Multiple Sclerosis Hub

DALLAS—Functional electrical stimulation (FES) cycling may be an effective exercise option in people who have moderate to severe multiple sclerosis (MS), reported Deborah Backus, PhD, and colleagues at the 2014 Cooperative Meeting of CMSC and ACTRIMS.

Her study included 16 people with MS who had an Expanded Disability Status Scale score of greater than 6.5. Subjects trained two to three times per week for about one month (ie, in a total of 12 sessions) on the RT-300 FES cycle, and the intensity of FES was adjusted for each participant’s comfort level. “The goal was to cycle at 40 to 50 rpm for 30 minutes, either actively or with electrical stimulation for assistance,” noted Dr. Backus, who is the Director of MS Research at the Eula C. and Andrew C. Carlos MS Rehabilitation and Wellness Program at the Shepherd Center in Atlanta.

The investigators analyzed data collected immediately before and after the four-week training period using the MS Quality of Life Inventory (MSQLI) subscales, Modified Ashworth Scale (MAS, spasticity), and manual muscle test (MMT, strength). The study authors also collected data from each training session to monitor subjects’ progress on the cycle and any status changes.

Fourteen participants (six females) completed the training. The researchers found that all persons maintained or increased the amount of time that they could cycle, and seven increased the resistance against which they cycled.

“The most important finding is that there were no adverse events, and no increase in any MS-related symptoms,” said Dr. Backus. “Participants demonstrated a significant increase in one measure of cognitive processing speed and a significant decrease in fatigue. There was no significant change in the other subscales of the MSQLI. There was neither a significant increase nor a decrease in MAS and MMT scores.”

The investigators also found that the type of MS and use of antispasticity medications, disease-modifying therapies, or dalfampridine or 4-aminopyridine “did not appear to influence the response to training.”

“Further study is required to examine the parameters of FES cycling that are most effective for people with different constellations of MS symptoms and to fully explore the potential benefits for optimizing function and improving health in people with moderate to severe MS,” Dr. Backus concluded.

—Colby Stong

DALLAS—Functional electrical stimulation (FES) cycling may be an effective exercise option in people who have moderate to severe multiple sclerosis (MS), reported Deborah Backus, PhD, and colleagues at the 2014 Cooperative Meeting of CMSC and ACTRIMS.

Her study included 16 people with MS who had an Expanded Disability Status Scale score of greater than 6.5. Subjects trained two to three times per week for about one month (ie, in a total of 12 sessions) on the RT-300 FES cycle, and the intensity of FES was adjusted for each participant’s comfort level. “The goal was to cycle at 40 to 50 rpm for 30 minutes, either actively or with electrical stimulation for assistance,” noted Dr. Backus, who is the Director of MS Research at the Eula C. and Andrew C. Carlos MS Rehabilitation and Wellness Program at the Shepherd Center in Atlanta.

The investigators analyzed data collected immediately before and after the four-week training period using the MS Quality of Life Inventory (MSQLI) subscales, Modified Ashworth Scale (MAS, spasticity), and manual muscle test (MMT, strength). The study authors also collected data from each training session to monitor subjects’ progress on the cycle and any status changes.

Fourteen participants (six females) completed the training. The researchers found that all persons maintained or increased the amount of time that they could cycle, and seven increased the resistance against which they cycled.

“The most important finding is that there were no adverse events, and no increase in any MS-related symptoms,” said Dr. Backus. “Participants demonstrated a significant increase in one measure of cognitive processing speed and a significant decrease in fatigue. There was no significant change in the other subscales of the MSQLI. There was neither a significant increase nor a decrease in MAS and MMT scores.”

The investigators also found that the type of MS and use of antispasticity medications, disease-modifying therapies, or dalfampridine or 4-aminopyridine “did not appear to influence the response to training.”

“Further study is required to examine the parameters of FES cycling that are most effective for people with different constellations of MS symptoms and to fully explore the potential benefits for optimizing function and improving health in people with moderate to severe MS,” Dr. Backus concluded.

—Colby Stong

DALLAS—Functional electrical stimulation (FES) cycling may be an effective exercise option in people who have moderate to severe multiple sclerosis (MS), reported Deborah Backus, PhD, and colleagues at the 2014 Cooperative Meeting of CMSC and ACTRIMS.

Her study included 16 people with MS who had an Expanded Disability Status Scale score of greater than 6.5. Subjects trained two to three times per week for about one month (ie, in a total of 12 sessions) on the RT-300 FES cycle, and the intensity of FES was adjusted for each participant’s comfort level. “The goal was to cycle at 40 to 50 rpm for 30 minutes, either actively or with electrical stimulation for assistance,” noted Dr. Backus, who is the Director of MS Research at the Eula C. and Andrew C. Carlos MS Rehabilitation and Wellness Program at the Shepherd Center in Atlanta.

The investigators analyzed data collected immediately before and after the four-week training period using the MS Quality of Life Inventory (MSQLI) subscales, Modified Ashworth Scale (MAS, spasticity), and manual muscle test (MMT, strength). The study authors also collected data from each training session to monitor subjects’ progress on the cycle and any status changes.

Fourteen participants (six females) completed the training. The researchers found that all persons maintained or increased the amount of time that they could cycle, and seven increased the resistance against which they cycled.

“The most important finding is that there were no adverse events, and no increase in any MS-related symptoms,” said Dr. Backus. “Participants demonstrated a significant increase in one measure of cognitive processing speed and a significant decrease in fatigue. There was no significant change in the other subscales of the MSQLI. There was neither a significant increase nor a decrease in MAS and MMT scores.”

The investigators also found that the type of MS and use of antispasticity medications, disease-modifying therapies, or dalfampridine or 4-aminopyridine “did not appear to influence the response to training.”

“Further study is required to examine the parameters of FES cycling that are most effective for people with different constellations of MS symptoms and to fully explore the potential benefits for optimizing function and improving health in people with moderate to severe MS,” Dr. Backus concluded.

—Colby Stong

PHILADELPHIA—A proposed revision of the diagnostic criteria for neuromyelitis optica takes into account newly appreciated variations in the disease’s clinical presentation. The new criteria, which were presented at the 66th Annual Meeting of the American Academy of Neurology, would offer potential diagnoses for patients who have symptoms but who do not have the serum antibodies usually associated with the disorder.

The document reflects the current understanding of neuromyelitis optica as a spectrum of clinical symptoms, said Dean Wingerchuk, MD, Professor of Neurology at the Mayo Clinic in Scottsdale, Arizona. Neuromyelitis optica spectrum disorder (NMOSD) was identified in 2007, one year after the existing diagnostic criteria were published.

“We wanted to encompass all patients who would have previously been diagnosed as having neuromyelitis optica or NMOSD,” in the new guidelines, said Dr. Wingerchuk. A new stratification of patients as antibody-positive or antibody-negative reflects the fact that not all patients are seropositive at presentation, particularly if they present early in the course of the disease; that antibody testing is not available or reliable everywhere; and that as-yet-unidentified antibodies might be implicated in the disorder.

The workgroup that authored the document consisted of 18 members from nine countries. It began its work in 2011. The proposed criteria need to be validated prospectively before they can be adopted widely, noted Dr. Wingerchuk, who was a primary author of the 2006 criteria.

The existing criteria require the presence of transverse myelitis, optic neuritis, and at least two of the following:

• Brain MRI findings that are nondiagnostic for multiple sclerosis (MS)
• A spinal cord lesion extending over three or more vertebral segments
• Seropositivity for NMO-IgG.

The newly proposed criteria include six core characteristics: optic neuritis, acute myelitis, area postrema syndrome (ie, nausea, vomiting, and hiccups), other brainstem syndromes, symptomatic narcolepsy or acute diencephalic syndrome with MRI findings, and symptomatic cerebral syndrome with MRI findings. Antibody-positive patients must have at least one core characteristic to be diagnosed with neuromyelitis optica, and no better explanation for their symptoms should be apparent.

Antibody-negative patients must meet stricter criteria to receive a diagnosis. They must have at least two of the core characteristics and meet the following requirements:

• At least one of the core symptoms must be optic neuritis, myelitis, or area postrema syndrome.
• The core characteristics must be disseminated in space.
• MRI findings must distinguish NMOSD from MS or other demyelinating disorders.

Prospective validation will require follow-up of patients who are seropositive at diagnosis but present with less common syndromes. Validation also will require detailed descriptions of seronegative groups to determine whether they eventually convert to a clinical NMOSD, concluded Dr. Wingerchuk.

—Michele G. Sullivan

PHILADELPHIA—A proposed revision of the diagnostic criteria for neuromyelitis optica takes into account newly appreciated variations in the disease’s clinical presentation. The new criteria, which were presented at the 66th Annual Meeting of the American Academy of Neurology, would offer potential diagnoses for patients who have symptoms but who do not have the serum antibodies usually associated with the disorder.

The document reflects the current understanding of neuromyelitis optica as a spectrum of clinical symptoms, said Dean Wingerchuk, MD, Professor of Neurology at the Mayo Clinic in Scottsdale, Arizona. Neuromyelitis optica spectrum disorder (NMOSD) was identified in 2007, one year after the existing diagnostic criteria were published.

“We wanted to encompass all patients who would have previously been diagnosed as having neuromyelitis optica or NMOSD,” in the new guidelines, said Dr. Wingerchuk. A new stratification of patients as antibody-positive or antibody-negative reflects the fact that not all patients are seropositive at presentation, particularly if they present early in the course of the disease; that antibody testing is not available or reliable everywhere; and that as-yet-unidentified antibodies might be implicated in the disorder.

The workgroup that authored the document consisted of 18 members from nine countries. It began its work in 2011. The proposed criteria need to be validated prospectively before they can be adopted widely, noted Dr. Wingerchuk, who was a primary author of the 2006 criteria.

The existing criteria require the presence of transverse myelitis, optic neuritis, and at least two of the following:

• Brain MRI findings that are nondiagnostic for multiple sclerosis (MS)
• A spinal cord lesion extending over three or more vertebral segments
• Seropositivity for NMO-IgG.

The newly proposed criteria include six core characteristics: optic neuritis, acute myelitis, area postrema syndrome (ie, nausea, vomiting, and hiccups), other brainstem syndromes, symptomatic narcolepsy or acute diencephalic syndrome with MRI findings, and symptomatic cerebral syndrome with MRI findings. Antibody-positive patients must have at least one core characteristic to be diagnosed with neuromyelitis optica, and no better explanation for their symptoms should be apparent.

Antibody-negative patients must meet stricter criteria to receive a diagnosis. They must have at least two of the core characteristics and meet the following requirements:

• At least one of the core symptoms must be optic neuritis, myelitis, or area postrema syndrome.
• The core characteristics must be disseminated in space.
• MRI findings must distinguish NMOSD from MS or other demyelinating disorders.

Prospective validation will require follow-up of patients who are seropositive at diagnosis but present with less common syndromes. Validation also will require detailed descriptions of seronegative groups to determine whether they eventually convert to a clinical NMOSD, concluded Dr. Wingerchuk.

—Michele G. Sullivan

PHILADELPHIA—A proposed revision of the diagnostic criteria for neuromyelitis optica takes into account newly appreciated variations in the disease’s clinical presentation. The new criteria, which were presented at the 66th Annual Meeting of the American Academy of Neurology, would offer potential diagnoses for patients who have symptoms but who do not have the serum antibodies usually associated with the disorder.

The document reflects the current understanding of neuromyelitis optica as a spectrum of clinical symptoms, said Dean Wingerchuk, MD, Professor of Neurology at the Mayo Clinic in Scottsdale, Arizona. Neuromyelitis optica spectrum disorder (NMOSD) was identified in 2007, one year after the existing diagnostic criteria were published.

“We wanted to encompass all patients who would have previously been diagnosed as having neuromyelitis optica or NMOSD,” in the new guidelines, said Dr. Wingerchuk. A new stratification of patients as antibody-positive or antibody-negative reflects the fact that not all patients are seropositive at presentation, particularly if they present early in the course of the disease; that antibody testing is not available or reliable everywhere; and that as-yet-unidentified antibodies might be implicated in the disorder.

The workgroup that authored the document consisted of 18 members from nine countries. It began its work in 2011. The proposed criteria need to be validated prospectively before they can be adopted widely, noted Dr. Wingerchuk, who was a primary author of the 2006 criteria.

The existing criteria require the presence of transverse myelitis, optic neuritis, and at least two of the following:

• Brain MRI findings that are nondiagnostic for multiple sclerosis (MS)
• A spinal cord lesion extending over three or more vertebral segments
• Seropositivity for NMO-IgG.

The newly proposed criteria include six core characteristics: optic neuritis, acute myelitis, area postrema syndrome (ie, nausea, vomiting, and hiccups), other brainstem syndromes, symptomatic narcolepsy or acute diencephalic syndrome with MRI findings, and symptomatic cerebral syndrome with MRI findings. Antibody-positive patients must have at least one core characteristic to be diagnosed with neuromyelitis optica, and no better explanation for their symptoms should be apparent.

Antibody-negative patients must meet stricter criteria to receive a diagnosis. They must have at least two of the core characteristics and meet the following requirements:

• At least one of the core symptoms must be optic neuritis, myelitis, or area postrema syndrome.
• The core characteristics must be disseminated in space.
• MRI findings must distinguish NMOSD from MS or other demyelinating disorders.

Prospective validation will require follow-up of patients who are seropositive at diagnosis but present with less common syndromes. Validation also will require detailed descriptions of seronegative groups to determine whether they eventually convert to a clinical NMOSD, concluded Dr. Wingerchuk.

—Michele G. Sullivan

PHILADELPHIA—Certain forms of medical marijuana can help treat symptoms of multiple sclerosis (MS), but they may not be helpful in treating levodopa-induced movements in Parkinson’s disease, researchers reported at the 66th Annual Meeting of the American Academy of Neurology (AAN).

The researchers did not find enough evidence to show whether medical marijuana is helpful in treating motor problems in Huntington’s disease, tics in Tourette syndrome, cervical dystonia, and seizures in epilepsy. These conclusions are part of AAN’s review of scientific research on the use of medical marijuana in brain diseases. The findings were published in the April 29, 2014, print issue of Neurology.

“This review by the world’s largest association for neurologists is intended to help neurologists and their patients understand the current research on medical marijuana for the treatment of certain brain diseases,” said review author Barbara S. Koppel, MD, of New York Medical College in Valhalla, and Fellow of the AAN. “The AAN review also highlights the need for more high-quality studies of the long-term efficacy and safety of medical marijuana in the treatment of neurologic diseases.”

The AAN review concluded that only the pill or oral spray forms of medical marijuana can help treat symptoms of MS, including spasticity, certain types of pain (ie, pain related to spasticity, including painful spasms, and painful burning and numbness), and overactive bladder. Most of the MS studies examined pill or oral spray forms of medical marijuana. Two studies examined smoked medical marijuana for treating MS symptoms, but these studies did not provide enough information to show whether smoked medical marijuana is effective. “It’s important to note that medical marijuana can worsen thinking and memory problems, and this is a concern, since many people with MS suffer from these problems already due to the disease itself,” said Dr. Koppel.

In addition, the AAN review concluded that medical marijuana, in the form of synthetic tetrahydrocannabinol (THC) pills, likely does not help relieve abnormal movements that can develop in the late stages of Parkinson’s disease as a result of levodopa.

Medical marijuana use does entail safety concerns. In at least two studies, participants reported side effects such as nausea, increased weakness, behavioral or mood changes, suicidal thoughts or hallucinations, dizziness or fainting symptoms, fatigue, and feelings of intoxication. There were reports of two seizures. Mood changes and suicidal thoughts are of special concern for people with neurologic illness, who are at an increased risk for depression and suicide. The risk of serious psychologic effects is approximately 1%, according to the studies.

The only two medical marijuana pills with FDA approval contain THC. “The psychoactive side effects, such as feeling intoxicated, seemed to come from the THC,” said Dr. Koppel. “They’re trying to create pills that are leaning more toward the cannabinoid, which has the therapeutic effects with fewer psychoactive side effects.”

Clinicians who practice in states where medical marijuana is legal may recommend the drug for the MS symptoms that respond to it, Dr. Koppel added. “The problem is that the studies are done very rigorously with a certain amount of THC versus cannabinoid. The type of marijuana you can buy so far is not so rigorously defined.” Clinicians also should warn their patients about marijuana’s potential side effects.

In general, medical marijuana is prescribed as a treatment only when standard treatment has not helped. In most of the studies reviewed, patients were allowed to continue their standard treatments. The AAN review is endorsed by the American Autonomic Society, the American Epilepsy Society, and the International Rett Syndrome Foundation.

—Erik Greb

New Drugs May Offer Hope for Migraine Prevention
Two new studies may offer hope for patients with migraine. Both studies involve drugs for migraine prophylaxis rather than acute treatment. These studies are among the first to test monoclonal antibodies for the prevention of migraine, and both are directed against calcitonin gene-related peptide (CGRP), a relatively new target in migraine prevention. Both are phase II studies.

One study involved 163 patients who had migraine from five to 14 days per month. The patients received either a placebo or a single IV dose of a drug called ALD403. After the initial injection, study participants were followed for 24 weeks. Those who received the drug had an average of 5.6 fewer migraine days per month, a 66% decrease, compared with 4.6 fewer days per month for those who received a placebo, or a 52% decrease. Sixteen percent of those who received the drug had no migraine days at 12 weeks, while none of those who received the placebo were free from migraine at that point.

There were no differences in side effects between those receiving the drug and those receiving the placebo.

“These results may potentially represent a new era in preventive therapy for migraine,” said Peter Goadsby, MD, PhD, of the University of California, San Francisco, who was an investigator in both studies.

“Migraine remains poorly treated, and there are few effective and well-tolerated treatments approved that prevent attacks from occurring,” said coinvestigator David Dodick, MD, of Mayo Clinic Arizona in Phoenix. “There is a huge treatment need for migraine—the third most common and seventh most disabling medical disorder in the world.”

In the second study, 217 patients who had migraine four to 14 days per month received biweekly subcutaneous injections of either a placebo or a drug called LY2951742 for 12 weeks.

Those who received the drug had an average of 4.2 fewer migraine days per month at 12 weeks, or a 63% decrease, while those who received placebo had three fewer migraine days per month, or a 42% decrease. Those who received the drug were more likely to have side effects including pain at the injection site, upper respiratory tract infections, and abdominal pain, but overall the drug was considered to be safe and well tolerated.

“We’re cautiously optimistic that a new era of mechanism-based migraine prevention is beginning,” Dr. Dodick said.

Botulinum Toxin for Poststroke Spasticity—Could a Higher Dosage Yield Greater Benefit?
Although patients with poststroke spasticity are generally satisfied with their botulinum toxin treatment, many individuals may derive additional benefit with higher dosages and shorter injection intervals than the standard 12-week regimen, researchers reported at the 66th Annual Meeting of the American Academy of Neurology.

Djamel Bensmail, MD, PhD, and colleagues conducted two cross-sectional surveys among patients and physicians in Canada, France, Germany, and the United States. A total of 79 eligible patients had received two or more treatments of abobotulinumtoxinA, incobotulinumtoxinA, or onabotulinumtoxinA for poststroke spasticity. The investigators gathered data regarding current and prior botulinum toxin treatments along with physician and patient treatment satisfaction. All 105 participating physicians had treated patients with poststroke spasticity and had three or more years’ experience of injecting botulinum toxin.

“Botulinum toxin injections are the first-line treatment for patients with poststroke spasticity,” stated Dr. Bensmail, from the Department of Physical Medicine and Rehabilitation, R. Poincaré Hospital, AP-HP, University of Versailles Saint Quentin in Garches, France. “However, for some patients, treatment at the standard-of-care 12‑week interval may result in re-emergence of symptoms before reinjection.”

Sixty-one patients (77%) received onabotulinumtoxinA, 15 patients (19%) received abobotulinumtoxinA, and three patients (4%) received incobotulinumtoxinA. The researchers found that 40.5% of patients were overall very satisfied with the treatment, and 48.1% were somewhat satisfied with their current treatment.

“Satisfaction was highest at the time of peak effect and lowest just before reinjection,” stated the investigators. “While 78.9% of patients preferred injection intervals of less than or equal to 12 weeks, only 45.6% received such intervals. Intervals of 10 weeks or fewer were preferred by 43.4% of patients but received by just 6.3%. The mean interval was 13.7 weeks.”

Among the physicians surveyed, most (57.7%) were moderately or very satisfied (36.5%) with botulinum
toxin treatment for poststroke spasticity. However, the physicians also believed, on average, that 16.2% of patients would benefit from shorter injection intervals and that 24.6% would benefit from higher doses than those that are approved.

—Colby Stong

Potential Targets and Interventions for Parkinson’s Disease
A trio of studies from researchers at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia demonstrate new approaches to understanding, treating, and potentially staving off Parkinson’s disease. Studies show that factors such as estrogen exposure and statin use have an impact on the onset of Parkinson’s disease. And a new look at telemedicine demonstrates feasibility in providing care for patients with Parkinson’s disease using remote video visits to expand access and center care around the needs of the patients.

Statins May Delay Onset of Parkinson’s Disease
Research presented by Yosef Berlyand, an undergraduate in the laboratory of Alice Chen-Plotkin, MD, MSc, Assistant Professor of Neurology, suggests that statins may be beneficial in Parkinson’s disease. In collaboration with Roy Alcalay, MD, and colleagues at the Columbia University School of Medicine, members of Dr. Chen-Plotkin’s research group demonstrated that blood levels of the protein apolipoprotein A1 (ApoA1) are lower in people with Parkinson’s disease than in those without the disease. Patients with Parkinson’s disease taking statins, which can elevate levels of ApoA1, had an older age of disease onset, which appears to be driven by taking statins.

Previous work led by Dr. Chen-Plotkin suggested that ApoA1 levels may be a new biomarker for Parkinson’s disease risk. The team is now conducting a follow-up study on plasma ApoA1 and statins, evaluating participants in the Michael J. Fox Foundation’s Parkinson’s Progression Marker Initiative cohort to confirm whether ApoA1-modifying drugs such as statins may be a promising neuroprotective therapy for Parkinson’s disease.

Estrogen Investigated for Protection From Parkinson’s Disease
In another study, an analysis by Kara Smith, MD, a movement disorders fellow in Neurology at the Perelman School of Medicine, and colleagues investigated the role that estrogen plays in decreasing the lifetime risk of Parkinson’s disease, in light of the fact that men have a relative risk of 1.5 for having Parkinson’s disease compared with women. In a systematic review of studies using animal models of Parkinson’s disease, the research team found consistent evidence that 17β-estradiol, in particular, may play a key role in binding to the estrogen receptor and protecting cells from Parkinson’s pathology. The team said that further research needs to look at 17β-estradiol in more accurate models of Parkinson’s disease before results can be translated to clinical trials in patients with Parkinson’s disease.

Telemedicine Improves Access to Specialty Parkinson’s Care
To help remove barriers to specialty care experienced by many patients who live far from care or have disabilities that make it difficult to travel, University of Pennsylvania researchers examined use of telemedicine visits to increase access to specialty care for patients with Parkinson’s disease.

A research team led by Jayne Wilkinson, MD, and Meredith Spinder, MD, conducted a randomized controlled trial using video telemedicine in the patient’s home or at a facility near the patient. In the case of this study, that location was VA Community-Based Outpatient Clinics, which connected them to a neurologist specializing in movement disorders and Parkinson’s disease who was based at the Parkinson’s Disease Research, Education, and Clinical Center at the Philadelphia VA Medical Center.

Early results demonstrate that the process of using telemedicine for Parkinson’s disease care is feasible, provided similar quality of life, care, and communication, and significantly decreased travel.

Acetazolamide May Improve Vision in Patients With Idiopathic Intracranial Hypertension
When administered with a low-sodium weight-reduction diet, acetazolamide modestly improves visual field function in patients with idiopathic intracranial hypertension, according to research presented at the 66th Annual Meeting of the American Academy of Neurology. The drug and diet together may be more effective than the diet alone for improving vision. Acetazolamide also may prevent further progression of visual loss in these patients.

Michael Wall, MD, Professor of Neurology at the University of Iowa Carver College of Medicine in Iowa City, and colleagues enrolled 165 participants with idiopathic intracranial hypertension and mild visual loss in a multicenter study. Patients’ mean age was 29, and all but four participants were women. All patients received a low-sodium weight-reduction diet. Participants were randomized to as much as 4 g/day of acetazolamide or matching placebo and followed up for six months.

The trial’s primary end point was the change in perimetric mean deviation (PMD) from baseline to month six in the most affected eye, as measured by Humphrey Field Analyzer. PMD is a measure of global visual field loss with a range of 2 to −32 dB. Larger negative values indicate greater vision loss.

At six months, the mean improvement in PMD was greater with acetazolamide (1.43 dB) than with placebo (0.71 dB). In addition, papilledema grade improved from 2.76 to 1.45 for patients receiving acetazolamide, compared with an improvement from 2.76 to 2.15 for patients receiving placebo. Vision-related quality of life, as measured by the Visual Function Questionnaire 25, improved from 82.97 to 91.30 for patients receiving acetazolamide, compared with an improvement from 82.97 to 84.95 for patients receiving placebo. Participants assigned to acetazolamide also lost 7.50 kg, compared with 3.45 kg for patients receiving placebo.

Idiopathic intracranial hypertension primarily affects young women who are overweight or obese. The disease’s incidence ranges from 10 to 20 patients per 100,000, and incidence increases with increasing BMI. The condition presents with persistent debilitating headaches and visual loss.

Acetazolamide previously has been used to treat idiopathic and secondary intracranial hypertension syndromes. The drug has been on the market “for a long time” and “is a fairly benign medication,” said Natalia Rost, MD, Associate Director of Acute Stroke Services at Massachusetts General Hospital in Boston. Some patients who take acetazolamide report tremors, added Dr. Rost, who described Dr. Wall’s study.

—Erik Greb

A Link Between Caffeinated Soda and Huntington’s Disease?
Total lifetime caffeinated soda consumption may be associated with an earlier onset of Huntington’s disease, reported Caroline Tanner, MD, PhD, and colleagues at the 66th Annual Meeting of the American Academy of Neurology.

The researchers sought to assess the role of various health and lifestyle factors on phenoconversion in persons who are at risk for Huntington’s disease with the CAG expansion (CAG >37). All participants were enrolled in the Prospective Huntington at Risk Observational Study. Previous research has found that the environment may cause 60% of the variance in disease onset age that is not due to CAGn, as well as an association between caffeine use and an earlier age of Huntington’s disease onset.

With the use of self-report questionnaires, the investigators analyzed participants’ exposure to tobacco, caffeine, alcohol, nonsteroidal anti-inflammatory drugs, vitamins, estrogen in women, head injury, physical activity, and cognitive activity. The researchers compared the time from baseline to motor phenoconversion between exposure groups in CAG >37 subjects by using Cox proportional hazards analyses that were adjusted for age, gender, and CAGn.

A total of 247 persons with CAG >37 completed the questionnaire. Some risk factors, such as caffeine, were “very common,” occurring in 99% of subjects, noted Dr. Tanner, who is the Director of Clinical Research at the Parkinson’s Institute and Clinical Center in Sunnyvale, California. The mean follow-up was 4.2 years (SD, 2), during which 36 persons phenoconverted.

“Drinking larger amounts of caffeinated soda predicted shorter time to phenoconversion,” said Dr. Tanner. “Six percent of low lifetime caffeinated soda consumers phenoconverted, compared with 13% of moderate consumers and 22% of high consumers.”

The hazard ratios for phenoconversion were 3.08 for moderate caffeinated soda consumers and 5.86 for high caffeinated soda consumers. Dr. Tanner noted that the association between lifetime caffeinated soda consumption and earlier onset of Huntington’s disease “was not seen with other caffeinated beverages and may be spurious. Other lifestyle risk factors associated with Parkinson’s disease or Alzheimer’s disease did not modify time to phenoconversion in Huntington’s disease.”

—Colby Stong

PHILADELPHIA—Certain forms of medical marijuana can help treat symptoms of multiple sclerosis (MS), but they may not be helpful in treating levodopa-induced movements in Parkinson’s disease, researchers reported at the 66th Annual Meeting of the American Academy of Neurology (AAN).

The researchers did not find enough evidence to show whether medical marijuana is helpful in treating motor problems in Huntington’s disease, tics in Tourette syndrome, cervical dystonia, and seizures in epilepsy. These conclusions are part of AAN’s review of scientific research on the use of medical marijuana in brain diseases. The findings were published in the April 29, 2014, print issue of Neurology.

“This review by the world’s largest association for neurologists is intended to help neurologists and their patients understand the current research on medical marijuana for the treatment of certain brain diseases,” said review author Barbara S. Koppel, MD, of New York Medical College in Valhalla, and Fellow of the AAN. “The AAN review also highlights the need for more high-quality studies of the long-term efficacy and safety of medical marijuana in the treatment of neurologic diseases.”

The AAN review concluded that only the pill or oral spray forms of medical marijuana can help treat symptoms of MS, including spasticity, certain types of pain (ie, pain related to spasticity, including painful spasms, and painful burning and numbness), and overactive bladder. Most of the MS studies examined pill or oral spray forms of medical marijuana. Two studies examined smoked medical marijuana for treating MS symptoms, but these studies did not provide enough information to show whether smoked medical marijuana is effective. “It’s important to note that medical marijuana can worsen thinking and memory problems, and this is a concern, since many people with MS suffer from these problems already due to the disease itself,” said Dr. Koppel.

In addition, the AAN review concluded that medical marijuana, in the form of synthetic tetrahydrocannabinol (THC) pills, likely does not help relieve abnormal movements that can develop in the late stages of Parkinson’s disease as a result of levodopa.

Medical marijuana use does entail safety concerns. In at least two studies, participants reported side effects such as nausea, increased weakness, behavioral or mood changes, suicidal thoughts or hallucinations, dizziness or fainting symptoms, fatigue, and feelings of intoxication. There were reports of two seizures. Mood changes and suicidal thoughts are of special concern for people with neurologic illness, who are at an increased risk for depression and suicide. The risk of serious psychologic effects is approximately 1%, according to the studies.

The only two medical marijuana pills with FDA approval contain THC. “The psychoactive side effects, such as feeling intoxicated, seemed to come from the THC,” said Dr. Koppel. “They’re trying to create pills that are leaning more toward the cannabinoid, which has the therapeutic effects with fewer psychoactive side effects.”

Clinicians who practice in states where medical marijuana is legal may recommend the drug for the MS symptoms that respond to it, Dr. Koppel added. “The problem is that the studies are done very rigorously with a certain amount of THC versus cannabinoid. The type of marijuana you can buy so far is not so rigorously defined.” Clinicians also should warn their patients about marijuana’s potential side effects.

In general, medical marijuana is prescribed as a treatment only when standard treatment has not helped. In most of the studies reviewed, patients were allowed to continue their standard treatments. The AAN review is endorsed by the American Autonomic Society, the American Epilepsy Society, and the International Rett Syndrome Foundation.

—Erik Greb

New Drugs May Offer Hope for Migraine Prevention
Two new studies may offer hope for patients with migraine. Both studies involve drugs for migraine prophylaxis rather than acute treatment. These studies are among the first to test monoclonal antibodies for the prevention of migraine, and both are directed against calcitonin gene-related peptide (CGRP), a relatively new target in migraine prevention. Both are phase II studies.

One study involved 163 patients who had migraine from five to 14 days per month. The patients received either a placebo or a single IV dose of a drug called ALD403. After the initial injection, study participants were followed for 24 weeks. Those who received the drug had an average of 5.6 fewer migraine days per month, a 66% decrease, compared with 4.6 fewer days per month for those who received a placebo, or a 52% decrease. Sixteen percent of those who received the drug had no migraine days at 12 weeks, while none of those who received the placebo were free from migraine at that point.

There were no differences in side effects between those receiving the drug and those receiving the placebo.

“These results may potentially represent a new era in preventive therapy for migraine,” said Peter Goadsby, MD, PhD, of the University of California, San Francisco, who was an investigator in both studies.

“Migraine remains poorly treated, and there are few effective and well-tolerated treatments approved that prevent attacks from occurring,” said coinvestigator David Dodick, MD, of Mayo Clinic Arizona in Phoenix. “There is a huge treatment need for migraine—the third most common and seventh most disabling medical disorder in the world.”

In the second study, 217 patients who had migraine four to 14 days per month received biweekly subcutaneous injections of either a placebo or a drug called LY2951742 for 12 weeks.

Those who received the drug had an average of 4.2 fewer migraine days per month at 12 weeks, or a 63% decrease, while those who received placebo had three fewer migraine days per month, or a 42% decrease. Those who received the drug were more likely to have side effects including pain at the injection site, upper respiratory tract infections, and abdominal pain, but overall the drug was considered to be safe and well tolerated.

“We’re cautiously optimistic that a new era of mechanism-based migraine prevention is beginning,” Dr. Dodick said.

Botulinum Toxin for Poststroke Spasticity—Could a Higher Dosage Yield Greater Benefit?
Although patients with poststroke spasticity are generally satisfied with their botulinum toxin treatment, many individuals may derive additional benefit with higher dosages and shorter injection intervals than the standard 12-week regimen, researchers reported at the 66th Annual Meeting of the American Academy of Neurology.

Djamel Bensmail, MD, PhD, and colleagues conducted two cross-sectional surveys among patients and physicians in Canada, France, Germany, and the United States. A total of 79 eligible patients had received two or more treatments of abobotulinumtoxinA, incobotulinumtoxinA, or onabotulinumtoxinA for poststroke spasticity. The investigators gathered data regarding current and prior botulinum toxin treatments along with physician and patient treatment satisfaction. All 105 participating physicians had treated patients with poststroke spasticity and had three or more years’ experience of injecting botulinum toxin.

“Botulinum toxin injections are the first-line treatment for patients with poststroke spasticity,” stated Dr. Bensmail, from the Department of Physical Medicine and Rehabilitation, R. Poincaré Hospital, AP-HP, University of Versailles Saint Quentin in Garches, France. “However, for some patients, treatment at the standard-of-care 12‑week interval may result in re-emergence of symptoms before reinjection.”

Sixty-one patients (77%) received onabotulinumtoxinA, 15 patients (19%) received abobotulinumtoxinA, and three patients (4%) received incobotulinumtoxinA. The researchers found that 40.5% of patients were overall very satisfied with the treatment, and 48.1% were somewhat satisfied with their current treatment.

“Satisfaction was highest at the time of peak effect and lowest just before reinjection,” stated the investigators. “While 78.9% of patients preferred injection intervals of less than or equal to 12 weeks, only 45.6% received such intervals. Intervals of 10 weeks or fewer were preferred by 43.4% of patients but received by just 6.3%. The mean interval was 13.7 weeks.”

Among the physicians surveyed, most (57.7%) were moderately or very satisfied (36.5%) with botulinum
toxin treatment for poststroke spasticity. However, the physicians also believed, on average, that 16.2% of patients would benefit from shorter injection intervals and that 24.6% would benefit from higher doses than those that are approved.

—Colby Stong

Potential Targets and Interventions for Parkinson’s Disease
A trio of studies from researchers at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia demonstrate new approaches to understanding, treating, and potentially staving off Parkinson’s disease. Studies show that factors such as estrogen exposure and statin use have an impact on the onset of Parkinson’s disease. And a new look at telemedicine demonstrates feasibility in providing care for patients with Parkinson’s disease using remote video visits to expand access and center care around the needs of the patients.

Statins May Delay Onset of Parkinson’s Disease
Research presented by Yosef Berlyand, an undergraduate in the laboratory of Alice Chen-Plotkin, MD, MSc, Assistant Professor of Neurology, suggests that statins may be beneficial in Parkinson’s disease. In collaboration with Roy Alcalay, MD, and colleagues at the Columbia University School of Medicine, members of Dr. Chen-Plotkin’s research group demonstrated that blood levels of the protein apolipoprotein A1 (ApoA1) are lower in people with Parkinson’s disease than in those without the disease. Patients with Parkinson’s disease taking statins, which can elevate levels of ApoA1, had an older age of disease onset, which appears to be driven by taking statins.

Previous work led by Dr. Chen-Plotkin suggested that ApoA1 levels may be a new biomarker for Parkinson’s disease risk. The team is now conducting a follow-up study on plasma ApoA1 and statins, evaluating participants in the Michael J. Fox Foundation’s Parkinson’s Progression Marker Initiative cohort to confirm whether ApoA1-modifying drugs such as statins may be a promising neuroprotective therapy for Parkinson’s disease.

Estrogen Investigated for Protection From Parkinson’s Disease
In another study, an analysis by Kara Smith, MD, a movement disorders fellow in Neurology at the Perelman School of Medicine, and colleagues investigated the role that estrogen plays in decreasing the lifetime risk of Parkinson’s disease, in light of the fact that men have a relative risk of 1.5 for having Parkinson’s disease compared with women. In a systematic review of studies using animal models of Parkinson’s disease, the research team found consistent evidence that 17β-estradiol, in particular, may play a key role in binding to the estrogen receptor and protecting cells from Parkinson’s pathology. The team said that further research needs to look at 17β-estradiol in more accurate models of Parkinson’s disease before results can be translated to clinical trials in patients with Parkinson’s disease.

Telemedicine Improves Access to Specialty Parkinson’s Care
To help remove barriers to specialty care experienced by many patients who live far from care or have disabilities that make it difficult to travel, University of Pennsylvania researchers examined use of telemedicine visits to increase access to specialty care for patients with Parkinson’s disease.

A research team led by Jayne Wilkinson, MD, and Meredith Spinder, MD, conducted a randomized controlled trial using video telemedicine in the patient’s home or at a facility near the patient. In the case of this study, that location was VA Community-Based Outpatient Clinics, which connected them to a neurologist specializing in movement disorders and Parkinson’s disease who was based at the Parkinson’s Disease Research, Education, and Clinical Center at the Philadelphia VA Medical Center.

Early results demonstrate that the process of using telemedicine for Parkinson’s disease care is feasible, provided similar quality of life, care, and communication, and significantly decreased travel.

Acetazolamide May Improve Vision in Patients With Idiopathic Intracranial Hypertension
When administered with a low-sodium weight-reduction diet, acetazolamide modestly improves visual field function in patients with idiopathic intracranial hypertension, according to research presented at the 66th Annual Meeting of the American Academy of Neurology. The drug and diet together may be more effective than the diet alone for improving vision. Acetazolamide also may prevent further progression of visual loss in these patients.

Michael Wall, MD, Professor of Neurology at the University of Iowa Carver College of Medicine in Iowa City, and colleagues enrolled 165 participants with idiopathic intracranial hypertension and mild visual loss in a multicenter study. Patients’ mean age was 29, and all but four participants were women. All patients received a low-sodium weight-reduction diet. Participants were randomized to as much as 4 g/day of acetazolamide or matching placebo and followed up for six months.

The trial’s primary end point was the change in perimetric mean deviation (PMD) from baseline to month six in the most affected eye, as measured by Humphrey Field Analyzer. PMD is a measure of global visual field loss with a range of 2 to −32 dB. Larger negative values indicate greater vision loss.

At six months, the mean improvement in PMD was greater with acetazolamide (1.43 dB) than with placebo (0.71 dB). In addition, papilledema grade improved from 2.76 to 1.45 for patients receiving acetazolamide, compared with an improvement from 2.76 to 2.15 for patients receiving placebo. Vision-related quality of life, as measured by the Visual Function Questionnaire 25, improved from 82.97 to 91.30 for patients receiving acetazolamide, compared with an improvement from 82.97 to 84.95 for patients receiving placebo. Participants assigned to acetazolamide also lost 7.50 kg, compared with 3.45 kg for patients receiving placebo.

Idiopathic intracranial hypertension primarily affects young women who are overweight or obese. The disease’s incidence ranges from 10 to 20 patients per 100,000, and incidence increases with increasing BMI. The condition presents with persistent debilitating headaches and visual loss.

Acetazolamide previously has been used to treat idiopathic and secondary intracranial hypertension syndromes. The drug has been on the market “for a long time” and “is a fairly benign medication,” said Natalia Rost, MD, Associate Director of Acute Stroke Services at Massachusetts General Hospital in Boston. Some patients who take acetazolamide report tremors, added Dr. Rost, who described Dr. Wall’s study.

—Erik Greb

A Link Between Caffeinated Soda and Huntington’s Disease?
Total lifetime caffeinated soda consumption may be associated with an earlier onset of Huntington’s disease, reported Caroline Tanner, MD, PhD, and colleagues at the 66th Annual Meeting of the American Academy of Neurology.

The researchers sought to assess the role of various health and lifestyle factors on phenoconversion in persons who are at risk for Huntington’s disease with the CAG expansion (CAG >37). All participants were enrolled in the Prospective Huntington at Risk Observational Study. Previous research has found that the environment may cause 60% of the variance in disease onset age that is not due to CAGn, as well as an association between caffeine use and an earlier age of Huntington’s disease onset.

With the use of self-report questionnaires, the investigators analyzed participants’ exposure to tobacco, caffeine, alcohol, nonsteroidal anti-inflammatory drugs, vitamins, estrogen in women, head injury, physical activity, and cognitive activity. The researchers compared the time from baseline to motor phenoconversion between exposure groups in CAG >37 subjects by using Cox proportional hazards analyses that were adjusted for age, gender, and CAGn.

A total of 247 persons with CAG >37 completed the questionnaire. Some risk factors, such as caffeine, were “very common,” occurring in 99% of subjects, noted Dr. Tanner, who is the Director of Clinical Research at the Parkinson’s Institute and Clinical Center in Sunnyvale, California. The mean follow-up was 4.2 years (SD, 2), during which 36 persons phenoconverted.

“Drinking larger amounts of caffeinated soda predicted shorter time to phenoconversion,” said Dr. Tanner. “Six percent of low lifetime caffeinated soda consumers phenoconverted, compared with 13% of moderate consumers and 22% of high consumers.”

The hazard ratios for phenoconversion were 3.08 for moderate caffeinated soda consumers and 5.86 for high caffeinated soda consumers. Dr. Tanner noted that the association between lifetime caffeinated soda consumption and earlier onset of Huntington’s disease “was not seen with other caffeinated beverages and may be spurious. Other lifestyle risk factors associated with Parkinson’s disease or Alzheimer’s disease did not modify time to phenoconversion in Huntington’s disease.”

—Colby Stong

PHILADELPHIA—Certain forms of medical marijuana can help treat symptoms of multiple sclerosis (MS), but they may not be helpful in treating levodopa-induced movements in Parkinson’s disease, researchers reported at the 66th Annual Meeting of the American Academy of Neurology (AAN).

The researchers did not find enough evidence to show whether medical marijuana is helpful in treating motor problems in Huntington’s disease, tics in Tourette syndrome, cervical dystonia, and seizures in epilepsy. These conclusions are part of AAN’s review of scientific research on the use of medical marijuana in brain diseases. The findings were published in the April 29, 2014, print issue of Neurology.

“This review by the world’s largest association for neurologists is intended to help neurologists and their patients understand the current research on medical marijuana for the treatment of certain brain diseases,” said review author Barbara S. Koppel, MD, of New York Medical College in Valhalla, and Fellow of the AAN. “The AAN review also highlights the need for more high-quality studies of the long-term efficacy and safety of medical marijuana in the treatment of neurologic diseases.”

The AAN review concluded that only the pill or oral spray forms of medical marijuana can help treat symptoms of MS, including spasticity, certain types of pain (ie, pain related to spasticity, including painful spasms, and painful burning and numbness), and overactive bladder. Most of the MS studies examined pill or oral spray forms of medical marijuana. Two studies examined smoked medical marijuana for treating MS symptoms, but these studies did not provide enough information to show whether smoked medical marijuana is effective. “It’s important to note that medical marijuana can worsen thinking and memory problems, and this is a concern, since many people with MS suffer from these problems already due to the disease itself,” said Dr. Koppel.

In addition, the AAN review concluded that medical marijuana, in the form of synthetic tetrahydrocannabinol (THC) pills, likely does not help relieve abnormal movements that can develop in the late stages of Parkinson’s disease as a result of levodopa.

Medical marijuana use does entail safety concerns. In at least two studies, participants reported side effects such as nausea, increased weakness, behavioral or mood changes, suicidal thoughts or hallucinations, dizziness or fainting symptoms, fatigue, and feelings of intoxication. There were reports of two seizures. Mood changes and suicidal thoughts are of special concern for people with neurologic illness, who are at an increased risk for depression and suicide. The risk of serious psychologic effects is approximately 1%, according to the studies.

The only two medical marijuana pills with FDA approval contain THC. “The psychoactive side effects, such as feeling intoxicated, seemed to come from the THC,” said Dr. Koppel. “They’re trying to create pills that are leaning more toward the cannabinoid, which has the therapeutic effects with fewer psychoactive side effects.”

Clinicians who practice in states where medical marijuana is legal may recommend the drug for the MS symptoms that respond to it, Dr. Koppel added. “The problem is that the studies are done very rigorously with a certain amount of THC versus cannabinoid. The type of marijuana you can buy so far is not so rigorously defined.” Clinicians also should warn their patients about marijuana’s potential side effects.

In general, medical marijuana is prescribed as a treatment only when standard treatment has not helped. In most of the studies reviewed, patients were allowed to continue their standard treatments. The AAN review is endorsed by the American Autonomic Society, the American Epilepsy Society, and the International Rett Syndrome Foundation.

—Erik Greb

New Drugs May Offer Hope for Migraine Prevention
Two new studies may offer hope for patients with migraine. Both studies involve drugs for migraine prophylaxis rather than acute treatment. These studies are among the first to test monoclonal antibodies for the prevention of migraine, and both are directed against calcitonin gene-related peptide (CGRP), a relatively new target in migraine prevention. Both are phase II studies.

One study involved 163 patients who had migraine from five to 14 days per month. The patients received either a placebo or a single IV dose of a drug called ALD403. After the initial injection, study participants were followed for 24 weeks. Those who received the drug had an average of 5.6 fewer migraine days per month, a 66% decrease, compared with 4.6 fewer days per month for those who received a placebo, or a 52% decrease. Sixteen percent of those who received the drug had no migraine days at 12 weeks, while none of those who received the placebo were free from migraine at that point.

There were no differences in side effects between those receiving the drug and those receiving the placebo.

“These results may potentially represent a new era in preventive therapy for migraine,” said Peter Goadsby, MD, PhD, of the University of California, San Francisco, who was an investigator in both studies.

“Migraine remains poorly treated, and there are few effective and well-tolerated treatments approved that prevent attacks from occurring,” said coinvestigator David Dodick, MD, of Mayo Clinic Arizona in Phoenix. “There is a huge treatment need for migraine—the third most common and seventh most disabling medical disorder in the world.”

In the second study, 217 patients who had migraine four to 14 days per month received biweekly subcutaneous injections of either a placebo or a drug called LY2951742 for 12 weeks.

Those who received the drug had an average of 4.2 fewer migraine days per month at 12 weeks, or a 63% decrease, while those who received placebo had three fewer migraine days per month, or a 42% decrease. Those who received the drug were more likely to have side effects including pain at the injection site, upper respiratory tract infections, and abdominal pain, but overall the drug was considered to be safe and well tolerated.

“We’re cautiously optimistic that a new era of mechanism-based migraine prevention is beginning,” Dr. Dodick said.

Botulinum Toxin for Poststroke Spasticity—Could a Higher Dosage Yield Greater Benefit?
Although patients with poststroke spasticity are generally satisfied with their botulinum toxin treatment, many individuals may derive additional benefit with higher dosages and shorter injection intervals than the standard 12-week regimen, researchers reported at the 66th Annual Meeting of the American Academy of Neurology.

Djamel Bensmail, MD, PhD, and colleagues conducted two cross-sectional surveys among patients and physicians in Canada, France, Germany, and the United States. A total of 79 eligible patients had received two or more treatments of abobotulinumtoxinA, incobotulinumtoxinA, or onabotulinumtoxinA for poststroke spasticity. The investigators gathered data regarding current and prior botulinum toxin treatments along with physician and patient treatment satisfaction. All 105 participating physicians had treated patients with poststroke spasticity and had three or more years’ experience of injecting botulinum toxin.

“Botulinum toxin injections are the first-line treatment for patients with poststroke spasticity,” stated Dr. Bensmail, from the Department of Physical Medicine and Rehabilitation, R. Poincaré Hospital, AP-HP, University of Versailles Saint Quentin in Garches, France. “However, for some patients, treatment at the standard-of-care 12‑week interval may result in re-emergence of symptoms before reinjection.”

Sixty-one patients (77%) received onabotulinumtoxinA, 15 patients (19%) received abobotulinumtoxinA, and three patients (4%) received incobotulinumtoxinA. The researchers found that 40.5% of patients were overall very satisfied with the treatment, and 48.1% were somewhat satisfied with their current treatment.

“Satisfaction was highest at the time of peak effect and lowest just before reinjection,” stated the investigators. “While 78.9% of patients preferred injection intervals of less than or equal to 12 weeks, only 45.6% received such intervals. Intervals of 10 weeks or fewer were preferred by 43.4% of patients but received by just 6.3%. The mean interval was 13.7 weeks.”

Among the physicians surveyed, most (57.7%) were moderately or very satisfied (36.5%) with botulinum
toxin treatment for poststroke spasticity. However, the physicians also believed, on average, that 16.2% of patients would benefit from shorter injection intervals and that 24.6% would benefit from higher doses than those that are approved.

—Colby Stong

Potential Targets and Interventions for Parkinson’s Disease
A trio of studies from researchers at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia demonstrate new approaches to understanding, treating, and potentially staving off Parkinson’s disease. Studies show that factors such as estrogen exposure and statin use have an impact on the onset of Parkinson’s disease. And a new look at telemedicine demonstrates feasibility in providing care for patients with Parkinson’s disease using remote video visits to expand access and center care around the needs of the patients.

Statins May Delay Onset of Parkinson’s Disease
Research presented by Yosef Berlyand, an undergraduate in the laboratory of Alice Chen-Plotkin, MD, MSc, Assistant Professor of Neurology, suggests that statins may be beneficial in Parkinson’s disease. In collaboration with Roy Alcalay, MD, and colleagues at the Columbia University School of Medicine, members of Dr. Chen-Plotkin’s research group demonstrated that blood levels of the protein apolipoprotein A1 (ApoA1) are lower in people with Parkinson’s disease than in those without the disease. Patients with Parkinson’s disease taking statins, which can elevate levels of ApoA1, had an older age of disease onset, which appears to be driven by taking statins.

Previous work led by Dr. Chen-Plotkin suggested that ApoA1 levels may be a new biomarker for Parkinson’s disease risk. The team is now conducting a follow-up study on plasma ApoA1 and statins, evaluating participants in the Michael J. Fox Foundation’s Parkinson’s Progression Marker Initiative cohort to confirm whether ApoA1-modifying drugs such as statins may be a promising neuroprotective therapy for Parkinson’s disease.

Estrogen Investigated for Protection From Parkinson’s Disease
In another study, an analysis by Kara Smith, MD, a movement disorders fellow in Neurology at the Perelman School of Medicine, and colleagues investigated the role that estrogen plays in decreasing the lifetime risk of Parkinson’s disease, in light of the fact that men have a relative risk of 1.5 for having Parkinson’s disease compared with women. In a systematic review of studies using animal models of Parkinson’s disease, the research team found consistent evidence that 17β-estradiol, in particular, may play a key role in binding to the estrogen receptor and protecting cells from Parkinson’s pathology. The team said that further research needs to look at 17β-estradiol in more accurate models of Parkinson’s disease before results can be translated to clinical trials in patients with Parkinson’s disease.

Telemedicine Improves Access to Specialty Parkinson’s Care
To help remove barriers to specialty care experienced by many patients who live far from care or have disabilities that make it difficult to travel, University of Pennsylvania researchers examined use of telemedicine visits to increase access to specialty care for patients with Parkinson’s disease.

A research team led by Jayne Wilkinson, MD, and Meredith Spinder, MD, conducted a randomized controlled trial using video telemedicine in the patient’s home or at a facility near the patient. In the case of this study, that location was VA Community-Based Outpatient Clinics, which connected them to a neurologist specializing in movement disorders and Parkinson’s disease who was based at the Parkinson’s Disease Research, Education, and Clinical Center at the Philadelphia VA Medical Center.

Early results demonstrate that the process of using telemedicine for Parkinson’s disease care is feasible, provided similar quality of life, care, and communication, and significantly decreased travel.

Acetazolamide May Improve Vision in Patients With Idiopathic Intracranial Hypertension
When administered with a low-sodium weight-reduction diet, acetazolamide modestly improves visual field function in patients with idiopathic intracranial hypertension, according to research presented at the 66th Annual Meeting of the American Academy of Neurology. The drug and diet together may be more effective than the diet alone for improving vision. Acetazolamide also may prevent further progression of visual loss in these patients.

Michael Wall, MD, Professor of Neurology at the University of Iowa Carver College of Medicine in Iowa City, and colleagues enrolled 165 participants with idiopathic intracranial hypertension and mild visual loss in a multicenter study. Patients’ mean age was 29, and all but four participants were women. All patients received a low-sodium weight-reduction diet. Participants were randomized to as much as 4 g/day of acetazolamide or matching placebo and followed up for six months.

The trial’s primary end point was the change in perimetric mean deviation (PMD) from baseline to month six in the most affected eye, as measured by Humphrey Field Analyzer. PMD is a measure of global visual field loss with a range of 2 to −32 dB. Larger negative values indicate greater vision loss.

At six months, the mean improvement in PMD was greater with acetazolamide (1.43 dB) than with placebo (0.71 dB). In addition, papilledema grade improved from 2.76 to 1.45 for patients receiving acetazolamide, compared with an improvement from 2.76 to 2.15 for patients receiving placebo. Vision-related quality of life, as measured by the Visual Function Questionnaire 25, improved from 82.97 to 91.30 for patients receiving acetazolamide, compared with an improvement from 82.97 to 84.95 for patients receiving placebo. Participants assigned to acetazolamide also lost 7.50 kg, compared with 3.45 kg for patients receiving placebo.

Idiopathic intracranial hypertension primarily affects young women who are overweight or obese. The disease’s incidence ranges from 10 to 20 patients per 100,000, and incidence increases with increasing BMI. The condition presents with persistent debilitating headaches and visual loss.

Acetazolamide previously has been used to treat idiopathic and secondary intracranial hypertension syndromes. The drug has been on the market “for a long time” and “is a fairly benign medication,” said Natalia Rost, MD, Associate Director of Acute Stroke Services at Massachusetts General Hospital in Boston. Some patients who take acetazolamide report tremors, added Dr. Rost, who described Dr. Wall’s study.

—Erik Greb

A Link Between Caffeinated Soda and Huntington’s Disease?
Total lifetime caffeinated soda consumption may be associated with an earlier onset of Huntington’s disease, reported Caroline Tanner, MD, PhD, and colleagues at the 66th Annual Meeting of the American Academy of Neurology.

The researchers sought to assess the role of various health and lifestyle factors on phenoconversion in persons who are at risk for Huntington’s disease with the CAG expansion (CAG >37). All participants were enrolled in the Prospective Huntington at Risk Observational Study. Previous research has found that the environment may cause 60% of the variance in disease onset age that is not due to CAGn, as well as an association between caffeine use and an earlier age of Huntington’s disease onset.

With the use of self-report questionnaires, the investigators analyzed participants’ exposure to tobacco, caffeine, alcohol, nonsteroidal anti-inflammatory drugs, vitamins, estrogen in women, head injury, physical activity, and cognitive activity. The researchers compared the time from baseline to motor phenoconversion between exposure groups in CAG >37 subjects by using Cox proportional hazards analyses that were adjusted for age, gender, and CAGn.

A total of 247 persons with CAG >37 completed the questionnaire. Some risk factors, such as caffeine, were “very common,” occurring in 99% of subjects, noted Dr. Tanner, who is the Director of Clinical Research at the Parkinson’s Institute and Clinical Center in Sunnyvale, California. The mean follow-up was 4.2 years (SD, 2), during which 36 persons phenoconverted.

“Drinking larger amounts of caffeinated soda predicted shorter time to phenoconversion,” said Dr. Tanner. “Six percent of low lifetime caffeinated soda consumers phenoconverted, compared with 13% of moderate consumers and 22% of high consumers.”

The hazard ratios for phenoconversion were 3.08 for moderate caffeinated soda consumers and 5.86 for high caffeinated soda consumers. Dr. Tanner noted that the association between lifetime caffeinated soda consumption and earlier onset of Huntington’s disease “was not seen with other caffeinated beverages and may be spurious. Other lifestyle risk factors associated with Parkinson’s disease or Alzheimer’s disease did not modify time to phenoconversion in Huntington’s disease.”

—Colby Stong

PHILADELPHIA—Daily treatment with estriol and glatiramer acetate may reduce multiple sclerosis (MS) relapses significantly, compared with placebo and glatiramer acetate, according to research presented at the 66th Annual Meeting of the American Academy of Neurology. The difference may become evident within 12 months of treatment. Cognitive scores also may improve within 12 months of treatment with estriol and glatiramer acetate, compared with placebo plus glatiramer acetate.

A previous study of women with MS who were not pregnant indicated that the pregnancy hormone estriol was associated with a significant decrease in the number and volume of gadolinium-enhancing lesions on MRI. To examine the hormone’s effect on relapse rate, Rhonda Voskuhl, MD, Jack H. Skirball Chair of MS Research at the University of California, Los Angeles (UCLA), and colleagues conducted a randomized controlled trial of women with relapsing-remitting MS.

Comparing Estriol With Placebo in Patients With Active MS
Eligible patients were between ages 18 and 50, had active disease, and had an Expanded Disability Status Scale (EDSS) score between 0 and 4.5. Women who were pregnant, breastfeeding, taking hormone replacement therapy, or taking oral contraceptives were excluded from the trial.

Patients were randomized to glatiramer acetate injections (20 mg/day) and oral estriol (8 mg/day) or to glatiramer acetate injections and placebo. Gynecologists examined the patients before, during, and after the study. Each patient was examined at three- to six-month intervals during the trial. Patients also underwent mammograms before and after the study. In addition, at baseline, three months, six months, 12 months, 18 months, and 24 months, the investigators measured participants’ estriol levels, administered the EDSS, and administered the MS Functional Composite.

A total of 82 patients received glatiramer acetate plus estriol, and 76 patients received glatiramer acetate plus placebo. The trial’s dropout rate was 29%. Baseline characteristics were similar in both patient groups. Participants’ mean age was approximately 38, and their mean EDSS score was 2.2.

Estriol Was Associated With Reduced Relapse Rate
At 12 months, the annualized relapse rate was 47% lower among patients receiving estriol and glatiramer acetate, compared with patients receiving placebo and glatiramer acetate. After month 12, the group receiving estriol and glatiramer acetate had few relapses and few gadolinium-enhancing lesions on MRI, and the group’s annualized relapse rate remained stable and low at 24 months. Participants receiving placebo and glatiramer acetate had fewer relapses at month 24 than at baseline, and the difference in annualized relapse rate between the two groups decreased to 32%.

After 12 months of treatment, scores on the Paced Auditory Serial Addition Test (PASAT) at 3 and 2 seconds improved by approximately 6% (ie, 3 points), compared with scores at baseline, among patients receiving estriol and glatiramer acetate. The change largely resulted from a 12% improvement (ie, six to seven points) among participants scoring less than 55 at baseline, which reflected cognitive disability. The investigators observed no change in patients who scored higher than 55 (ie, those with little cognitive disability) at baseline. After 24 months of treatment, patients receiving estriol plus glatiramer acetate continued to have high PASAT scores, and participants receiving placebo plus glatiramer acetate began to improve.

Dr. Voskuhl is conducting an ongoing study at UCLA, the University of New Mexico, the University of Pennsylvania, and the University of Colorado that involves treatment with estriol in combination with most of the currently approved treatments for MS, including injectables and newer oral treatments. The goal of the study is to examine the effect of estriol on cognition.

—Erik Greb

PHILADELPHIA—Daily treatment with estriol and glatiramer acetate may reduce multiple sclerosis (MS) relapses significantly, compared with placebo and glatiramer acetate, according to research presented at the 66th Annual Meeting of the American Academy of Neurology. The difference may become evident within 12 months of treatment. Cognitive scores also may improve within 12 months of treatment with estriol and glatiramer acetate, compared with placebo plus glatiramer acetate.

A previous study of women with MS who were not pregnant indicated that the pregnancy hormone estriol was associated with a significant decrease in the number and volume of gadolinium-enhancing lesions on MRI. To examine the hormone’s effect on relapse rate, Rhonda Voskuhl, MD, Jack H. Skirball Chair of MS Research at the University of California, Los Angeles (UCLA), and colleagues conducted a randomized controlled trial of women with relapsing-remitting MS.

Comparing Estriol With Placebo in Patients With Active MS
Eligible patients were between ages 18 and 50, had active disease, and had an Expanded Disability Status Scale (EDSS) score between 0 and 4.5. Women who were pregnant, breastfeeding, taking hormone replacement therapy, or taking oral contraceptives were excluded from the trial.

Patients were randomized to glatiramer acetate injections (20 mg/day) and oral estriol (8 mg/day) or to glatiramer acetate injections and placebo. Gynecologists examined the patients before, during, and after the study. Each patient was examined at three- to six-month intervals during the trial. Patients also underwent mammograms before and after the study. In addition, at baseline, three months, six months, 12 months, 18 months, and 24 months, the investigators measured participants’ estriol levels, administered the EDSS, and administered the MS Functional Composite.

A total of 82 patients received glatiramer acetate plus estriol, and 76 patients received glatiramer acetate plus placebo. The trial’s dropout rate was 29%. Baseline characteristics were similar in both patient groups. Participants’ mean age was approximately 38, and their mean EDSS score was 2.2.

Estriol Was Associated With Reduced Relapse Rate
At 12 months, the annualized relapse rate was 47% lower among patients receiving estriol and glatiramer acetate, compared with patients receiving placebo and glatiramer acetate. After month 12, the group receiving estriol and glatiramer acetate had few relapses and few gadolinium-enhancing lesions on MRI, and the group’s annualized relapse rate remained stable and low at 24 months. Participants receiving placebo and glatiramer acetate had fewer relapses at month 24 than at baseline, and the difference in annualized relapse rate between the two groups decreased to 32%.

After 12 months of treatment, scores on the Paced Auditory Serial Addition Test (PASAT) at 3 and 2 seconds improved by approximately 6% (ie, 3 points), compared with scores at baseline, among patients receiving estriol and glatiramer acetate. The change largely resulted from a 12% improvement (ie, six to seven points) among participants scoring less than 55 at baseline, which reflected cognitive disability. The investigators observed no change in patients who scored higher than 55 (ie, those with little cognitive disability) at baseline. After 24 months of treatment, patients receiving estriol plus glatiramer acetate continued to have high PASAT scores, and participants receiving placebo plus glatiramer acetate began to improve.

Dr. Voskuhl is conducting an ongoing study at UCLA, the University of New Mexico, the University of Pennsylvania, and the University of Colorado that involves treatment with estriol in combination with most of the currently approved treatments for MS, including injectables and newer oral treatments. The goal of the study is to examine the effect of estriol on cognition.

—Erik Greb

PHILADELPHIA—Daily treatment with estriol and glatiramer acetate may reduce multiple sclerosis (MS) relapses significantly, compared with placebo and glatiramer acetate, according to research presented at the 66th Annual Meeting of the American Academy of Neurology. The difference may become evident within 12 months of treatment. Cognitive scores also may improve within 12 months of treatment with estriol and glatiramer acetate, compared with placebo plus glatiramer acetate.

A previous study of women with MS who were not pregnant indicated that the pregnancy hormone estriol was associated with a significant decrease in the number and volume of gadolinium-enhancing lesions on MRI. To examine the hormone’s effect on relapse rate, Rhonda Voskuhl, MD, Jack H. Skirball Chair of MS Research at the University of California, Los Angeles (UCLA), and colleagues conducted a randomized controlled trial of women with relapsing-remitting MS.

Comparing Estriol With Placebo in Patients With Active MS
Eligible patients were between ages 18 and 50, had active disease, and had an Expanded Disability Status Scale (EDSS) score between 0 and 4.5. Women who were pregnant, breastfeeding, taking hormone replacement therapy, or taking oral contraceptives were excluded from the trial.

Patients were randomized to glatiramer acetate injections (20 mg/day) and oral estriol (8 mg/day) or to glatiramer acetate injections and placebo. Gynecologists examined the patients before, during, and after the study. Each patient was examined at three- to six-month intervals during the trial. Patients also underwent mammograms before and after the study. In addition, at baseline, three months, six months, 12 months, 18 months, and 24 months, the investigators measured participants’ estriol levels, administered the EDSS, and administered the MS Functional Composite.

A total of 82 patients received glatiramer acetate plus estriol, and 76 patients received glatiramer acetate plus placebo. The trial’s dropout rate was 29%. Baseline characteristics were similar in both patient groups. Participants’ mean age was approximately 38, and their mean EDSS score was 2.2.

Estriol Was Associated With Reduced Relapse Rate
At 12 months, the annualized relapse rate was 47% lower among patients receiving estriol and glatiramer acetate, compared with patients receiving placebo and glatiramer acetate. After month 12, the group receiving estriol and glatiramer acetate had few relapses and few gadolinium-enhancing lesions on MRI, and the group’s annualized relapse rate remained stable and low at 24 months. Participants receiving placebo and glatiramer acetate had fewer relapses at month 24 than at baseline, and the difference in annualized relapse rate between the two groups decreased to 32%.

After 12 months of treatment, scores on the Paced Auditory Serial Addition Test (PASAT) at 3 and 2 seconds improved by approximately 6% (ie, 3 points), compared with scores at baseline, among patients receiving estriol and glatiramer acetate. The change largely resulted from a 12% improvement (ie, six to seven points) among participants scoring less than 55 at baseline, which reflected cognitive disability. The investigators observed no change in patients who scored higher than 55 (ie, those with little cognitive disability) at baseline. After 24 months of treatment, patients receiving estriol plus glatiramer acetate continued to have high PASAT scores, and participants receiving placebo plus glatiramer acetate began to improve.

Dr. Voskuhl is conducting an ongoing study at UCLA, the University of New Mexico, the University of Pennsylvania, and the University of Colorado that involves treatment with estriol in combination with most of the currently approved treatments for MS, including injectables and newer oral treatments. The goal of the study is to examine the effect of estriol on cognition.

—Erik Greb

PHILADELPHIA—Among patients with relapsing-remitting multiple sclerosis (MS), a thrice-weekly 40-mg subcutaneous dose of glatiramer acetate, which the FDA approved in January 2014, reduces the rate of injection-related adverse events by approximately 50%, compared with the standard dose of 20 mg/day, according to research presented at the 66th Annual Meeting of the American Academy of Neurology. The 40-mg dose is associated with a similar reduction in the rate of direct injection-site reactions.

In a separate study, early treatment with 40 mg of glatiramer acetate was associated with a 31% reduction in the number of confirmed relapses, compared with delayed treatment. Early treatment also was associated with a 67.5% likelihood of relapse freedom, compared with delayed treatment. Early treatment did not affect the rate of disease progression significantly, compared with delayed treatment, but the open-label extension study was not designed to assess disease progression.

The 40-mg dose of glatiramer acetate could affect patient compliance in several ways. For example, patients may prefer receiving injections three times per week to receiving daily injections, but the latter schedule may be easier for patients to remember than the former. “I counsel my patients who want less-frequent injections to set their calendars up [and] to be careful about what they’re doing, because it will take a little bit more behavior change or adaptation on their part to do this correctly,” said Jerry Wolinsky, MD, Interim Chair of the Department of Neurology at the University of Texas in Houston.

One problem with the long-term injection of glatiramer acetate is that patients may develop lipoatrophy. “We expect, but don’t know, that with fewer injections, what has been a major compliance problem for some patients in the long run may be put off for years by this kind of a preparation,” added Dr. Wolinsky.

Safety Study Compared 20-mg and 40-mg Doses
Dr. Wolinsky and colleagues performed an open-label, multicenter study to compare the acceptability and tolerability of two formulations of glatiramer acetate. For the study, the researchers enrolled 209 patients with relapsing-remitting MS who had been receiving daily 20-mg injections of glatiramer acetate for at least six months. Eligible participants were 18 or older, were fully ambulatory, had an Expanded Disability Status Scale (EDSS) score between 0 and 5.5, and were relapse-free in the 60 days before randomization.

The investigators randomized 101 participants to continue daily 20-mg injections of glatiramer acetate. The remaining 108 patients were randomized to 40-mg injections of glatiramer acetate three times per week. At the end of a four-month study period, patients were given the option of continuing on 40-mg injections until the trial was completed. Dr. Wolinsky and colleagues conducted various assessments, including subject-reported outcome questionnaires and standard examinations and testing.

The study population differed from that of the typical clinical trial in MS, said Dr. Wolinsky. Average age for patients in this trial was more than 50, and the population included a larger proportion of women than is common in similar studies. In addition, patients’ average disease duration was approximately 16 years, and average time to diagnosis ranged from 10 to 12 years. Participants had a low reported exacerbation rate and a low EDSS score at study entry.

Patients Found the 40-mg Dose Convenient
The trial’s primary end point was the rate of injection-related adverse events, and 40-mg injections of glatiramer acetate were associated with a significant reduction in these events. Secondary end points included the treatment’s effect on questionnaires of physical and psychological well-being (as measured by the MS Impact Scale 29) and subjects’ perceptions of convenience and satisfaction. The researchers found no significant differences between treatment arms in the physical or psychological scores of the MS Impact Scale 29. Convenience scores on the Treatment Satisfaction Questionnaire for Medication-9 appeared to favor the high dose of glatiramer acetate.

Most adverse events in the trial were related to the direct injection, and no new safety signals were reported for glatiramer acetate. “The 40-mg three-times-a-week dosing regime appears to be a favorable treatment option for patients who want glatiramer acetate treatment but prefer fewer subcutaneous injections,” concluded Dr. Wolinsky.

Researchers Examined Efficacy of 40-mg Injections
Omar Khan, MD, Chair and Professor of Neurology at Wayne State University School of Medicine in Detroit, and colleagues conducted an open-label extension study to assess the ongoing safety and efficacy of thrice-weekly subcutaneous 40-mg injections of glatiramer acetate. Of the approximately 1,400 participants in a previous placebo-controlled study, 1,253 patients with relapsing-remitting MS agreed to participate in the open-label extension. The investigators grouped patients into two distinct arms. Participants in the early-start arm had received 40-mg injections of glatiramer acetate thrice weekly for 12 months in the placebo-controlled trial, and they continued to receive this treatment in the extension. Patients in the delayed-start arm had received placebo for 12 months in the placebo-controlled study and received thrice-weekly 40-mg injections of glatiramer acetate in the extension. The clinical end point was the total number of confirmed relapses.

The participants’ average EDSS was approximately 2.8, and disease onset had occurred approximately seven and a half years previously, on average. The volume of T2 lesion load ranged from 17 cm³ to 20 cm³, which was “remarkably high” for patients with relapsing-remitting MS, said Dr. Khan. In most relapsing-remitting trials, T2 lesion load ranges between 7 cm³ and 9 cm³, he added.

Early Treatment Was Associated With Improved Outcomes
At the end of the placebo-controlled study, the new formulation of glatiramer acetate was associated with a 34% reduction in confirmed relapses, compared with placebo. At 12 months of the open-label extension, participants who had never been exposed to placebo had 31% fewer confirmed relapses, compared with patients in the delayed-start arm. The results emphasize “that starting treatment early makes a difference,” said Dr. Khan.

Many of the adverse events recorded during the extension were related to the local injection site. They included injection-site erythema, pain, pruritus, and swelling. Approximately 1% of patients had injection-site atrophy, which tends to appear in the second and third year of treatment with glatiramer acetate. Eight participants became pregnant during the study. Four had elective abortions, and four discontinued the study and gave birth to normal newborns.

The new formulation of glatiramer acetate appears to have a favorable safety profile that is similar to that of the conventional 20-mg formulation. The study is ongoing, and patients will have been followed up for 36 months, including the 12-month placebo-controlled phase, by the time of completion.

—Erik Greb

PHILADELPHIA—Among patients with relapsing-remitting multiple sclerosis (MS), a thrice-weekly 40-mg subcutaneous dose of glatiramer acetate, which the FDA approved in January 2014, reduces the rate of injection-related adverse events by approximately 50%, compared with the standard dose of 20 mg/day, according to research presented at the 66th Annual Meeting of the American Academy of Neurology. The 40-mg dose is associated with a similar reduction in the rate of direct injection-site reactions.

In a separate study, early treatment with 40 mg of glatiramer acetate was associated with a 31% reduction in the number of confirmed relapses, compared with delayed treatment. Early treatment also was associated with a 67.5% likelihood of relapse freedom, compared with delayed treatment. Early treatment did not affect the rate of disease progression significantly, compared with delayed treatment, but the open-label extension study was not designed to assess disease progression.

The 40-mg dose of glatiramer acetate could affect patient compliance in several ways. For example, patients may prefer receiving injections three times per week to receiving daily injections, but the latter schedule may be easier for patients to remember than the former. “I counsel my patients who want less-frequent injections to set their calendars up [and] to be careful about what they’re doing, because it will take a little bit more behavior change or adaptation on their part to do this correctly,” said Jerry Wolinsky, MD, Interim Chair of the Department of Neurology at the University of Texas in Houston.

One problem with the long-term injection of glatiramer acetate is that patients may develop lipoatrophy. “We expect, but don’t know, that with fewer injections, what has been a major compliance problem for some patients in the long run may be put off for years by this kind of a preparation,” added Dr. Wolinsky.

Safety Study Compared 20-mg and 40-mg Doses
Dr. Wolinsky and colleagues performed an open-label, multicenter study to compare the acceptability and tolerability of two formulations of glatiramer acetate. For the study, the researchers enrolled 209 patients with relapsing-remitting MS who had been receiving daily 20-mg injections of glatiramer acetate for at least six months. Eligible participants were 18 or older, were fully ambulatory, had an Expanded Disability Status Scale (EDSS) score between 0 and 5.5, and were relapse-free in the 60 days before randomization.

The investigators randomized 101 participants to continue daily 20-mg injections of glatiramer acetate. The remaining 108 patients were randomized to 40-mg injections of glatiramer acetate three times per week. At the end of a four-month study period, patients were given the option of continuing on 40-mg injections until the trial was completed. Dr. Wolinsky and colleagues conducted various assessments, including subject-reported outcome questionnaires and standard examinations and testing.

The study population differed from that of the typical clinical trial in MS, said Dr. Wolinsky. Average age for patients in this trial was more than 50, and the population included a larger proportion of women than is common in similar studies. In addition, patients’ average disease duration was approximately 16 years, and average time to diagnosis ranged from 10 to 12 years. Participants had a low reported exacerbation rate and a low EDSS score at study entry.

Patients Found the 40-mg Dose Convenient
The trial’s primary end point was the rate of injection-related adverse events, and 40-mg injections of glatiramer acetate were associated with a significant reduction in these events. Secondary end points included the treatment’s effect on questionnaires of physical and psychological well-being (as measured by the MS Impact Scale 29) and subjects’ perceptions of convenience and satisfaction. The researchers found no significant differences between treatment arms in the physical or psychological scores of the MS Impact Scale 29. Convenience scores on the Treatment Satisfaction Questionnaire for Medication-9 appeared to favor the high dose of glatiramer acetate.

Most adverse events in the trial were related to the direct injection, and no new safety signals were reported for glatiramer acetate. “The 40-mg three-times-a-week dosing regime appears to be a favorable treatment option for patients who want glatiramer acetate treatment but prefer fewer subcutaneous injections,” concluded Dr. Wolinsky.

Researchers Examined Efficacy of 40-mg Injections
Omar Khan, MD, Chair and Professor of Neurology at Wayne State University School of Medicine in Detroit, and colleagues conducted an open-label extension study to assess the ongoing safety and efficacy of thrice-weekly subcutaneous 40-mg injections of glatiramer acetate. Of the approximately 1,400 participants in a previous placebo-controlled study, 1,253 patients with relapsing-remitting MS agreed to participate in the open-label extension. The investigators grouped patients into two distinct arms. Participants in the early-start arm had received 40-mg injections of glatiramer acetate thrice weekly for 12 months in the placebo-controlled trial, and they continued to receive this treatment in the extension. Patients in the delayed-start arm had received placebo for 12 months in the placebo-controlled study and received thrice-weekly 40-mg injections of glatiramer acetate in the extension. The clinical end point was the total number of confirmed relapses.

The participants’ average EDSS was approximately 2.8, and disease onset had occurred approximately seven and a half years previously, on average. The volume of T2 lesion load ranged from 17 cm³ to 20 cm³, which was “remarkably high” for patients with relapsing-remitting MS, said Dr. Khan. In most relapsing-remitting trials, T2 lesion load ranges between 7 cm³ and 9 cm³, he added.

Early Treatment Was Associated With Improved Outcomes
At the end of the placebo-controlled study, the new formulation of glatiramer acetate was associated with a 34% reduction in confirmed relapses, compared with placebo. At 12 months of the open-label extension, participants who had never been exposed to placebo had 31% fewer confirmed relapses, compared with patients in the delayed-start arm. The results emphasize “that starting treatment early makes a difference,” said Dr. Khan.

Many of the adverse events recorded during the extension were related to the local injection site. They included injection-site erythema, pain, pruritus, and swelling. Approximately 1% of patients had injection-site atrophy, which tends to appear in the second and third year of treatment with glatiramer acetate. Eight participants became pregnant during the study. Four had elective abortions, and four discontinued the study and gave birth to normal newborns.

The new formulation of glatiramer acetate appears to have a favorable safety profile that is similar to that of the conventional 20-mg formulation. The study is ongoing, and patients will have been followed up for 36 months, including the 12-month placebo-controlled phase, by the time of completion.

—Erik Greb

PHILADELPHIA—Among patients with relapsing-remitting multiple sclerosis (MS), a thrice-weekly 40-mg subcutaneous dose of glatiramer acetate, which the FDA approved in January 2014, reduces the rate of injection-related adverse events by approximately 50%, compared with the standard dose of 20 mg/day, according to research presented at the 66th Annual Meeting of the American Academy of Neurology. The 40-mg dose is associated with a similar reduction in the rate of direct injection-site reactions.

In a separate study, early treatment with 40 mg of glatiramer acetate was associated with a 31% reduction in the number of confirmed relapses, compared with delayed treatment. Early treatment also was associated with a 67.5% likelihood of relapse freedom, compared with delayed treatment. Early treatment did not affect the rate of disease progression significantly, compared with delayed treatment, but the open-label extension study was not designed to assess disease progression.

The 40-mg dose of glatiramer acetate could affect patient compliance in several ways. For example, patients may prefer receiving injections three times per week to receiving daily injections, but the latter schedule may be easier for patients to remember than the former. “I counsel my patients who want less-frequent injections to set their calendars up [and] to be careful about what they’re doing, because it will take a little bit more behavior change or adaptation on their part to do this correctly,” said Jerry Wolinsky, MD, Interim Chair of the Department of Neurology at the University of Texas in Houston.

One problem with the long-term injection of glatiramer acetate is that patients may develop lipoatrophy. “We expect, but don’t know, that with fewer injections, what has been a major compliance problem for some patients in the long run may be put off for years by this kind of a preparation,” added Dr. Wolinsky.

Safety Study Compared 20-mg and 40-mg Doses
Dr. Wolinsky and colleagues performed an open-label, multicenter study to compare the acceptability and tolerability of two formulations of glatiramer acetate. For the study, the researchers enrolled 209 patients with relapsing-remitting MS who had been receiving daily 20-mg injections of glatiramer acetate for at least six months. Eligible participants were 18 or older, were fully ambulatory, had an Expanded Disability Status Scale (EDSS) score between 0 and 5.5, and were relapse-free in the 60 days before randomization.

The investigators randomized 101 participants to continue daily 20-mg injections of glatiramer acetate. The remaining 108 patients were randomized to 40-mg injections of glatiramer acetate three times per week. At the end of a four-month study period, patients were given the option of continuing on 40-mg injections until the trial was completed. Dr. Wolinsky and colleagues conducted various assessments, including subject-reported outcome questionnaires and standard examinations and testing.

The study population differed from that of the typical clinical trial in MS, said Dr. Wolinsky. Average age for patients in this trial was more than 50, and the population included a larger proportion of women than is common in similar studies. In addition, patients’ average disease duration was approximately 16 years, and average time to diagnosis ranged from 10 to 12 years. Participants had a low reported exacerbation rate and a low EDSS score at study entry.

Patients Found the 40-mg Dose Convenient
The trial’s primary end point was the rate of injection-related adverse events, and 40-mg injections of glatiramer acetate were associated with a significant reduction in these events. Secondary end points included the treatment’s effect on questionnaires of physical and psychological well-being (as measured by the MS Impact Scale 29) and subjects’ perceptions of convenience and satisfaction. The researchers found no significant differences between treatment arms in the physical or psychological scores of the MS Impact Scale 29. Convenience scores on the Treatment Satisfaction Questionnaire for Medication-9 appeared to favor the high dose of glatiramer acetate.

Most adverse events in the trial were related to the direct injection, and no new safety signals were reported for glatiramer acetate. “The 40-mg three-times-a-week dosing regime appears to be a favorable treatment option for patients who want glatiramer acetate treatment but prefer fewer subcutaneous injections,” concluded Dr. Wolinsky.

Researchers Examined Efficacy of 40-mg Injections
Omar Khan, MD, Chair and Professor of Neurology at Wayne State University School of Medicine in Detroit, and colleagues conducted an open-label extension study to assess the ongoing safety and efficacy of thrice-weekly subcutaneous 40-mg injections of glatiramer acetate. Of the approximately 1,400 participants in a previous placebo-controlled study, 1,253 patients with relapsing-remitting MS agreed to participate in the open-label extension. The investigators grouped patients into two distinct arms. Participants in the early-start arm had received 40-mg injections of glatiramer acetate thrice weekly for 12 months in the placebo-controlled trial, and they continued to receive this treatment in the extension. Patients in the delayed-start arm had received placebo for 12 months in the placebo-controlled study and received thrice-weekly 40-mg injections of glatiramer acetate in the extension. The clinical end point was the total number of confirmed relapses.

The participants’ average EDSS was approximately 2.8, and disease onset had occurred approximately seven and a half years previously, on average. The volume of T2 lesion load ranged from 17 cm³ to 20 cm³, which was “remarkably high” for patients with relapsing-remitting MS, said Dr. Khan. In most relapsing-remitting trials, T2 lesion load ranges between 7 cm³ and 9 cm³, he added.

Early Treatment Was Associated With Improved Outcomes
At the end of the placebo-controlled study, the new formulation of glatiramer acetate was associated with a 34% reduction in confirmed relapses, compared with placebo. At 12 months of the open-label extension, participants who had never been exposed to placebo had 31% fewer confirmed relapses, compared with patients in the delayed-start arm. The results emphasize “that starting treatment early makes a difference,” said Dr. Khan.

Many of the adverse events recorded during the extension were related to the local injection site. They included injection-site erythema, pain, pruritus, and swelling. Approximately 1% of patients had injection-site atrophy, which tends to appear in the second and third year of treatment with glatiramer acetate. Eight participants became pregnant during the study. Four had elective abortions, and four discontinued the study and gave birth to normal newborns.

The new formulation of glatiramer acetate appears to have a favorable safety profile that is similar to that of the conventional 20-mg formulation. The study is ongoing, and patients will have been followed up for 36 months, including the 12-month placebo-controlled phase, by the time of completion.

—Erik Greb

PHILADELPHIA—Certain forms of medical marijuana can help treat symptoms of multiple sclerosis (MS), but may not be helpful in treating levodopa-induced movements in Parkinson’s disease, researchers reported at the 66th Annual Meeting of the American Academy of Neurology (AAN). The researchers did not find enough evidence to show whether medical marijuana is helpful in treating motor problems in Huntington’s disease, tics in Tourette syndrome, cervical dystonia, and seizures in epilepsy. These conclusions are part of AAN’s review of scientific research on the use of medical marijuana in brain diseases. The findings were published in the April 29, 2014, print issue of Neurology.

“This review by the world’s largest association for neurologists is intended to help neurologists and their patients understand the current research on medical marijuana for the treatment of certain brain diseases,” said review author Barbara S. Koppel, MD, of New York Medical College in Valhalla, and Fellow of the AAN. “The AAN review also highlights the need for more high-quality studies of the long-term efficacy and safety of medical marijuana in the treatment of neurologic diseases.”

The AAN review concluded that only the pill or oral spray forms of medical marijuana can help treat symptoms of MS, including spasticity, certain types of pain (ie, pain related to spasticity, including painful spasms, and painful burning and numbness), and overactive bladder. Most of the MS studies examined pill or oral spray forms of medical marijuana. Two studies examined smoked medical marijuana for treating MS symptoms, but these studies did not provide enough information to show whether smoked medical marijuana is effective. “It’s important to note that medical marijuana can worsen thinking and memory problems, and this is a concern, since many people with MS suffer from these problems already due to the disease itself,” said Dr. Koppel.

In addition, the AAN review concluded that medical marijuana, in the form of synthetic tetrahydrocannabinol (THC) pills, likely does not help relieve abnormal movements that can develop in the late stages of Parkinson’s disease as a result of levodopa.

Medical marijuana use does entail safety concerns. In at least two studies, participants reported side effects such as nausea, increased weakness, behavioral or mood changes, suicidal thoughts or hallucinations, dizziness or fainting symptoms, fatigue, and feelings of intoxication. There were reports of two seizures. Mood changes and suicidal thoughts are of special concern for people with neurologic illness, who are at an increased risk for depression and suicide. The risk of serious psychologic effects is approximately 1%, according to the studies.

The only two medical marijuana pills with FDA approval contain THC. “The psychoactive side effects, like feeling intoxicated, seemed to come from the THC,” said Dr. Koppel. “They’re trying to create pills that are leaning more toward the cannabinoid, which has the therapeutic effects with fewer psychoactive side effects.”

Clinicians who practice in states where medical marijuana is legal may recommend the drug for the MS symptoms that respond to it, Dr. Koppel added. “The problem is that the studies are done very rigorously with a certain amount of THC versus cannabinoid. The type of marijuana you can buy so far is not so rigorously defined.” Clinicians also should warn their patients about marijuana’s potential side effects.

In general, medical marijuana is prescribed as a treatment only when standard treatment has not helped. In most of the studies reviewed, patients were allowed to continue their standard treatments. The AAN review is endorsed by the American Autonomic Society, the American Epilepsy Society, and the International Rett Syndrome Foundation.

—Erik Greb

PHILADELPHIA—Certain forms of medical marijuana can help treat symptoms of multiple sclerosis (MS), but may not be helpful in treating levodopa-induced movements in Parkinson’s disease, researchers reported at the 66th Annual Meeting of the American Academy of Neurology (AAN). The researchers did not find enough evidence to show whether medical marijuana is helpful in treating motor problems in Huntington’s disease, tics in Tourette syndrome, cervical dystonia, and seizures in epilepsy. These conclusions are part of AAN’s review of scientific research on the use of medical marijuana in brain diseases. The findings were published in the April 29, 2014, print issue of Neurology.

“This review by the world’s largest association for neurologists is intended to help neurologists and their patients understand the current research on medical marijuana for the treatment of certain brain diseases,” said review author Barbara S. Koppel, MD, of New York Medical College in Valhalla, and Fellow of the AAN. “The AAN review also highlights the need for more high-quality studies of the long-term efficacy and safety of medical marijuana in the treatment of neurologic diseases.”

The AAN review concluded that only the pill or oral spray forms of medical marijuana can help treat symptoms of MS, including spasticity, certain types of pain (ie, pain related to spasticity, including painful spasms, and painful burning and numbness), and overactive bladder. Most of the MS studies examined pill or oral spray forms of medical marijuana. Two studies examined smoked medical marijuana for treating MS symptoms, but these studies did not provide enough information to show whether smoked medical marijuana is effective. “It’s important to note that medical marijuana can worsen thinking and memory problems, and this is a concern, since many people with MS suffer from these problems already due to the disease itself,” said Dr. Koppel.

In addition, the AAN review concluded that medical marijuana, in the form of synthetic tetrahydrocannabinol (THC) pills, likely does not help relieve abnormal movements that can develop in the late stages of Parkinson’s disease as a result of levodopa.

Medical marijuana use does entail safety concerns. In at least two studies, participants reported side effects such as nausea, increased weakness, behavioral or mood changes, suicidal thoughts or hallucinations, dizziness or fainting symptoms, fatigue, and feelings of intoxication. There were reports of two seizures. Mood changes and suicidal thoughts are of special concern for people with neurologic illness, who are at an increased risk for depression and suicide. The risk of serious psychologic effects is approximately 1%, according to the studies.

The only two medical marijuana pills with FDA approval contain THC. “The psychoactive side effects, like feeling intoxicated, seemed to come from the THC,” said Dr. Koppel. “They’re trying to create pills that are leaning more toward the cannabinoid, which has the therapeutic effects with fewer psychoactive side effects.”

Clinicians who practice in states where medical marijuana is legal may recommend the drug for the MS symptoms that respond to it, Dr. Koppel added. “The problem is that the studies are done very rigorously with a certain amount of THC versus cannabinoid. The type of marijuana you can buy so far is not so rigorously defined.” Clinicians also should warn their patients about marijuana’s potential side effects.

In general, medical marijuana is prescribed as a treatment only when standard treatment has not helped. In most of the studies reviewed, patients were allowed to continue their standard treatments. The AAN review is endorsed by the American Autonomic Society, the American Epilepsy Society, and the International Rett Syndrome Foundation.

—Erik Greb

PHILADELPHIA—Certain forms of medical marijuana can help treat symptoms of multiple sclerosis (MS), but may not be helpful in treating levodopa-induced movements in Parkinson’s disease, researchers reported at the 66th Annual Meeting of the American Academy of Neurology (AAN). The researchers did not find enough evidence to show whether medical marijuana is helpful in treating motor problems in Huntington’s disease, tics in Tourette syndrome, cervical dystonia, and seizures in epilepsy. These conclusions are part of AAN’s review of scientific research on the use of medical marijuana in brain diseases. The findings were published in the April 29, 2014, print issue of Neurology.

“This review by the world’s largest association for neurologists is intended to help neurologists and their patients understand the current research on medical marijuana for the treatment of certain brain diseases,” said review author Barbara S. Koppel, MD, of New York Medical College in Valhalla, and Fellow of the AAN. “The AAN review also highlights the need for more high-quality studies of the long-term efficacy and safety of medical marijuana in the treatment of neurologic diseases.”

The AAN review concluded that only the pill or oral spray forms of medical marijuana can help treat symptoms of MS, including spasticity, certain types of pain (ie, pain related to spasticity, including painful spasms, and painful burning and numbness), and overactive bladder. Most of the MS studies examined pill or oral spray forms of medical marijuana. Two studies examined smoked medical marijuana for treating MS symptoms, but these studies did not provide enough information to show whether smoked medical marijuana is effective. “It’s important to note that medical marijuana can worsen thinking and memory problems, and this is a concern, since many people with MS suffer from these problems already due to the disease itself,” said Dr. Koppel.

In addition, the AAN review concluded that medical marijuana, in the form of synthetic tetrahydrocannabinol (THC) pills, likely does not help relieve abnormal movements that can develop in the late stages of Parkinson’s disease as a result of levodopa.

Medical marijuana use does entail safety concerns. In at least two studies, participants reported side effects such as nausea, increased weakness, behavioral or mood changes, suicidal thoughts or hallucinations, dizziness or fainting symptoms, fatigue, and feelings of intoxication. There were reports of two seizures. Mood changes and suicidal thoughts are of special concern for people with neurologic illness, who are at an increased risk for depression and suicide. The risk of serious psychologic effects is approximately 1%, according to the studies.

The only two medical marijuana pills with FDA approval contain THC. “The psychoactive side effects, like feeling intoxicated, seemed to come from the THC,” said Dr. Koppel. “They’re trying to create pills that are leaning more toward the cannabinoid, which has the therapeutic effects with fewer psychoactive side effects.”

Clinicians who practice in states where medical marijuana is legal may recommend the drug for the MS symptoms that respond to it, Dr. Koppel added. “The problem is that the studies are done very rigorously with a certain amount of THC versus cannabinoid. The type of marijuana you can buy so far is not so rigorously defined.” Clinicians also should warn their patients about marijuana’s potential side effects.

In general, medical marijuana is prescribed as a treatment only when standard treatment has not helped. In most of the studies reviewed, patients were allowed to continue their standard treatments. The AAN review is endorsed by the American Autonomic Society, the American Epilepsy Society, and the International Rett Syndrome Foundation.

—Erik Greb

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

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

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

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

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

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

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

—Sara Freeman

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

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

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

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

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

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

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

—Sara Freeman

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

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

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

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

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

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

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

—Sara Freeman

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

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

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

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

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

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

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

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

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

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

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

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

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

—Mary Ann Moon

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

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

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

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

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

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

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

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

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

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

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

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

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

—Mary Ann Moon

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

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

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

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

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

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

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

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

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

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

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

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

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

—Mary Ann Moon

The FDA has declined to approve alemtuzumab for the treatment of multiple sclerosis (MS), citing a lack of well-controlled data from clinical studies indicating that the benefits outweigh the risks of treatment—a decision that Genzyme, the manufacturer, plans to appeal.

Genzyme announced in a December 30, 2013, statement that the FDA had sent a Complete Response Letter regarding alemtuzumab, an IV-infused monoclonal antibody that binds to the CD52 antigen present at high levels on the surface of T and B lymphocytes. Complete response letters are sent when the FDA decides against approval, with explanations of outstanding issues that need to be resolved.

The proposed indication for alemtuzumab is for treatment of relapsing-remitting MS, with a risk evaluation and mitigation strategy (REMS) that addresses the drug’s serious risks, which include immune thrombocytopenia and thyroid-related adverse events. The company’s proposed trade name for the MS indication for alemtuzumab is Lemtrada.

“The FDA has taken the position that Genzyme has not submitted evidence from adequate and well-controlled studies that demonstrate the benefits of Lemtrada outweigh its serious adverse effects,” according to the Genzyme statement. “The conclusion is related to the design of the completed [phase III] active comparator studies of Lemtrada in relapsing-remitting MS patients.” The FDA also said that one or more “additional active comparator clinical trials of different design and execution” are needed before alemtuzumab is approved for MS, the statement said.

In the statement, Genzyme said that it “strongly disagrees with the FDA’s conclusions and plans to appeal the agency’s decision.”

The FDA’s Concerns
FDA reviewers made their concerns about alemtuzumab clear at a meeting of the FDA’s Peripheral and Central Nervous System advisory committee in November 2013 and in documents provided before the meeting.

The FDA raised concerns about the elevated rates of serious adverse events in patients treated with alemtuzumab and the open-label design of the clinical trials, questioning whether bias had an impact on the efficacy results. Patients and clinicians were not blinded to the treatment in those studies, which compared alemtuzumab to subcutaneous interferon beta-1a (Rebif) in about 1,400 patients and found significant reductions in the relapse rates among those treated with alemtuzumab (49% and 55%), compared with those on Rebif.

The advisory panel did not vote specifically on whether to recommend approval for MS. But while panelists agreed that the unblinded studies were likely biased, the majority voted 12–6 that the manufacturer had provided substantial evidence that the drug was effective for the proposed indication. Several panelists said they would recommend the drug only for patients with severe MS, as a second- or third-line treatment.

Study Investigators Comment
In an interview, one of the investigators in the studies, Jonathan L. Carter, MD, Associate Professor of Neurology at the Mayo Clinic in Scottsdale, Arizona, said the decision is disappointing because patients “who have broken through the standard first-line therapies” have an unmet need for treatment.

Another investigator, Lily K. Jung Henson, MD, concurs. “I don’t think the FDA recognizes that there is a need for alternative therapies with mechanisms of action that patients who have failed multiple therapies need.” Dr. Henson is a neurologist at the Swedish Neuroscience Institute in Seattle. “I have—and most of us who have large patient populations have—patients who have failed everything else, including natalizumab [Tysabri], and are holding on, waiting for this drug to be released and now have no options.”

Dr. Carter acknowledged the FDA reviewers’ concerns about the effect of unblinding, although he pointed out that it can be difficult to maintain blinding of patients and clinicians in studies of products with marked side effects, such as infusion reactions. Despite the potential effects of unblinding on clinical outcome measures, however, he noted that MRI data showing less enhancing lesion activity in alemtuzumab-treated patients, compared with those on Rebif, supported the drug’s efficacy.

On the issue of blinding, another investigator, Christopher C. LaGanke, MD, added that the phase III alemtuzumab studies were rater blinded. “The Expanded Disability Status Scale scores were done by a blinded rater. The relapses were looked at by an adjudication panel that was blinded to any treatment that the patients may have had. The raters of the neurocognitive test, the MS Functional Composite Score, were blinded, and the MRI raters were blinded. So the main assessors were blinded to what the treatment was.” Due to the side effect profiles of the medications, however, patient blinding would have been extremely difficult. “We would like to have everyone blinded in the study. That’s a goal, but here it was not very feasible,” said Dr. LaGanke, who is a private neurologist at North Central Neurology Associates, as well as Director of the Joanne P. LaGanke Multiple Sclerosis Center, both in Cullman, Alabama.

“If the FDA was going to make this decision a priori given the lack of blinding of the study, then I’m concerned that they ethically allowed my patients to take the risk and the sacrifices that they did to enroll and maintain themselves in this study,” Dr. LaGanke said. “And the results were no surprise from the phase II study; so at the end of the day, this has been the most effective treatment we’ve had for relapsing MS, as far as several outcomes, of any of our approved medications, and there was no novel safety signal. It wasn’t that there were differences in the results that would have created a difference in their opinion. So that really concerns me. I feel badly for my patients who went through all of that for naught because of the trial design, because the trial could have been halted from the get go.”

Dr. Henson echoed Dr. LaGanke’s empathy for her own MS patients. “More than anything else, I feel really badly for my patients who have been waiting for this drug because truly it is now back to the drawing board.”

Dr. Carter notes that there is a segment of the MS population—those who are positive for the JC virus antibody and are considered at increased risk for progressive multifocal leukoencephalopathy (PML) with natalizumab (Tysabri) therapy—for whom the options are slim to none.

“There are a lot of patients for whom alemtuzumab is not the right drug,” said Dr. Henson. “It is not as though I am going to recommend this drug to all my patients.” She notes, however, that she has patients with severe MS who have no other options that they can use at this point. “Where I would use this drug is in patients with aggressive disease who have failed the first-line or second-line therapies. It is most likely going to be a third-line therapy for patients who have failed the injectables, failed the orals, and plus or minus failed natalizumab.”

Available Elsewhere, But Not Here
Alemtuzumab was approved by the FDA in 2001 and marketed as Campath for B-cell chronic lymphocytic leukemia in the United States. But in September 2012, the company took Campath off the market and is providing it free of charge to leukemia patients in a distribution program. Alemtuzumab has been approved for MS in the European Union, Canada, and Australia. “It is disappointing that we in this country do not have access to this medication,” said Dr. LaGanke.

“The implications of this drug being approved in other countries,” Dr. Henson added, “are that we are going to be forced to try to find some way to get these patients the medication, get it paid for, and then figure out how to monitor these patients. That’s just crazy.”

—Elizabeth Mechcatie & Glenn Williams

The FDA has declined to approve alemtuzumab for the treatment of multiple sclerosis (MS), citing a lack of well-controlled data from clinical studies indicating that the benefits outweigh the risks of treatment—a decision that Genzyme, the manufacturer, plans to appeal.

Genzyme announced in a December 30, 2013, statement that the FDA had sent a Complete Response Letter regarding alemtuzumab, an IV-infused monoclonal antibody that binds to the CD52 antigen present at high levels on the surface of T and B lymphocytes. Complete response letters are sent when the FDA decides against approval, with explanations of outstanding issues that need to be resolved.

The proposed indication for alemtuzumab is for treatment of relapsing-remitting MS, with a risk evaluation and mitigation strategy (REMS) that addresses the drug’s serious risks, which include immune thrombocytopenia and thyroid-related adverse events. The company’s proposed trade name for the MS indication for alemtuzumab is Lemtrada.

“The FDA has taken the position that Genzyme has not submitted evidence from adequate and well-controlled studies that demonstrate the benefits of Lemtrada outweigh its serious adverse effects,” according to the Genzyme statement. “The conclusion is related to the design of the completed [phase III] active comparator studies of Lemtrada in relapsing-remitting MS patients.” The FDA also said that one or more “additional active comparator clinical trials of different design and execution” are needed before alemtuzumab is approved for MS, the statement said.

In the statement, Genzyme said that it “strongly disagrees with the FDA’s conclusions and plans to appeal the agency’s decision.”

The FDA’s Concerns
FDA reviewers made their concerns about alemtuzumab clear at a meeting of the FDA’s Peripheral and Central Nervous System advisory committee in November 2013 and in documents provided before the meeting.

The FDA raised concerns about the elevated rates of serious adverse events in patients treated with alemtuzumab and the open-label design of the clinical trials, questioning whether bias had an impact on the efficacy results. Patients and clinicians were not blinded to the treatment in those studies, which compared alemtuzumab to subcutaneous interferon beta-1a (Rebif) in about 1,400 patients and found significant reductions in the relapse rates among those treated with alemtuzumab (49% and 55%), compared with those on Rebif.

The advisory panel did not vote specifically on whether to recommend approval for MS. But while panelists agreed that the unblinded studies were likely biased, the majority voted 12–6 that the manufacturer had provided substantial evidence that the drug was effective for the proposed indication. Several panelists said they would recommend the drug only for patients with severe MS, as a second- or third-line treatment.

Study Investigators Comment
In an interview, one of the investigators in the studies, Jonathan L. Carter, MD, Associate Professor of Neurology at the Mayo Clinic in Scottsdale, Arizona, said the decision is disappointing because patients “who have broken through the standard first-line therapies” have an unmet need for treatment.

Another investigator, Lily K. Jung Henson, MD, concurs. “I don’t think the FDA recognizes that there is a need for alternative therapies with mechanisms of action that patients who have failed multiple therapies need.” Dr. Henson is a neurologist at the Swedish Neuroscience Institute in Seattle. “I have—and most of us who have large patient populations have—patients who have failed everything else, including natalizumab [Tysabri], and are holding on, waiting for this drug to be released and now have no options.”

Dr. Carter acknowledged the FDA reviewers’ concerns about the effect of unblinding, although he pointed out that it can be difficult to maintain blinding of patients and clinicians in studies of products with marked side effects, such as infusion reactions. Despite the potential effects of unblinding on clinical outcome measures, however, he noted that MRI data showing less enhancing lesion activity in alemtuzumab-treated patients, compared with those on Rebif, supported the drug’s efficacy.

On the issue of blinding, another investigator, Christopher C. LaGanke, MD, added that the phase III alemtuzumab studies were rater blinded. “The Expanded Disability Status Scale scores were done by a blinded rater. The relapses were looked at by an adjudication panel that was blinded to any treatment that the patients may have had. The raters of the neurocognitive test, the MS Functional Composite Score, were blinded, and the MRI raters were blinded. So the main assessors were blinded to what the treatment was.” Due to the side effect profiles of the medications, however, patient blinding would have been extremely difficult. “We would like to have everyone blinded in the study. That’s a goal, but here it was not very feasible,” said Dr. LaGanke, who is a private neurologist at North Central Neurology Associates, as well as Director of the Joanne P. LaGanke Multiple Sclerosis Center, both in Cullman, Alabama.

“If the FDA was going to make this decision a priori given the lack of blinding of the study, then I’m concerned that they ethically allowed my patients to take the risk and the sacrifices that they did to enroll and maintain themselves in this study,” Dr. LaGanke said. “And the results were no surprise from the phase II study; so at the end of the day, this has been the most effective treatment we’ve had for relapsing MS, as far as several outcomes, of any of our approved medications, and there was no novel safety signal. It wasn’t that there were differences in the results that would have created a difference in their opinion. So that really concerns me. I feel badly for my patients who went through all of that for naught because of the trial design, because the trial could have been halted from the get go.”

Dr. Henson echoed Dr. LaGanke’s empathy for her own MS patients. “More than anything else, I feel really badly for my patients who have been waiting for this drug because truly it is now back to the drawing board.”

Dr. Carter notes that there is a segment of the MS population—those who are positive for the JC virus antibody and are considered at increased risk for progressive multifocal leukoencephalopathy (PML) with natalizumab (Tysabri) therapy—for whom the options are slim to none.

“There are a lot of patients for whom alemtuzumab is not the right drug,” said Dr. Henson. “It is not as though I am going to recommend this drug to all my patients.” She notes, however, that she has patients with severe MS who have no other options that they can use at this point. “Where I would use this drug is in patients with aggressive disease who have failed the first-line or second-line therapies. It is most likely going to be a third-line therapy for patients who have failed the injectables, failed the orals, and plus or minus failed natalizumab.”

Available Elsewhere, But Not Here
Alemtuzumab was approved by the FDA in 2001 and marketed as Campath for B-cell chronic lymphocytic leukemia in the United States. But in September 2012, the company took Campath off the market and is providing it free of charge to leukemia patients in a distribution program. Alemtuzumab has been approved for MS in the European Union, Canada, and Australia. “It is disappointing that we in this country do not have access to this medication,” said Dr. LaGanke.

“The implications of this drug being approved in other countries,” Dr. Henson added, “are that we are going to be forced to try to find some way to get these patients the medication, get it paid for, and then figure out how to monitor these patients. That’s just crazy.”

—Elizabeth Mechcatie & Glenn Williams

The FDA has declined to approve alemtuzumab for the treatment of multiple sclerosis (MS), citing a lack of well-controlled data from clinical studies indicating that the benefits outweigh the risks of treatment—a decision that Genzyme, the manufacturer, plans to appeal.

Genzyme announced in a December 30, 2013, statement that the FDA had sent a Complete Response Letter regarding alemtuzumab, an IV-infused monoclonal antibody that binds to the CD52 antigen present at high levels on the surface of T and B lymphocytes. Complete response letters are sent when the FDA decides against approval, with explanations of outstanding issues that need to be resolved.

The proposed indication for alemtuzumab is for treatment of relapsing-remitting MS, with a risk evaluation and mitigation strategy (REMS) that addresses the drug’s serious risks, which include immune thrombocytopenia and thyroid-related adverse events. The company’s proposed trade name for the MS indication for alemtuzumab is Lemtrada.

“The FDA has taken the position that Genzyme has not submitted evidence from adequate and well-controlled studies that demonstrate the benefits of Lemtrada outweigh its serious adverse effects,” according to the Genzyme statement. “The conclusion is related to the design of the completed [phase III] active comparator studies of Lemtrada in relapsing-remitting MS patients.” The FDA also said that one or more “additional active comparator clinical trials of different design and execution” are needed before alemtuzumab is approved for MS, the statement said.

In the statement, Genzyme said that it “strongly disagrees with the FDA’s conclusions and plans to appeal the agency’s decision.”

The FDA’s Concerns
FDA reviewers made their concerns about alemtuzumab clear at a meeting of the FDA’s Peripheral and Central Nervous System advisory committee in November 2013 and in documents provided before the meeting.

The FDA raised concerns about the elevated rates of serious adverse events in patients treated with alemtuzumab and the open-label design of the clinical trials, questioning whether bias had an impact on the efficacy results. Patients and clinicians were not blinded to the treatment in those studies, which compared alemtuzumab to subcutaneous interferon beta-1a (Rebif) in about 1,400 patients and found significant reductions in the relapse rates among those treated with alemtuzumab (49% and 55%), compared with those on Rebif.

The advisory panel did not vote specifically on whether to recommend approval for MS. But while panelists agreed that the unblinded studies were likely biased, the majority voted 12–6 that the manufacturer had provided substantial evidence that the drug was effective for the proposed indication. Several panelists said they would recommend the drug only for patients with severe MS, as a second- or third-line treatment.

Study Investigators Comment
In an interview, one of the investigators in the studies, Jonathan L. Carter, MD, Associate Professor of Neurology at the Mayo Clinic in Scottsdale, Arizona, said the decision is disappointing because patients “who have broken through the standard first-line therapies” have an unmet need for treatment.

Another investigator, Lily K. Jung Henson, MD, concurs. “I don’t think the FDA recognizes that there is a need for alternative therapies with mechanisms of action that patients who have failed multiple therapies need.” Dr. Henson is a neurologist at the Swedish Neuroscience Institute in Seattle. “I have—and most of us who have large patient populations have—patients who have failed everything else, including natalizumab [Tysabri], and are holding on, waiting for this drug to be released and now have no options.”

Dr. Carter acknowledged the FDA reviewers’ concerns about the effect of unblinding, although he pointed out that it can be difficult to maintain blinding of patients and clinicians in studies of products with marked side effects, such as infusion reactions. Despite the potential effects of unblinding on clinical outcome measures, however, he noted that MRI data showing less enhancing lesion activity in alemtuzumab-treated patients, compared with those on Rebif, supported the drug’s efficacy.

On the issue of blinding, another investigator, Christopher C. LaGanke, MD, added that the phase III alemtuzumab studies were rater blinded. “The Expanded Disability Status Scale scores were done by a blinded rater. The relapses were looked at by an adjudication panel that was blinded to any treatment that the patients may have had. The raters of the neurocognitive test, the MS Functional Composite Score, were blinded, and the MRI raters were blinded. So the main assessors were blinded to what the treatment was.” Due to the side effect profiles of the medications, however, patient blinding would have been extremely difficult. “We would like to have everyone blinded in the study. That’s a goal, but here it was not very feasible,” said Dr. LaGanke, who is a private neurologist at North Central Neurology Associates, as well as Director of the Joanne P. LaGanke Multiple Sclerosis Center, both in Cullman, Alabama.

“If the FDA was going to make this decision a priori given the lack of blinding of the study, then I’m concerned that they ethically allowed my patients to take the risk and the sacrifices that they did to enroll and maintain themselves in this study,” Dr. LaGanke said. “And the results were no surprise from the phase II study; so at the end of the day, this has been the most effective treatment we’ve had for relapsing MS, as far as several outcomes, of any of our approved medications, and there was no novel safety signal. It wasn’t that there were differences in the results that would have created a difference in their opinion. So that really concerns me. I feel badly for my patients who went through all of that for naught because of the trial design, because the trial could have been halted from the get go.”

Dr. Henson echoed Dr. LaGanke’s empathy for her own MS patients. “More than anything else, I feel really badly for my patients who have been waiting for this drug because truly it is now back to the drawing board.”

Dr. Carter notes that there is a segment of the MS population—those who are positive for the JC virus antibody and are considered at increased risk for progressive multifocal leukoencephalopathy (PML) with natalizumab (Tysabri) therapy—for whom the options are slim to none.

“There are a lot of patients for whom alemtuzumab is not the right drug,” said Dr. Henson. “It is not as though I am going to recommend this drug to all my patients.” She notes, however, that she has patients with severe MS who have no other options that they can use at this point. “Where I would use this drug is in patients with aggressive disease who have failed the first-line or second-line therapies. It is most likely going to be a third-line therapy for patients who have failed the injectables, failed the orals, and plus or minus failed natalizumab.”

Available Elsewhere, But Not Here
Alemtuzumab was approved by the FDA in 2001 and marketed as Campath for B-cell chronic lymphocytic leukemia in the United States. But in September 2012, the company took Campath off the market and is providing it free of charge to leukemia patients in a distribution program. Alemtuzumab has been approved for MS in the European Union, Canada, and Australia. “It is disappointing that we in this country do not have access to this medication,” said Dr. LaGanke.

“The implications of this drug being approved in other countries,” Dr. Henson added, “are that we are going to be forced to try to find some way to get these patients the medication, get it paid for, and then figure out how to monitor these patients. That’s just crazy.”

—Elizabeth Mechcatie & Glenn Williams