunosuppressant medication at any point prior to taking natalizumab increased the risk for PML.

Antibodies Precede PML

In samples taken from four large clinical treatment trials, approximately 55% of patients with multiple sclerosis had anti-JCV antibodies, Dr. Meena Subramanyam said. (JCV infection is necessary for the development of PML.) In comparison, anti-JCV antibodies were detected in the blood of 100% of 25 patients who later were diagnosed with PML and from 100% of 39 patients with samples taken at or around the time of PML diagnosis.

"This shows that the PML patients were exposed to the virus prior to natalizumab treatment," Dr. Subramanyam said. She and her associates hold stock in and are employees of Biogen Idec, which comarkets Tysabri with Elan Pharmaceuticals.

In 17 of the 25 patients with blood samples prior to PML diagnosis, additional samples were taken after starting natalizumab. Another 39 patients had samples taken at the time of PML diagnosis or soon after. All were positive for anti-JCV antibodies. Treatment of PML for 17-98 months did not affect anti-JCV antibody positivity, though overall antibody levels fell.

The investigators used a unique two-step enzyme-linked immunosorbent assay to detect antibodies. Biogen Idec and Elan Pharmaceuticals plan to make the assay commercially available in Europe in May 2011 and in the United States soon after that, Dr. Subramanyam said.

Large clinical studies are ongoing to test the utility of anti-JCV antibody status for stratifying the risk of PML in patients given natalizumab for multiple sclerosis.

Serum Concentration Predicts Risk

The risk for PML increases after 2 years or more of natalizumab use, previous data show. A new study of biochemical samples from 207 patients on natalizumab for multiple sclerosis found that plasma concentrations of the drug increase over time, peaking after 20 months of therapy, reported Dr. John F. Foley of the Rocky Mountain Multiple Sclerosis Clinic, Salt Lake City, and his associates.

For comparison, they looked at data from two phase III trials of natalizumab, in which they also found longitudinal increases in mean natalizumab concentrations.

In the current study, samples taken in each 28- to 30-day infusion interval showed a mean 56% increase in drug concentrations over 45 months. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) trial, serum concentrations increased 70% over 30 months. In the Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis (SENTINEL) trial, drug concentrations increased 99% over 30 months.

Theoretically, if elevated natalizumab concentrations are found to be associated with elevated risk for PML, it may be possible to make kinetic manipulations by changing dosing or adjusting infusion intervals to lower the risk for PML, Dr. Foley said. Studies are ongoing to explore this hypothesis.

Higher Survival With Early Diagnosis

Postmarketing data since November 2004 show that 78,800 patients worldwide have taken natalizumab and 102 of these patients developed PML. A study of the first 79 cases of PML found that 63 (80%) were alive in December 2010. Follow-up visits with these survivors ranged from 1 to 29 months since PML diagnosis. In the 16 patients who died, the time from diagnosis to death ranged from 1 to 11 months, reported Dr. Patrick Vermersch of the University of Lille (France) and his associates.

In all cases, natalizumab was stopped when signs or symptoms suggesting PML appeared, and most patients were treated by plasma exchange or immunoadsorption to rapidly remove the drug from circulation.

Compared with the patients who died, survivors were younger when diagnosed with PML, had a shorter time from symptom onset to diagnosis of PML, and had more localized disease on brain MRI. The likelihood of survival was not affected by the duration of natalizumab use or prior use of immunosuppressive therapy.

The median age at diagnosis of PML was 43 years in survivors and 53 years in those who died. The mean time from PML symptom onset to diagnosis was 34 days in survivors and 54 days in those who died. Among 70 patients with brain MRIs, 29 of the survivors (54%) had unilobar PML extensions, compared with 2 (12%) of those who died.

Among the 38 survivors with at least 6 months of follow-up since PML diagnosis, 5 (13%) had mild disability as rated on the Karnofsky Performance Scale, 19 (50%) had moderate disability, and 14 (37%) had severe disability.

The findings suggest that earlier diagnosis through enhanced clinical vigilance and optimal management of PML might improve outcomes, Dr. Vermersch said.

Data on the first 35 confirmed cases of PML will be published in the May issues of the journal Neurology.

PML Presentation Can Be Subtle

PML usually presents as an aggressive disease with symptoms of visual, motor, language, neurobehavioral, and cognitive changes. Seizures also can occur. Dr. Kristen Babinski of New York University and her associates presented a case of PML that presented in a 26-year-old man being treated for multiple sclerosis whose only symptom of PML was subacute amotivational syndrome.

After his 42nd infusion of natalizumab, a brain MRI showed not only signals typical of multiple sclerosis but new abnormalities in the left frontal white matter. The patient’s brother reported that the patient had become depressed, unmotivated, nihilistic, hopeless, and cynical. An ultrasensitive quantitative polymerase chain reaction (PCR) analysis found JCV DNA in the patient’s cerebrospinal fluid. Findings on MR spectroscopy supported a PML diagnosis.

He stopped taking natalizumab and received treatment for PML. Seven months later, brain imaging shows no signs of PML and his cognitive function and mood have improved, Dr. Babinski said. The patient is being treated for multiple sclerosis with daily glatiramer acetate (Copaxone) injections, monthly infusions of IV immunoglobulin, and monthly methylprednisolone infusions, with 4-aminopyridine (Ampyra), mirtazapine (Remeron), and clonazepam for management of symptoms.

The case suggests that recommended yearly brain MRIs in patients on natalizumab are not frequent enough and that ultrasensitive quantitative PCR and MR spectroscopy may be useful to diagnose PML, Dr. Babinski said. Her institution now performs brain MRI every 6 months in these patients, she said.

Immunosuppressant History Is Relevant

A study of postmarketing data from 2,943 patients taking natalizumab for multiple sclerosis in Canada, Europe, and Australia identified no unknown safety concerns and confirmed that the risk for PML increases with longer use of natalizumab and with any prior use of immunosuppressive therapy.

The risk for PML was 0% in patients untreated for multiple sclerosis before starting natalizumab, 0.1% in patients who had taken one or more disease-modifying drugs, and 0.5% in patients previously treated with an immunosuppressive therapy for multiple sclerosis, reported Dr. Helmut Butzkueven of the University of Melbourne and his associates.

Mean annualized relapse rates on natalizumab therapy were lowest in the therapy-naive patients (0.17) and highest in patients with a history of immunosuppressive therapy (0.36) or those who had switched between glatiramer acetate and interferon therapy (0.29). The risk of serious adverse events was 0.3% in the therapy-naive group, 0.9% in patients on one or more disease-modifying drugs when starting natalizumab, and 1.3% in those with a history of immunosuppressive therapy.

The Food and Drug Administration recently updated the natalizumab (Tysabri) label to include new information about the risk for progressive multifocal leukoencephalopathy (PML) associated with use of the drug. Tysabri is approved to treat multiple sclerosis and Crohn’s disease.

The previous label had warned that using an immunosuppressive medication at the same time as Tysabri may increase the risk of developing PML. The label now includes a warning that taking an immunosuppressive drug at any point prior to taking Tysabri increases the risk for PML. The immunosuppressive drugs include mitoxantrone (Novantrone), azathioprine (Imuran), methotrexate, cyclophosphamide (Cytoxan), or mycophenolate (CellCept).

The updated label also includes a new table listing rates of PML by the number of Tysabri infusions.

Biogen Idec and Elan Pharmaceuticals, which comarket Tysabri, funded most of the studies. Except for Dr. Babinski, each of the presenters and some of their coinvestigators disclosed financial associations with Biogen Idec and other pharmaceutical companies.

HONOLULU – Results of five diverse studies on the risk of progressive multifocal leukoencephalopathy when using natalizumab to treat multiple sclerosis could change the way clinicians decide how to manage these patients.

In one of five presentations about natalizumab (Tysabri) that were given during one session at the annual meeting of the American Academy of Neurology, researchers confirmed that the presence of anti-JC virus (JCV) antibodies always precedes development of progressive multifocal leukoencephalopathy (PML). As a part of their study, the investigators developed a new assay to identify antibody-negative patients who could be at lower risk for PML when taking natalizumab. Another study looked at using serum natalizumab concentrations to predict the risk of PML.

A separate study found that earlier diagnosis of PML after symptom onset was associated with increased survival. A case presentation of PML presenting only with subacute amotivational syndrome raised questions about the need for more frequent brain MRIs. Another study confirmed that a history of taking an immunosuppressant medication at any point prior to taking natalizumab increased the risk for PML.

Antibodies Precede PML

In samples taken from four large clinical treatment trials, approximately 55% of patients with multiple sclerosis had anti-JCV antibodies, Dr. Meena Subramanyam said. (JCV infection is necessary for the development of PML.) In comparison, anti-JCV antibodies were detected in the blood of 100% of 25 patients who later were diagnosed with PML and from 100% of 39 patients with samples taken at or around the time of PML diagnosis.

"This shows that the PML patients were exposed to the virus prior to natalizumab treatment," Dr. Subramanyam said. She and her associates hold stock in and are employees of Biogen Idec, which comarkets Tysabri with Elan Pharmaceuticals.

In 17 of the 25 patients with blood samples prior to PML diagnosis, additional samples were taken after starting natalizumab. Another 39 patients had samples taken at the time of PML diagnosis or soon after. All were positive for anti-JCV antibodies. Treatment of PML for 17-98 months did not affect anti-JCV antibody positivity, though overall antibody levels fell.

The investigators used a unique two-step enzyme-linked immunosorbent assay to detect antibodies. Biogen Idec and Elan Pharmaceuticals plan to make the assay commercially available in Europe in May 2011 and in the United States soon after that, Dr. Subramanyam said.

Large clinical studies are ongoing to test the utility of anti-JCV antibody status for stratifying the risk of PML in patients given natalizumab for multiple sclerosis.

Serum Concentration Predicts Risk

The risk for PML increases after 2 years or more of natalizumab use, previous data show. A new study of biochemical samples from 207 patients on natalizumab for multiple sclerosis found that plasma concentrations of the drug increase over time, peaking after 20 months of therapy, reported Dr. John F. Foley of the Rocky Mountain Multiple Sclerosis Clinic, Salt Lake City, and his associates.

For comparison, they looked at data from two phase III trials of natalizumab, in which they also found longitudinal increases in mean natalizumab concentrations.

In the current study, samples taken in each 28- to 30-day infusion interval showed a mean 56% increase in drug concentrations over 45 months. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) trial, serum concentrations increased 70% over 30 months. In the Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis (SENTINEL) trial, drug concentrations increased 99% over 30 months.

Theoretically, if elevated natalizumab concentrations are found to be associated with elevated risk for PML, it may be possible to make kinetic manipulations by changing dosing or adjusting infusion intervals to lower the risk for PML, Dr. Foley said. Studies are ongoing to explore this hypothesis.

Higher Survival With Early Diagnosis

Postmarketing data since November 2004 show that 78,800 patients worldwide have taken natalizumab and 102 of these patients developed PML. A study of the first 79 cases of PML found that 63 (80%) were alive in December 2010. Follow-up visits with these survivors ranged from 1 to 29 months since PML diagnosis. In the 16 patients who died, the time from diagnosis to death ranged from 1 to 11 months, reported Dr. Patrick Vermersch of the University of Lille (France) and his associates.

In all cases, natalizumab was stopped when signs or symptoms suggesting PML appeared, and most patients were treated by plasma exchange or immunoadsorption to rapidly remove the drug from circulation.

Compared with the patients who died, survivors were younger when diagnosed with PML, had a shorter time from symptom onset to diagnosis of PML, and had more localized disease on brain MRI. The likelihood of survival was not affected by the duration of natalizumab use or prior use of immunosuppressive therapy.

The median age at diagnosis of PML was 43 years in survivors and 53 years in those who died. The mean time from PML symptom onset to diagnosis was 34 days in survivors and 54 days in those who died. Among 70 patients with brain MRIs, 29 of the survivors (54%) had unilobar PML extensions, compared with 2 (12%) of those who died.

Among the 38 survivors with at least 6 months of follow-up since PML diagnosis, 5 (13%) had mild disability as rated on the Karnofsky Performance Scale, 19 (50%) had moderate disability, and 14 (37%) had severe disability.

The findings suggest that earlier diagnosis through enhanced clinical vigilance and optimal management of PML might improve outcomes, Dr. Vermersch said.

Data on the first 35 confirmed cases of PML will be published in the May issues of the journal Neurology.

PML Presentation Can Be Subtle

PML usually presents as an aggressive disease with symptoms of visual, motor, language, neurobehavioral, and cognitive changes. Seizures also can occur. Dr. Kristen Babinski of New York University and her associates presented a case of PML that presented in a 26-year-old man being treated for multiple sclerosis whose only symptom of PML was subacute amotivational syndrome.

After his 42nd infusion of natalizumab, a brain MRI showed not only signals typical of multiple sclerosis but new abnormalities in the left frontal white matter. The patient’s brother reported that the patient had become depressed, unmotivated, nihilistic, hopeless, and cynical. An ultrasensitive quantitative polymerase chain reaction (PCR) analysis found JCV DNA in the patient’s cerebrospinal fluid. Findings on MR spectroscopy supported a PML diagnosis.

He stopped taking natalizumab and received treatment for PML. Seven months later, brain imaging shows no signs of PML and his cognitive function and mood have improved, Dr. Babinski said. The patient is being treated for multiple sclerosis with daily glatiramer acetate (Copaxone) injections, monthly infusions of IV immunoglobulin, and monthly methylprednisolone infusions, with 4-aminopyridine (Ampyra), mirtazapine (Remeron), and clonazepam for management of symptoms.

The case suggests that recommended yearly brain MRIs in patients on natalizumab are not frequent enough and that ultrasensitive quantitative PCR and MR spectroscopy may be useful to diagnose PML, Dr. Babinski said. Her institution now performs brain MRI every 6 months in these patients, she said.

Immunosuppressant History Is Relevant

A study of postmarketing data from 2,943 patients taking natalizumab for multiple sclerosis in Canada, Europe, and Australia identified no unknown safety concerns and confirmed that the risk for PML increases with longer use of natalizumab and with any prior use of immunosuppressive therapy.

The risk for PML was 0% in patients untreated for multiple sclerosis before starting natalizumab, 0.1% in patients who had taken one or more disease-modifying drugs, and 0.5% in patients previously treated with an immunosuppressive therapy for multiple sclerosis, reported Dr. Helmut Butzkueven of the University of Melbourne and his associates.

Mean annualized relapse rates on natalizumab therapy were lowest in the therapy-naive patients (0.17) and highest in patients with a history of immunosuppressive therapy (0.36) or those who had switched between glatiramer acetate and interferon therapy (0.29). The risk of serious adverse events was 0.3% in the therapy-naive group, 0.9% in patients on one or more disease-modifying drugs when starting natalizumab, and 1.3% in those with a history of immunosuppressive therapy.

The Food and Drug Administration recently updated the natalizumab (Tysabri) label to include new information about the risk for progressive multifocal leukoencephalopathy (PML) associated with use of the drug. Tysabri is approved to treat multiple sclerosis and Crohn’s disease.

The previous label had warned that using an immunosuppressive medication at the same time as Tysabri may increase the risk of developing PML. The label now includes a warning that taking an immunosuppressive drug at any point prior to taking Tysabri increases the risk for PML. The immunosuppressive drugs include mitoxantrone (Novantrone), azathioprine (Imuran), methotrexate, cyclophosphamide (Cytoxan), or mycophenolate (CellCept).

The updated label also includes a new table listing rates of PML by the number of Tysabri infusions.

Biogen Idec and Elan Pharmaceuticals, which comarket Tysabri, funded most of the studies. Except for Dr. Babinski, each of the presenters and some of their coinvestigators disclosed financial associations with Biogen Idec and other pharmaceutical companies.

LOS ANGELES – Evidence from a preliminary study suggests that the arteriopathy called fibromuscular dysplasia appears differently in children than in adults.

In fact, what most neurologists diagnose as fibromuscular dysplasia in children with arterial ischemic stroke might not be fibromuscular dysplasia at all, but is more likely to be transient cerebral arteriopathy (TCA) of childhood, Dr. Adam Kirton said at the conference.

Little is know about the causes of arteriopathy, the most common cause of childhood arterial ischemic stroke. One cause is fibromuscular dysplasia, a group of idiopathic, noninflammatory arteriopathies that classically involve cerebral and renal vessels in whites.

"There’s never been a systematic look at the role of fibromuscular dysplasia in childhood stroke," said Dr. Kirton, director of the pediatric stroke program at Alberta (Calgary) Children’s Hospital. He and his associates analyzed data from 81 cases of childhood stroke that had references to fibromuscular dysplasia or renal artery disease.

Of the 15 cases obtained from two large Canadian registries and 66 cases gleaned from the medical literature, 27 had pathologically proven fibromuscular dysplasia, 31 were clinically diagnosed, and the remaining 23 cases were grouped as "other" diagnoses.

The records provided sufficient detail on 19 of the 27 pathologically proven cases to show that 17 of the 19 (89%) were classified as intimal fibroplasia, a type that is rarely seen in adults. Angiography of these patients showed nonspecific findings such as focal narrowing or stenosis, he said at the meeting, sponsored by the American Heart Association.

The other 2 of the 19 cases were classified as medial hyperplasia, and the remaining 8 cases could not be classified. Notably, none of the 19 had medial fibroplasia or dysplasia, the type typically seen in adults with stroke. "This is the one you learn about in medical school" that has a unique "string of beads" appearance on angiography, he said.

Conventional angiography was performed in 26 of 27 children with pathologically-proven fibromuscular dysplasia. Only 5 (20%) showed a "string of beads" appearance, compared with more than half of the clinically diagnosed group, a significant difference. The pathologically-proven group, however, had significantly higher rates of the moyamoya intake pattern and of renal artery stenosis or renal hypertension than did the clinically diagnosed group.

Of 21 children in the pathologically-proven group who underwent systemic evaluations, 16 (76%) had evidence of systemic arteriopathy outside of the brain and kidneys, "supporting the idea that a lot of fibromuscular dysplasia is really a systemic arterial disease in children," Dr. Kirton said.

There was no evidence of the female predominance for fibromuscular dysplasia that has been observed in adult cases. Nine children in the pathologically-proven group (33%) first presented with neurological symptoms in the first year of life, compared with only three children in the clinically diagnosed group (10%).

Children in the pathologically proven group were significantly more likely to have poor outcomes, to have disease recurrence, and to die, compared with the clinically diagnosed group.

Among 23 patients with pathologically proven fibromuscular dysplasia who were followed for an average of 43 months, 15 had poor outcomes (65%), 8 had recurrences (35%) and 10 died (43%). "There’s a selection bias here, because some of these children died before they could get to pathology," Dr. Kirton noted.

Among 30 children in the clinically diagnosed group who were followed for an average of 22 months, 10 had poor outcomes (33%), 2 had recurrences (7%) and 1 died (3%).

The clinically diagnosed cases more closely resembled TCA than fibromuscular dysplasia, he suggested. The former were more likely to be previously healthy patients with unilateral disease that had a "string of beads" appearance, less likely to have renal artery stenosis or hypertension, and less likely to develop recurrence.

"We are not able to accurately diagnose fibromuscular dysplasia clinically," Dr. Kirton said. "If you see a ‘string of beads,’ it doesn’t necessarily mean fibromuscular dysplasia. In fact, our data would argue that it suggests something else."

Dr. Kirton said the investigators have no relevant conflicts of interest.

LOS ANGELES – Evidence from a preliminary study suggests that the arteriopathy called fibromuscular dysplasia appears differently in children than in adults.

In fact, what most neurologists diagnose as fibromuscular dysplasia in children with arterial ischemic stroke might not be fibromuscular dysplasia at all, but is more likely to be transient cerebral arteriopathy (TCA) of childhood, Dr. Adam Kirton said at the conference.

Little is know about the causes of arteriopathy, the most common cause of childhood arterial ischemic stroke. One cause is fibromuscular dysplasia, a group of idiopathic, noninflammatory arteriopathies that classically involve cerebral and renal vessels in whites.

"There’s never been a systematic look at the role of fibromuscular dysplasia in childhood stroke," said Dr. Kirton, director of the pediatric stroke program at Alberta (Calgary) Children’s Hospital. He and his associates analyzed data from 81 cases of childhood stroke that had references to fibromuscular dysplasia or renal artery disease.

Of the 15 cases obtained from two large Canadian registries and 66 cases gleaned from the medical literature, 27 had pathologically proven fibromuscular dysplasia, 31 were clinically diagnosed, and the remaining 23 cases were grouped as "other" diagnoses.

The records provided sufficient detail on 19 of the 27 pathologically proven cases to show that 17 of the 19 (89%) were classified as intimal fibroplasia, a type that is rarely seen in adults. Angiography of these patients showed nonspecific findings such as focal narrowing or stenosis, he said at the meeting, sponsored by the American Heart Association.

The other 2 of the 19 cases were classified as medial hyperplasia, and the remaining 8 cases could not be classified. Notably, none of the 19 had medial fibroplasia or dysplasia, the type typically seen in adults with stroke. "This is the one you learn about in medical school" that has a unique "string of beads" appearance on angiography, he said.

Conventional angiography was performed in 26 of 27 children with pathologically-proven fibromuscular dysplasia. Only 5 (20%) showed a "string of beads" appearance, compared with more than half of the clinically diagnosed group, a significant difference. The pathologically-proven group, however, had significantly higher rates of the moyamoya intake pattern and of renal artery stenosis or renal hypertension than did the clinically diagnosed group.

Of 21 children in the pathologically-proven group who underwent systemic evaluations, 16 (76%) had evidence of systemic arteriopathy outside of the brain and kidneys, "supporting the idea that a lot of fibromuscular dysplasia is really a systemic arterial disease in children," Dr. Kirton said.

There was no evidence of the female predominance for fibromuscular dysplasia that has been observed in adult cases. Nine children in the pathologically-proven group (33%) first presented with neurological symptoms in the first year of life, compared with only three children in the clinically diagnosed group (10%).

Children in the pathologically proven group were significantly more likely to have poor outcomes, to have disease recurrence, and to die, compared with the clinically diagnosed group.

Among 23 patients with pathologically proven fibromuscular dysplasia who were followed for an average of 43 months, 15 had poor outcomes (65%), 8 had recurrences (35%) and 10 died (43%). "There’s a selection bias here, because some of these children died before they could get to pathology," Dr. Kirton noted.

Among 30 children in the clinically diagnosed group who were followed for an average of 22 months, 10 had poor outcomes (33%), 2 had recurrences (7%) and 1 died (3%).

The clinically diagnosed cases more closely resembled TCA than fibromuscular dysplasia, he suggested. The former were more likely to be previously healthy patients with unilateral disease that had a "string of beads" appearance, less likely to have renal artery stenosis or hypertension, and less likely to develop recurrence.

"We are not able to accurately diagnose fibromuscular dysplasia clinically," Dr. Kirton said. "If you see a ‘string of beads,’ it doesn’t necessarily mean fibromuscular dysplasia. In fact, our data would argue that it suggests something else."

Dr. Kirton said the investigators have no relevant conflicts of interest.

LOS ANGELES – Evidence from a preliminary study suggests that the arteriopathy called fibromuscular dysplasia appears differently in children than in adults.

In fact, what most neurologists diagnose as fibromuscular dysplasia in children with arterial ischemic stroke might not be fibromuscular dysplasia at all, but is more likely to be transient cerebral arteriopathy (TCA) of childhood, Dr. Adam Kirton said at the conference.

Little is know about the causes of arteriopathy, the most common cause of childhood arterial ischemic stroke. One cause is fibromuscular dysplasia, a group of idiopathic, noninflammatory arteriopathies that classically involve cerebral and renal vessels in whites.

"There’s never been a systematic look at the role of fibromuscular dysplasia in childhood stroke," said Dr. Kirton, director of the pediatric stroke program at Alberta (Calgary) Children’s Hospital. He and his associates analyzed data from 81 cases of childhood stroke that had references to fibromuscular dysplasia or renal artery disease.

Of the 15 cases obtained from two large Canadian registries and 66 cases gleaned from the medical literature, 27 had pathologically proven fibromuscular dysplasia, 31 were clinically diagnosed, and the remaining 23 cases were grouped as "other" diagnoses.

The records provided sufficient detail on 19 of the 27 pathologically proven cases to show that 17 of the 19 (89%) were classified as intimal fibroplasia, a type that is rarely seen in adults. Angiography of these patients showed nonspecific findings such as focal narrowing or stenosis, he said at the meeting, sponsored by the American Heart Association.

The other 2 of the 19 cases were classified as medial hyperplasia, and the remaining 8 cases could not be classified. Notably, none of the 19 had medial fibroplasia or dysplasia, the type typically seen in adults with stroke. "This is the one you learn about in medical school" that has a unique "string of beads" appearance on angiography, he said.

Conventional angiography was performed in 26 of 27 children with pathologically-proven fibromuscular dysplasia. Only 5 (20%) showed a "string of beads" appearance, compared with more than half of the clinically diagnosed group, a significant difference. The pathologically-proven group, however, had significantly higher rates of the moyamoya intake pattern and of renal artery stenosis or renal hypertension than did the clinically diagnosed group.

Of 21 children in the pathologically-proven group who underwent systemic evaluations, 16 (76%) had evidence of systemic arteriopathy outside of the brain and kidneys, "supporting the idea that a lot of fibromuscular dysplasia is really a systemic arterial disease in children," Dr. Kirton said.

There was no evidence of the female predominance for fibromuscular dysplasia that has been observed in adult cases. Nine children in the pathologically-proven group (33%) first presented with neurological symptoms in the first year of life, compared with only three children in the clinically diagnosed group (10%).

Children in the pathologically proven group were significantly more likely to have poor outcomes, to have disease recurrence, and to die, compared with the clinically diagnosed group.

Among 23 patients with pathologically proven fibromuscular dysplasia who were followed for an average of 43 months, 15 had poor outcomes (65%), 8 had recurrences (35%) and 10 died (43%). "There’s a selection bias here, because some of these children died before they could get to pathology," Dr. Kirton noted.

Among 30 children in the clinically diagnosed group who were followed for an average of 22 months, 10 had poor outcomes (33%), 2 had recurrences (7%) and 1 died (3%).

The clinically diagnosed cases more closely resembled TCA than fibromuscular dysplasia, he suggested. The former were more likely to be previously healthy patients with unilateral disease that had a "string of beads" appearance, less likely to have renal artery stenosis or hypertension, and less likely to develop recurrence.

"We are not able to accurately diagnose fibromuscular dysplasia clinically," Dr. Kirton said. "If you see a ‘string of beads,’ it doesn’t necessarily mean fibromuscular dysplasia. In fact, our data would argue that it suggests something else."

Dr. Kirton said the investigators have no relevant conflicts of interest.