CMSC: Consortium of Multiple Sclerosis Centers

SAN DIEGO – Glatiramer acetate and interferon beta-1a used in combination were no more effective for patients with relapsing-remitting multiple sclerosis than were either agent alone in a 3-year, randomized trial.

On quality of life measures, monotherapy and combination therapy proved largely equal – and equally well tolerated – in the "CombiRx" study, in which half of the patients got the combination and a quarter got either glatiramer acetate (Copaxone) or interferon beta-1a (Avonex) alone plus a placebo.

CombiRx was conceived at time when interferon beta-1a (IFN-beta-1a) and glatiramer acetate (GA) were the only disease-modifying options for MS; investigators naturally wondered if they’d work better together, said Dr. Lael Stone, a CombiRx investigator and MS specialist at the Cleveland Clinic.

But with natalizumab and fingolimod now on the market, and dimethyl fumarate (also known as BG-12) in the Food and Drug Administration pipeline, times have changed.

It’s never been common to use GA and IFN-beta-1a together, and with newer agents available, "we look at [the CombiRx findings] in 2012 and say ‘that’s not very interesting.’ There were slight indications that" the combination, or one agent or the other, was "better in this respect and not so good in that respect, but it was relatively underwhelming," Dr. Stone said at the Fourth Cooperative Meeting on Multiple Sclerosis.

The size of the study – 1,008 treatment-naive patients – and its duration are what remain important. "They can pull out all sorts of other types of data about what happens to MRIs and what happens to the quality of life" in MS. "They can also look at biomarkers [and genetics]. The database was just locked in April, so this is still going to be gone through in much more detail. What’s going to be most interesting are the other things that come out" of this study, she said.

Almost three-quarters of the CombiRx participants were women. They were 38 years old, on average, and 88% of them were white. Their mean baseline Expanded Disability Status Scale (EDSS) score was about 2.0, and mean disease duration 1.2 years.

Almost half the participants reported very good general health at baseline and 37% excellent general health. Most remained healthy throughout the study. "Everyone did very well. There were very minimal changes from baseline to the last observed MSQLI [Multiple Sclerosis Quality of Life Inventory]," the battery of scales used in CombiRx to see how participants fared, said investigator Stacey Cofield, Ph.D., a biostatician at the University of Alabama at Birmingham.

Mental health and perceived-support scores actually improved over the course of the study, she said, although fatigue, bladder, bowel, and cognitive impairment scores worsened slightly. Overall, "these were very small changes. None of them stand out as being very meaningful," Dr. Cofield said.

Combination therapy showed a half-point benefit on the 22-point bladder control scale, the only scale out of 11 that showed any significant difference between mono and combination therapy.

In the monotherapy groups, IFN-beta-1a patients fared slight better than GA patients on the mental health scale, with no change in the IFN-beta-1a group, but a 3.3 point drop in the 100-point scale in the GA group over 3 years. Conversely, GA patients fared slightly better on the bladder scale, with a 1.5 point improvement vs. a 0.6 point improvement in the IFN-beta-1a group.

Overall, CombiRx had "very low rates of progression and very low amounts of MRI activity," Dr. Cofield said at the meeting, sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee on Treatment and Research in Multiple Sclerosis.

Dr. Cofield reported financial ties to Teva Neuroscience and Centocor Ortho Biotech Services. Other investigators reported numerous ties to pharmaceutical companies, including Teva Neuroscience, which donated the Copaxone used in the trial, and Biogen Idec, which donated the Avonex.

SAN DIEGO – Glatiramer acetate and interferon beta-1a used in combination were no more effective for patients with relapsing-remitting multiple sclerosis than were either agent alone in a 3-year, randomized trial.

On quality of life measures, monotherapy and combination therapy proved largely equal – and equally well tolerated – in the "CombiRx" study, in which half of the patients got the combination and a quarter got either glatiramer acetate (Copaxone) or interferon beta-1a (Avonex) alone plus a placebo.

CombiRx was conceived at time when interferon beta-1a (IFN-beta-1a) and glatiramer acetate (GA) were the only disease-modifying options for MS; investigators naturally wondered if they’d work better together, said Dr. Lael Stone, a CombiRx investigator and MS specialist at the Cleveland Clinic.

But with natalizumab and fingolimod now on the market, and dimethyl fumarate (also known as BG-12) in the Food and Drug Administration pipeline, times have changed.

It’s never been common to use GA and IFN-beta-1a together, and with newer agents available, "we look at [the CombiRx findings] in 2012 and say ‘that’s not very interesting.’ There were slight indications that" the combination, or one agent or the other, was "better in this respect and not so good in that respect, but it was relatively underwhelming," Dr. Stone said at the Fourth Cooperative Meeting on Multiple Sclerosis.

The size of the study – 1,008 treatment-naive patients – and its duration are what remain important. "They can pull out all sorts of other types of data about what happens to MRIs and what happens to the quality of life" in MS. "They can also look at biomarkers [and genetics]. The database was just locked in April, so this is still going to be gone through in much more detail. What’s going to be most interesting are the other things that come out" of this study, she said.

Almost three-quarters of the CombiRx participants were women. They were 38 years old, on average, and 88% of them were white. Their mean baseline Expanded Disability Status Scale (EDSS) score was about 2.0, and mean disease duration 1.2 years.

Almost half the participants reported very good general health at baseline and 37% excellent general health. Most remained healthy throughout the study. "Everyone did very well. There were very minimal changes from baseline to the last observed MSQLI [Multiple Sclerosis Quality of Life Inventory]," the battery of scales used in CombiRx to see how participants fared, said investigator Stacey Cofield, Ph.D., a biostatician at the University of Alabama at Birmingham.

Mental health and perceived-support scores actually improved over the course of the study, she said, although fatigue, bladder, bowel, and cognitive impairment scores worsened slightly. Overall, "these were very small changes. None of them stand out as being very meaningful," Dr. Cofield said.

Combination therapy showed a half-point benefit on the 22-point bladder control scale, the only scale out of 11 that showed any significant difference between mono and combination therapy.

In the monotherapy groups, IFN-beta-1a patients fared slight better than GA patients on the mental health scale, with no change in the IFN-beta-1a group, but a 3.3 point drop in the 100-point scale in the GA group over 3 years. Conversely, GA patients fared slightly better on the bladder scale, with a 1.5 point improvement vs. a 0.6 point improvement in the IFN-beta-1a group.

Overall, CombiRx had "very low rates of progression and very low amounts of MRI activity," Dr. Cofield said at the meeting, sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee on Treatment and Research in Multiple Sclerosis.

Dr. Cofield reported financial ties to Teva Neuroscience and Centocor Ortho Biotech Services. Other investigators reported numerous ties to pharmaceutical companies, including Teva Neuroscience, which donated the Copaxone used in the trial, and Biogen Idec, which donated the Avonex.

SAN DIEGO – Glatiramer acetate and interferon beta-1a used in combination were no more effective for patients with relapsing-remitting multiple sclerosis than were either agent alone in a 3-year, randomized trial.

On quality of life measures, monotherapy and combination therapy proved largely equal – and equally well tolerated – in the "CombiRx" study, in which half of the patients got the combination and a quarter got either glatiramer acetate (Copaxone) or interferon beta-1a (Avonex) alone plus a placebo.

CombiRx was conceived at time when interferon beta-1a (IFN-beta-1a) and glatiramer acetate (GA) were the only disease-modifying options for MS; investigators naturally wondered if they’d work better together, said Dr. Lael Stone, a CombiRx investigator and MS specialist at the Cleveland Clinic.

But with natalizumab and fingolimod now on the market, and dimethyl fumarate (also known as BG-12) in the Food and Drug Administration pipeline, times have changed.

It’s never been common to use GA and IFN-beta-1a together, and with newer agents available, "we look at [the CombiRx findings] in 2012 and say ‘that’s not very interesting.’ There were slight indications that" the combination, or one agent or the other, was "better in this respect and not so good in that respect, but it was relatively underwhelming," Dr. Stone said at the Fourth Cooperative Meeting on Multiple Sclerosis.

The size of the study – 1,008 treatment-naive patients – and its duration are what remain important. "They can pull out all sorts of other types of data about what happens to MRIs and what happens to the quality of life" in MS. "They can also look at biomarkers [and genetics]. The database was just locked in April, so this is still going to be gone through in much more detail. What’s going to be most interesting are the other things that come out" of this study, she said.

Almost three-quarters of the CombiRx participants were women. They were 38 years old, on average, and 88% of them were white. Their mean baseline Expanded Disability Status Scale (EDSS) score was about 2.0, and mean disease duration 1.2 years.

Almost half the participants reported very good general health at baseline and 37% excellent general health. Most remained healthy throughout the study. "Everyone did very well. There were very minimal changes from baseline to the last observed MSQLI [Multiple Sclerosis Quality of Life Inventory]," the battery of scales used in CombiRx to see how participants fared, said investigator Stacey Cofield, Ph.D., a biostatician at the University of Alabama at Birmingham.

Mental health and perceived-support scores actually improved over the course of the study, she said, although fatigue, bladder, bowel, and cognitive impairment scores worsened slightly. Overall, "these were very small changes. None of them stand out as being very meaningful," Dr. Cofield said.

Combination therapy showed a half-point benefit on the 22-point bladder control scale, the only scale out of 11 that showed any significant difference between mono and combination therapy.

In the monotherapy groups, IFN-beta-1a patients fared slight better than GA patients on the mental health scale, with no change in the IFN-beta-1a group, but a 3.3 point drop in the 100-point scale in the GA group over 3 years. Conversely, GA patients fared slightly better on the bladder scale, with a 1.5 point improvement vs. a 0.6 point improvement in the IFN-beta-1a group.

Overall, CombiRx had "very low rates of progression and very low amounts of MRI activity," Dr. Cofield said at the meeting, sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee on Treatment and Research in Multiple Sclerosis.

Dr. Cofield reported financial ties to Teva Neuroscience and Centocor Ortho Biotech Services. Other investigators reported numerous ties to pharmaceutical companies, including Teva Neuroscience, which donated the Copaxone used in the trial, and Biogen Idec, which donated the Avonex.

SAN DIEGO – Full results of the second phase III trial of dimethyl fumarate in patients with relapsing-remitting multiple sclerosis show that the investigational drug significantly reduces annualized relapse rates and MRI lesions over the course of 2 years

The results of the study, called CONFIRM (Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis), are in line with those of an earlier phase III study called DEFINE. But unlike the earlier trial, CONFIRM did not demonstrate a statistically significant benefit for disease progression based on the Expanded Disability Status Scale (EDSS).

Even so, the two studies indicate that dimethyl fumarate, also known as BG-12, "has a future as an oral therapeutic option for patients with relapsing MS," said Dr. Theodore Phillips, an MS researcher at the Baylor Institute for Immunology Research and clinical professor in the neurology department at the University of Texas Southwestern Medical Center, both in Dallas.

The drug is under review by the Food and Drug Administration. "Hopefully, we won’t have to wait for a decision much past the first quarter of 2013," Dr. Phillips said at the Fourth Cooperative Meeting on Multiple Sclerosis.

"People are very excited about BG-12 because it’s a much better tolerated oral, we think, than fingolimod (Gilenya)," which it will compete against, Dr. Lael Stone, an MS specialist at the Cleveland Clinic, said about the study.

"The question [will] be, ‘Is it as good as promised?’ " she said.

The trial randomized 359 patients to BG-12 240 mg twice daily, 345 patients to BG-12 240 mg three times daily, 350 to subcutaneous glatiramer acetate (GA) 20 mg daily, and 363 to placebo.

About 70% of the subjects were women, with approximately 1.4 relapses in the prior year and a mean EDSS score of about 2.6. The average age in the trial was about 37 years.

The annualized relapse rate was 0.401 in the placebo group, 0.224 in the BG-12 twice-daily group (44% reduction versus placebo), 0.198 in the BG-12 three-times-daily group (51% reduction), and 0.286 in the GA group (29% reduction). These rates correspond to hazard ratios for relapse of 0.66, 0.55, and 0.71, respectively. The results were statistically significant.

About 17% of placebo, 13% of BG-12, and 15.6% of GA patients experienced disease progression in the trial. The differences did not reach significance, perhaps because progression rates overall were low, unlike the earlier trial, where 27% of placebo patients progressed, Dr. Phillips said.

About 140 patients in each arm were included in the MRI analysis. The placebo arm had an adjusted mean of 17.4 new or newly enlarging T2 hyperintense lesions and 7 new T1 hypointense lesions. Both BG-12 arms had a mean of about 5 new or newly enlarging T2 lesions and just under 3 T1 lesions. The GA group had a mean of 8 T2 lesions and 4.1 T1 lesions. The differences versus placebo were significant.

Flushing and gastrointestinal complaints were the most common side effects of BG-12, but they decreased after the first month of the trial. Mean lymphocyte counts fell during the first 6-12 months, but remained within normal limits throughout the study.

No opportunistic infections or malignancies were reported in the BG-12 groups. The twice-daily arm had two cellulitis cases, whereas the three-times-daily arm had one. No cellulitis was reported in the placebo and GA arms.

The meeting was sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

The CONFIRM trial was funded by the maker of BG-12, Biogen Idec. Dr. Phillips reported financial relationships with Biogen, Avanir, Genzyme, Novartis, Teva, and Roche. Dr. Stone said she had no disclosures.

SAN DIEGO – Full results of the second phase III trial of dimethyl fumarate in patients with relapsing-remitting multiple sclerosis show that the investigational drug significantly reduces annualized relapse rates and MRI lesions over the course of 2 years

The results of the study, called CONFIRM (Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis), are in line with those of an earlier phase III study called DEFINE. But unlike the earlier trial, CONFIRM did not demonstrate a statistically significant benefit for disease progression based on the Expanded Disability Status Scale (EDSS).

Even so, the two studies indicate that dimethyl fumarate, also known as BG-12, "has a future as an oral therapeutic option for patients with relapsing MS," said Dr. Theodore Phillips, an MS researcher at the Baylor Institute for Immunology Research and clinical professor in the neurology department at the University of Texas Southwestern Medical Center, both in Dallas.

The drug is under review by the Food and Drug Administration. "Hopefully, we won’t have to wait for a decision much past the first quarter of 2013," Dr. Phillips said at the Fourth Cooperative Meeting on Multiple Sclerosis.

"People are very excited about BG-12 because it’s a much better tolerated oral, we think, than fingolimod (Gilenya)," which it will compete against, Dr. Lael Stone, an MS specialist at the Cleveland Clinic, said about the study.

"The question [will] be, ‘Is it as good as promised?’ " she said.

The trial randomized 359 patients to BG-12 240 mg twice daily, 345 patients to BG-12 240 mg three times daily, 350 to subcutaneous glatiramer acetate (GA) 20 mg daily, and 363 to placebo.

About 70% of the subjects were women, with approximately 1.4 relapses in the prior year and a mean EDSS score of about 2.6. The average age in the trial was about 37 years.

The annualized relapse rate was 0.401 in the placebo group, 0.224 in the BG-12 twice-daily group (44% reduction versus placebo), 0.198 in the BG-12 three-times-daily group (51% reduction), and 0.286 in the GA group (29% reduction). These rates correspond to hazard ratios for relapse of 0.66, 0.55, and 0.71, respectively. The results were statistically significant.

About 17% of placebo, 13% of BG-12, and 15.6% of GA patients experienced disease progression in the trial. The differences did not reach significance, perhaps because progression rates overall were low, unlike the earlier trial, where 27% of placebo patients progressed, Dr. Phillips said.

About 140 patients in each arm were included in the MRI analysis. The placebo arm had an adjusted mean of 17.4 new or newly enlarging T2 hyperintense lesions and 7 new T1 hypointense lesions. Both BG-12 arms had a mean of about 5 new or newly enlarging T2 lesions and just under 3 T1 lesions. The GA group had a mean of 8 T2 lesions and 4.1 T1 lesions. The differences versus placebo were significant.

Flushing and gastrointestinal complaints were the most common side effects of BG-12, but they decreased after the first month of the trial. Mean lymphocyte counts fell during the first 6-12 months, but remained within normal limits throughout the study.

No opportunistic infections or malignancies were reported in the BG-12 groups. The twice-daily arm had two cellulitis cases, whereas the three-times-daily arm had one. No cellulitis was reported in the placebo and GA arms.

The meeting was sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

The CONFIRM trial was funded by the maker of BG-12, Biogen Idec. Dr. Phillips reported financial relationships with Biogen, Avanir, Genzyme, Novartis, Teva, and Roche. Dr. Stone said she had no disclosures.

SAN DIEGO – Full results of the second phase III trial of dimethyl fumarate in patients with relapsing-remitting multiple sclerosis show that the investigational drug significantly reduces annualized relapse rates and MRI lesions over the course of 2 years

The results of the study, called CONFIRM (Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis), are in line with those of an earlier phase III study called DEFINE. But unlike the earlier trial, CONFIRM did not demonstrate a statistically significant benefit for disease progression based on the Expanded Disability Status Scale (EDSS).

Even so, the two studies indicate that dimethyl fumarate, also known as BG-12, "has a future as an oral therapeutic option for patients with relapsing MS," said Dr. Theodore Phillips, an MS researcher at the Baylor Institute for Immunology Research and clinical professor in the neurology department at the University of Texas Southwestern Medical Center, both in Dallas.

The drug is under review by the Food and Drug Administration. "Hopefully, we won’t have to wait for a decision much past the first quarter of 2013," Dr. Phillips said at the Fourth Cooperative Meeting on Multiple Sclerosis.

"People are very excited about BG-12 because it’s a much better tolerated oral, we think, than fingolimod (Gilenya)," which it will compete against, Dr. Lael Stone, an MS specialist at the Cleveland Clinic, said about the study.

"The question [will] be, ‘Is it as good as promised?’ " she said.

The trial randomized 359 patients to BG-12 240 mg twice daily, 345 patients to BG-12 240 mg three times daily, 350 to subcutaneous glatiramer acetate (GA) 20 mg daily, and 363 to placebo.

About 70% of the subjects were women, with approximately 1.4 relapses in the prior year and a mean EDSS score of about 2.6. The average age in the trial was about 37 years.

The annualized relapse rate was 0.401 in the placebo group, 0.224 in the BG-12 twice-daily group (44% reduction versus placebo), 0.198 in the BG-12 three-times-daily group (51% reduction), and 0.286 in the GA group (29% reduction). These rates correspond to hazard ratios for relapse of 0.66, 0.55, and 0.71, respectively. The results were statistically significant.

About 17% of placebo, 13% of BG-12, and 15.6% of GA patients experienced disease progression in the trial. The differences did not reach significance, perhaps because progression rates overall were low, unlike the earlier trial, where 27% of placebo patients progressed, Dr. Phillips said.

About 140 patients in each arm were included in the MRI analysis. The placebo arm had an adjusted mean of 17.4 new or newly enlarging T2 hyperintense lesions and 7 new T1 hypointense lesions. Both BG-12 arms had a mean of about 5 new or newly enlarging T2 lesions and just under 3 T1 lesions. The GA group had a mean of 8 T2 lesions and 4.1 T1 lesions. The differences versus placebo were significant.

Flushing and gastrointestinal complaints were the most common side effects of BG-12, but they decreased after the first month of the trial. Mean lymphocyte counts fell during the first 6-12 months, but remained within normal limits throughout the study.

No opportunistic infections or malignancies were reported in the BG-12 groups. The twice-daily arm had two cellulitis cases, whereas the three-times-daily arm had one. No cellulitis was reported in the placebo and GA arms.

The meeting was sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

The CONFIRM trial was funded by the maker of BG-12, Biogen Idec. Dr. Phillips reported financial relationships with Biogen, Avanir, Genzyme, Novartis, Teva, and Roche. Dr. Stone said she had no disclosures.

SAN DIEGO – Metronidazole-induced encephalopathy should be considered when patients on the antibiotic are worked up for suspected multiple sclerosis, according to a case study and literature review from researchers at the Mount Sinai School of Medicine in New York.

A Crohn’s disease patient in his mid-30s who had been on metronidazole for almost 7 years presented there with a years-long diagnosis of multiple sclerosis, but MS wasn’t his problem. Doctors at the center figured out he had metronidazole-induced encephalopathy (MIE).

He had been started on 500 mg three times daily for a few months in early 2004, and then restarted on the same regimen in mid-2005. His first neurologic attack – primarily gait ataxia and dysarthria, along with nonenhancing T2 hyperintensities on MRI – came about a month later. Nonetheless, he remained on 250 mg twice daily to 500 mg three times daily until early 2011, and suffered several more attacks, notably after dosage increases. His cumulative metronidazole dose was 2,133.5 g.

Forty-one days after the patient stopped taking metronidazole, his ataxia and dysarthria were almost completely resolved; 7 months later, he was almost clear on brain MRI, with only small residua. His sole remaining complaints were poor memory, attention, and motivation.

"Neurologists should be alert to the possibility of metronidazole-induced encephalopathy in the differential diagnosis of demyelinating disease, especially in view of its potential reversibility," said lead investigator Dr. Corey McGraw, a neurologist at the school’s Corinne Goldsmith Dickinson Center for Multiple Sclerosis.

It’s widely known that metronidazole can cause peripheral neuropathy, but it is much less known that it can also cause toxic encephalopathy that mimics demyelination, he said at the Fourth Cooperative Meeting on Multiple Sclerosis.

"This is an under-recognized neurologic disease among American neurologists. Most of the [63 reported] cases have been in Korea and India, where it may be more recognized. I and my much-more-senior colleagues had never heard of metronidazole-induced encephalopathy before this case. Neurologists are probably missing it," Dr. McGraw said.

The giveaway in the Crohn’s patient’s case was that he had the same signs and symptoms with each attack, whereas MS tends to migrate around the body.

In many ways, he was a typical MIE patient.

Of the 63 cases reviewed by Dr. McGraw, 44 (70%) had MRI T2 hyperintensities of the cerebellar dentate nuclei that were the same as those found in the Crohn’s disease patient, and 19 (30%) had T2 hyperintensities of the corpus callosum splenium. Those and other MIE findings are "classic for a toxic encephalopathy," he said at the meeting, which was sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Dysarthria and gait ataxia are common, too, as well as problems with mentation, arm coordination, leg strength, and seizures.

The cumulative mean metronidazole dose in the 63 cases was 106.1 g (range, 3-1,095 g). The mean time from first dose to first neurologic attack was 67 days (range, 2-730 days). Symptoms resolved in anywhere from 1 to 420 days after metronidazole was stopped.

The "wide ranges in time to clinical manifestations and total cumulative doses may obscure the appropriate diagnosis," Dr. McGraw noted.

Dr. McGraw said that he had no relevant disclosures.

SAN DIEGO – Metronidazole-induced encephalopathy should be considered when patients on the antibiotic are worked up for suspected multiple sclerosis, according to a case study and literature review from researchers at the Mount Sinai School of Medicine in New York.

A Crohn’s disease patient in his mid-30s who had been on metronidazole for almost 7 years presented there with a years-long diagnosis of multiple sclerosis, but MS wasn’t his problem. Doctors at the center figured out he had metronidazole-induced encephalopathy (MIE).

He had been started on 500 mg three times daily for a few months in early 2004, and then restarted on the same regimen in mid-2005. His first neurologic attack – primarily gait ataxia and dysarthria, along with nonenhancing T2 hyperintensities on MRI – came about a month later. Nonetheless, he remained on 250 mg twice daily to 500 mg three times daily until early 2011, and suffered several more attacks, notably after dosage increases. His cumulative metronidazole dose was 2,133.5 g.

Forty-one days after the patient stopped taking metronidazole, his ataxia and dysarthria were almost completely resolved; 7 months later, he was almost clear on brain MRI, with only small residua. His sole remaining complaints were poor memory, attention, and motivation.

"Neurologists should be alert to the possibility of metronidazole-induced encephalopathy in the differential diagnosis of demyelinating disease, especially in view of its potential reversibility," said lead investigator Dr. Corey McGraw, a neurologist at the school’s Corinne Goldsmith Dickinson Center for Multiple Sclerosis.

It’s widely known that metronidazole can cause peripheral neuropathy, but it is much less known that it can also cause toxic encephalopathy that mimics demyelination, he said at the Fourth Cooperative Meeting on Multiple Sclerosis.

"This is an under-recognized neurologic disease among American neurologists. Most of the [63 reported] cases have been in Korea and India, where it may be more recognized. I and my much-more-senior colleagues had never heard of metronidazole-induced encephalopathy before this case. Neurologists are probably missing it," Dr. McGraw said.

The giveaway in the Crohn’s patient’s case was that he had the same signs and symptoms with each attack, whereas MS tends to migrate around the body.

In many ways, he was a typical MIE patient.

Of the 63 cases reviewed by Dr. McGraw, 44 (70%) had MRI T2 hyperintensities of the cerebellar dentate nuclei that were the same as those found in the Crohn’s disease patient, and 19 (30%) had T2 hyperintensities of the corpus callosum splenium. Those and other MIE findings are "classic for a toxic encephalopathy," he said at the meeting, which was sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Dysarthria and gait ataxia are common, too, as well as problems with mentation, arm coordination, leg strength, and seizures.

The cumulative mean metronidazole dose in the 63 cases was 106.1 g (range, 3-1,095 g). The mean time from first dose to first neurologic attack was 67 days (range, 2-730 days). Symptoms resolved in anywhere from 1 to 420 days after metronidazole was stopped.

The "wide ranges in time to clinical manifestations and total cumulative doses may obscure the appropriate diagnosis," Dr. McGraw noted.

Dr. McGraw said that he had no relevant disclosures.

SAN DIEGO – Metronidazole-induced encephalopathy should be considered when patients on the antibiotic are worked up for suspected multiple sclerosis, according to a case study and literature review from researchers at the Mount Sinai School of Medicine in New York.

A Crohn’s disease patient in his mid-30s who had been on metronidazole for almost 7 years presented there with a years-long diagnosis of multiple sclerosis, but MS wasn’t his problem. Doctors at the center figured out he had metronidazole-induced encephalopathy (MIE).

He had been started on 500 mg three times daily for a few months in early 2004, and then restarted on the same regimen in mid-2005. His first neurologic attack – primarily gait ataxia and dysarthria, along with nonenhancing T2 hyperintensities on MRI – came about a month later. Nonetheless, he remained on 250 mg twice daily to 500 mg three times daily until early 2011, and suffered several more attacks, notably after dosage increases. His cumulative metronidazole dose was 2,133.5 g.

Forty-one days after the patient stopped taking metronidazole, his ataxia and dysarthria were almost completely resolved; 7 months later, he was almost clear on brain MRI, with only small residua. His sole remaining complaints were poor memory, attention, and motivation.

"Neurologists should be alert to the possibility of metronidazole-induced encephalopathy in the differential diagnosis of demyelinating disease, especially in view of its potential reversibility," said lead investigator Dr. Corey McGraw, a neurologist at the school’s Corinne Goldsmith Dickinson Center for Multiple Sclerosis.

It’s widely known that metronidazole can cause peripheral neuropathy, but it is much less known that it can also cause toxic encephalopathy that mimics demyelination, he said at the Fourth Cooperative Meeting on Multiple Sclerosis.

"This is an under-recognized neurologic disease among American neurologists. Most of the [63 reported] cases have been in Korea and India, where it may be more recognized. I and my much-more-senior colleagues had never heard of metronidazole-induced encephalopathy before this case. Neurologists are probably missing it," Dr. McGraw said.

The giveaway in the Crohn’s patient’s case was that he had the same signs and symptoms with each attack, whereas MS tends to migrate around the body.

In many ways, he was a typical MIE patient.

Of the 63 cases reviewed by Dr. McGraw, 44 (70%) had MRI T2 hyperintensities of the cerebellar dentate nuclei that were the same as those found in the Crohn’s disease patient, and 19 (30%) had T2 hyperintensities of the corpus callosum splenium. Those and other MIE findings are "classic for a toxic encephalopathy," he said at the meeting, which was sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Dysarthria and gait ataxia are common, too, as well as problems with mentation, arm coordination, leg strength, and seizures.

The cumulative mean metronidazole dose in the 63 cases was 106.1 g (range, 3-1,095 g). The mean time from first dose to first neurologic attack was 67 days (range, 2-730 days). Symptoms resolved in anywhere from 1 to 420 days after metronidazole was stopped.

The "wide ranges in time to clinical manifestations and total cumulative doses may obscure the appropriate diagnosis," Dr. McGraw noted.

Dr. McGraw said that he had no relevant disclosures.

SAN DIEGO – Tetrahydrocannabinol, the main active ingredient in marijuana, did not slow the progression of multiple sclerosis in a 3-year, randomized trial of 493 British patients with primary or secondary progressive forms of the disease.

Some patients with lower baseline EDSS (Expanded Disability Status Scale) scores appeared to have delayed progression, but the trial did not have enough statistical power to allow comparison of subgroups.

©ron hilton/iStockphoto.com

In the Cannabinoid Use in Progressive Inflammatory Brain Disease (CUPID) trial, investigators randomized 329 patients to 14-28 mg of tetrahydrocannabinol (THC)/day in capsule form based on weight, and 164 to placebo. Their mean baseline EDSS score was about 5.8 (range, 4.0-6.5). Patients were, on average, 52 years old; and about 60% were women.

None were on disease-modifying therapies, but most were on pain relievers and other medications for symptom relief. The patients agreed to otherwise abstain from marijuana during the study.

Compared with placebo, the hazard ratio for EDSS progression in the THC group – defined as a 1-point increase for patients starting at or below 5, and a half-point increase for those starting above – was 0.92 (95% CI, 0.68-1.23) after adjustment for disease type, age, and other variables.

There were no statistical differences in brain volume loss on MRI, Multiple Sclerosis Impact Scale scores, and several secondary outcomes, including the 25-foot timed walk and 9-hole peg tests.

On post hoc analysis, there was a hint of delayed progression in patients with baseline EDSS scores below 6; 26 (76%) of 34 placebo patients in that group progressed, compared with only 44 (58%) of 76 in the THC group.

"The lower EDSS scores do seem to suggest a treatment effect, but we did not have much power to detect that effect. I do think that there are probably going to be subgroups that do respond more than others," said lead investigator Dr. John Zajicek, a professor of clinical neuroscience at Plymouth (England) University.

Overall, he called the results "disappointing." Although "there is sufficient evidence to use cannabinoids" for relieving muscle stiffness, spasticity, pain, urinary disturbances, and other MS symptoms, it could be that THC simply does not slow progression in primary or secondary progressive MS. No drug has yet been proven to do so, Dr. Zajicek said at the Fourth Cooperative Meeting on Multiple Sclerosis.

The results might also have been obscured because there was very little progression in either the THC or placebo groups. "We were expecting 70% progression, but we got just over 40%, so most of the outcome measures did not change very much over 3 years. It’s very difficult to find a treatment effect when your outcome measures aren’t changing," he said.

About 60% of the THC patients complained of dizziness or lightheadedness, and 51% of thought or perception changes, both far more common than in the placebo group, but fewer THC patients reported musculoskeletal pain (26% vs. 37% in the placebo group) and fewer developed urinary tract infections (26% vs. 35%).

The meeting was sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis. Dr. Zajicek said he had no relevant disclosures.

SAN DIEGO – Tetrahydrocannabinol, the main active ingredient in marijuana, did not slow the progression of multiple sclerosis in a 3-year, randomized trial of 493 British patients with primary or secondary progressive forms of the disease.

Some patients with lower baseline EDSS (Expanded Disability Status Scale) scores appeared to have delayed progression, but the trial did not have enough statistical power to allow comparison of subgroups.

©ron hilton/iStockphoto.com

In the Cannabinoid Use in Progressive Inflammatory Brain Disease (CUPID) trial, investigators randomized 329 patients to 14-28 mg of tetrahydrocannabinol (THC)/day in capsule form based on weight, and 164 to placebo. Their mean baseline EDSS score was about 5.8 (range, 4.0-6.5). Patients were, on average, 52 years old; and about 60% were women.

None were on disease-modifying therapies, but most were on pain relievers and other medications for symptom relief. The patients agreed to otherwise abstain from marijuana during the study.

Compared with placebo, the hazard ratio for EDSS progression in the THC group – defined as a 1-point increase for patients starting at or below 5, and a half-point increase for those starting above – was 0.92 (95% CI, 0.68-1.23) after adjustment for disease type, age, and other variables.

There were no statistical differences in brain volume loss on MRI, Multiple Sclerosis Impact Scale scores, and several secondary outcomes, including the 25-foot timed walk and 9-hole peg tests.

On post hoc analysis, there was a hint of delayed progression in patients with baseline EDSS scores below 6; 26 (76%) of 34 placebo patients in that group progressed, compared with only 44 (58%) of 76 in the THC group.

"The lower EDSS scores do seem to suggest a treatment effect, but we did not have much power to detect that effect. I do think that there are probably going to be subgroups that do respond more than others," said lead investigator Dr. John Zajicek, a professor of clinical neuroscience at Plymouth (England) University.

Overall, he called the results "disappointing." Although "there is sufficient evidence to use cannabinoids" for relieving muscle stiffness, spasticity, pain, urinary disturbances, and other MS symptoms, it could be that THC simply does not slow progression in primary or secondary progressive MS. No drug has yet been proven to do so, Dr. Zajicek said at the Fourth Cooperative Meeting on Multiple Sclerosis.

The results might also have been obscured because there was very little progression in either the THC or placebo groups. "We were expecting 70% progression, but we got just over 40%, so most of the outcome measures did not change very much over 3 years. It’s very difficult to find a treatment effect when your outcome measures aren’t changing," he said.

About 60% of the THC patients complained of dizziness or lightheadedness, and 51% of thought or perception changes, both far more common than in the placebo group, but fewer THC patients reported musculoskeletal pain (26% vs. 37% in the placebo group) and fewer developed urinary tract infections (26% vs. 35%).

The meeting was sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis. Dr. Zajicek said he had no relevant disclosures.

SAN DIEGO – Tetrahydrocannabinol, the main active ingredient in marijuana, did not slow the progression of multiple sclerosis in a 3-year, randomized trial of 493 British patients with primary or secondary progressive forms of the disease.

Some patients with lower baseline EDSS (Expanded Disability Status Scale) scores appeared to have delayed progression, but the trial did not have enough statistical power to allow comparison of subgroups.

©ron hilton/iStockphoto.com

In the Cannabinoid Use in Progressive Inflammatory Brain Disease (CUPID) trial, investigators randomized 329 patients to 14-28 mg of tetrahydrocannabinol (THC)/day in capsule form based on weight, and 164 to placebo. Their mean baseline EDSS score was about 5.8 (range, 4.0-6.5). Patients were, on average, 52 years old; and about 60% were women.

None were on disease-modifying therapies, but most were on pain relievers and other medications for symptom relief. The patients agreed to otherwise abstain from marijuana during the study.

Compared with placebo, the hazard ratio for EDSS progression in the THC group – defined as a 1-point increase for patients starting at or below 5, and a half-point increase for those starting above – was 0.92 (95% CI, 0.68-1.23) after adjustment for disease type, age, and other variables.

There were no statistical differences in brain volume loss on MRI, Multiple Sclerosis Impact Scale scores, and several secondary outcomes, including the 25-foot timed walk and 9-hole peg tests.

On post hoc analysis, there was a hint of delayed progression in patients with baseline EDSS scores below 6; 26 (76%) of 34 placebo patients in that group progressed, compared with only 44 (58%) of 76 in the THC group.

"The lower EDSS scores do seem to suggest a treatment effect, but we did not have much power to detect that effect. I do think that there are probably going to be subgroups that do respond more than others," said lead investigator Dr. John Zajicek, a professor of clinical neuroscience at Plymouth (England) University.

Overall, he called the results "disappointing." Although "there is sufficient evidence to use cannabinoids" for relieving muscle stiffness, spasticity, pain, urinary disturbances, and other MS symptoms, it could be that THC simply does not slow progression in primary or secondary progressive MS. No drug has yet been proven to do so, Dr. Zajicek said at the Fourth Cooperative Meeting on Multiple Sclerosis.

The results might also have been obscured because there was very little progression in either the THC or placebo groups. "We were expecting 70% progression, but we got just over 40%, so most of the outcome measures did not change very much over 3 years. It’s very difficult to find a treatment effect when your outcome measures aren’t changing," he said.

About 60% of the THC patients complained of dizziness or lightheadedness, and 51% of thought or perception changes, both far more common than in the placebo group, but fewer THC patients reported musculoskeletal pain (26% vs. 37% in the placebo group) and fewer developed urinary tract infections (26% vs. 35%).

The meeting was sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis. Dr. Zajicek said he had no relevant disclosures.

SAN DIEGO – An emergency department at an academic medical institution with a multiple sclerosis center missed diagnosing multiple sclerosis in nearly 40% of patients who were later diagnosed with the disease, calling into question what the rate of missed cases might be at smaller centers staffed by fewer specialists.

The retrospective study analyzed assessments for neurologic symptoms during 49 emergency department (ED) visits at the Mount Sinai School of Medicine in New York that were made by 49 people who were later diagnosed with MS. The researchers judged most of those presentations to be initial manifestations of the disease.

Just 30 of the visits (61%) resulted in a diagnosis of MS or demyelinating disease, either in the ED or on subsequent admission, Dr. Stephen Krieger said at the Fourth Cooperative Meeting on Multiple Sclerosis, which was sponsored by the Consortium of Multiple Sclerosis Centers and the America’s Committee for Treatment and Research in Multiple Sclerosis.

The diagnosis was missed in the remaining 19 (39%) visits, an important finding because early diagnosis and treatment leads to better MS outcomes. About a third of the patients involved in those visits still hadn’t been diagnosed 6 months later. It took more than a year to diagnose a few of them. "Those are the patients we have to look at to see what could have been done differently," said senior investigator Dr. Krieger, an MS specialist at the Corinne Goldsmith Dickinson Center for MS at Mount Sinai.

The risk of delayed diagnosis seemed to be greatest for men, the middle aged, and those with vague neurologic symptoms – all of whom are nontraditional MS patients – but the study didn’t have enough patients to demonstrate those findings statistically. Patients who were admitted from the ED, however, were more likely to be diagnosed quickly than were nonadmitted patients.

"Emergency department presentations for acute neurologic symptoms are an important opportunity to diagnose and treat clinically isolated syndrome and MS. There’s room to make that diagnosis more rapidly," Dr. Krieger said.

Even though the project was a single-center study, Dr. Krieger noted that Mount Sinai is an academic center with a busy neurology department, a neurology residency, and a multiple sclerosis center. In short, "we are sort of a best case scenario. A lot of other emergency departments without as much access to MS specialists may" have a harder time making a prompt diagnosis, he said.

His team plans to analyze demographic data and symptom presentations to develop robust predictive factors for delayed MS diagnoses.

Although the findings are concerning, Dr. Lael Stone, an MS specialist at the Cleveland Clinic, noted that the situation has improved in recent years. "It used to be that [the elapsed time between] first symptoms [and] diagnosis was on the order of 9 years. That has gone down dramatically," she said.

Even so, "we have a ways to go in terms of picking up MS in the [emergency department], which we should be able to do," she said at the meeting.

Vague and confusing neurologic symptoms remain a problem. The demyelinating disease neuromyelitis optica, for example, can present with month-long intractable vomiting, years before the condition is diagnosed.

"The intractable vomiting goes to the GI doctor or to the [ED]. I doubt that the [ED or GI specialist] thinks this might be neuromyelitis optica," she said.

Among the 49 ED visits for neurologic symptoms at Mount Sinai, almost half were for sensory symptoms; the remainder were for vision changes, weakness, balance problems, diplopia, and vertigo.

Bayer Healthcare Pharmaceuticals funded for the study. Dr. Krieger said he is a paid consultant for Acorda Therapeutics, Bayer Healthcare Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme, Novartis, and Questcor. He receives fees from Teva Neuroscience for non-CME services. Dr. Stone said she has no relevant disclosures.

SAN DIEGO – An emergency department at an academic medical institution with a multiple sclerosis center missed diagnosing multiple sclerosis in nearly 40% of patients who were later diagnosed with the disease, calling into question what the rate of missed cases might be at smaller centers staffed by fewer specialists.

The retrospective study analyzed assessments for neurologic symptoms during 49 emergency department (ED) visits at the Mount Sinai School of Medicine in New York that were made by 49 people who were later diagnosed with MS. The researchers judged most of those presentations to be initial manifestations of the disease.

Just 30 of the visits (61%) resulted in a diagnosis of MS or demyelinating disease, either in the ED or on subsequent admission, Dr. Stephen Krieger said at the Fourth Cooperative Meeting on Multiple Sclerosis, which was sponsored by the Consortium of Multiple Sclerosis Centers and the America’s Committee for Treatment and Research in Multiple Sclerosis.

The diagnosis was missed in the remaining 19 (39%) visits, an important finding because early diagnosis and treatment leads to better MS outcomes. About a third of the patients involved in those visits still hadn’t been diagnosed 6 months later. It took more than a year to diagnose a few of them. "Those are the patients we have to look at to see what could have been done differently," said senior investigator Dr. Krieger, an MS specialist at the Corinne Goldsmith Dickinson Center for MS at Mount Sinai.

The risk of delayed diagnosis seemed to be greatest for men, the middle aged, and those with vague neurologic symptoms – all of whom are nontraditional MS patients – but the study didn’t have enough patients to demonstrate those findings statistically. Patients who were admitted from the ED, however, were more likely to be diagnosed quickly than were nonadmitted patients.

"Emergency department presentations for acute neurologic symptoms are an important opportunity to diagnose and treat clinically isolated syndrome and MS. There’s room to make that diagnosis more rapidly," Dr. Krieger said.

Even though the project was a single-center study, Dr. Krieger noted that Mount Sinai is an academic center with a busy neurology department, a neurology residency, and a multiple sclerosis center. In short, "we are sort of a best case scenario. A lot of other emergency departments without as much access to MS specialists may" have a harder time making a prompt diagnosis, he said.

His team plans to analyze demographic data and symptom presentations to develop robust predictive factors for delayed MS diagnoses.

Although the findings are concerning, Dr. Lael Stone, an MS specialist at the Cleveland Clinic, noted that the situation has improved in recent years. "It used to be that [the elapsed time between] first symptoms [and] diagnosis was on the order of 9 years. That has gone down dramatically," she said.

Even so, "we have a ways to go in terms of picking up MS in the [emergency department], which we should be able to do," she said at the meeting.

Vague and confusing neurologic symptoms remain a problem. The demyelinating disease neuromyelitis optica, for example, can present with month-long intractable vomiting, years before the condition is diagnosed.

"The intractable vomiting goes to the GI doctor or to the [ED]. I doubt that the [ED or GI specialist] thinks this might be neuromyelitis optica," she said.

Among the 49 ED visits for neurologic symptoms at Mount Sinai, almost half were for sensory symptoms; the remainder were for vision changes, weakness, balance problems, diplopia, and vertigo.

Bayer Healthcare Pharmaceuticals funded for the study. Dr. Krieger said he is a paid consultant for Acorda Therapeutics, Bayer Healthcare Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme, Novartis, and Questcor. He receives fees from Teva Neuroscience for non-CME services. Dr. Stone said she has no relevant disclosures.

SAN DIEGO – An emergency department at an academic medical institution with a multiple sclerosis center missed diagnosing multiple sclerosis in nearly 40% of patients who were later diagnosed with the disease, calling into question what the rate of missed cases might be at smaller centers staffed by fewer specialists.

The retrospective study analyzed assessments for neurologic symptoms during 49 emergency department (ED) visits at the Mount Sinai School of Medicine in New York that were made by 49 people who were later diagnosed with MS. The researchers judged most of those presentations to be initial manifestations of the disease.

Just 30 of the visits (61%) resulted in a diagnosis of MS or demyelinating disease, either in the ED or on subsequent admission, Dr. Stephen Krieger said at the Fourth Cooperative Meeting on Multiple Sclerosis, which was sponsored by the Consortium of Multiple Sclerosis Centers and the America’s Committee for Treatment and Research in Multiple Sclerosis.

The diagnosis was missed in the remaining 19 (39%) visits, an important finding because early diagnosis and treatment leads to better MS outcomes. About a third of the patients involved in those visits still hadn’t been diagnosed 6 months later. It took more than a year to diagnose a few of them. "Those are the patients we have to look at to see what could have been done differently," said senior investigator Dr. Krieger, an MS specialist at the Corinne Goldsmith Dickinson Center for MS at Mount Sinai.

The risk of delayed diagnosis seemed to be greatest for men, the middle aged, and those with vague neurologic symptoms – all of whom are nontraditional MS patients – but the study didn’t have enough patients to demonstrate those findings statistically. Patients who were admitted from the ED, however, were more likely to be diagnosed quickly than were nonadmitted patients.

"Emergency department presentations for acute neurologic symptoms are an important opportunity to diagnose and treat clinically isolated syndrome and MS. There’s room to make that diagnosis more rapidly," Dr. Krieger said.

Even though the project was a single-center study, Dr. Krieger noted that Mount Sinai is an academic center with a busy neurology department, a neurology residency, and a multiple sclerosis center. In short, "we are sort of a best case scenario. A lot of other emergency departments without as much access to MS specialists may" have a harder time making a prompt diagnosis, he said.

His team plans to analyze demographic data and symptom presentations to develop robust predictive factors for delayed MS diagnoses.

Although the findings are concerning, Dr. Lael Stone, an MS specialist at the Cleveland Clinic, noted that the situation has improved in recent years. "It used to be that [the elapsed time between] first symptoms [and] diagnosis was on the order of 9 years. That has gone down dramatically," she said.

Even so, "we have a ways to go in terms of picking up MS in the [emergency department], which we should be able to do," she said at the meeting.

Vague and confusing neurologic symptoms remain a problem. The demyelinating disease neuromyelitis optica, for example, can present with month-long intractable vomiting, years before the condition is diagnosed.

"The intractable vomiting goes to the GI doctor or to the [ED]. I doubt that the [ED or GI specialist] thinks this might be neuromyelitis optica," she said.

Among the 49 ED visits for neurologic symptoms at Mount Sinai, almost half were for sensory symptoms; the remainder were for vision changes, weakness, balance problems, diplopia, and vertigo.

Bayer Healthcare Pharmaceuticals funded for the study. Dr. Krieger said he is a paid consultant for Acorda Therapeutics, Bayer Healthcare Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme, Novartis, and Questcor. He receives fees from Teva Neuroscience for non-CME services. Dr. Stone said she has no relevant disclosures.