SAN DIEGO—Studies encompassing a wide range of therapeutic approaches for neurologic disorders were presented at the 130th Annual Meeting of the American Neurological Association. Included were reports on the use of an anticonvulsant for the cessation of cluster headaches, a novel formulation of a monoamine oxidase B (MAO-B) inhibitor for Parkinson’s disease, the long-term value of interferon beta-1b (INFB-1b) in multiple sclerosis (MS), a comparison of a common bipolar agent and an antipsychotic thienobenzodiazepine for the improvement of neurocognition in bipolar disorder, and a recently approved nonbenzodiapezine sleep agent for insomnia.

NOVEL THERAPY FOR CLUSTER HEADACHE

Intravenous (IV) levetiracetam is a powerful addition to medications for cluster headache flare-ups, acting rapidly to eliminate ongoing headaches, said John Claude Krusz, PhD, MD, Medical Director of the Anodyne Headache and PainCare Center, Dallas. “Intravenous administration of medication is considered ideal for terminating an ongoing [cluster headache] attack, and several options currently exist: IV steroids, IV sodium valproate, subcutaneous sumatriptan, and IV DHE-45. The availability of another rapid-acting, nontoxic IV agent would give the clinician more options for terminating the cluster attacks,” he said.

As levetiracetam has been shown to be efficacious orally in intractable migraine, Dr. Krusz and colleagues conducted a pilot study to determine the value of IV levetiracetam for treating acute or new flare-ups of cluster headaches. Eight cluster headache patients, all male, were treated with an average IV levetiracetam dose of 5,625 mg (range, 3,400 to 11,200 mg) administered over 90 minutes and were given oral levetiracetam for prophylaxis.

All patients reported cessation of cluster headache attacks with IV levetiracetam treatment. In one patient, additional medication strategies were added to oral levetiracetam to control residual cluster headache symptoms. The lack of side effects—despite dosing in excess of that typically used for seizure management—demonstrated the safety and tolerability of this approach, according to the team.

UNIQUE SELEGILINE FORMULATION BENEFICIAL IN PARKINSON’S DISEASE

Selegiline, a potent irreversible MAO-B inhibitor, administered as an orally disintegrating tablet (ODT), is safe and effective as long-term adjunctive therapy in patients with Parkinson’s disease who experience a deterioration of levodopa response, said Mark F. Lew, MD, Professor of Neurology, Keck School of Medicine, University of Southern California, Los Angeles.

“A notable improvement in the reduction of ‘off’ time was maintained over the course of four years of treatment with selegiline ODT,” Dr. Lew pointed out. “This is a very encouraging result given the presumed disease progression over this extended period of time and the observation that the efficacy of most Parkinson’s disease drugs diminishes over time.”

These findings were reached from an open-label extension study in patients with Parkinson’s disease who completed one of two multicenter, randomized, double-blind, placebo-controlled studies or an open-label study of selegiline ODT. Since use of conventional selegiline as an adjunct to levodopa for improved motor control has been limited by low bioavailability, extensive first-pass hepatic metabolism, and the production of amphetamine metabolites, a new formulation of selegiline ODT has been developed to overcome these limitations. By rapidly dissolving in the mouth and undergoing pregastric absorption, selegiline ODT achieves high plasma concentrations of the parent drug, increasing bioavailability and reducing the chance of first-pass hepatic metabolism and decreasing the production of unwanted metabolites.

The objective of the study was to confirm the long-term safety and efficacy of selegiline ODT 2.5 mg once daily in 248 patients with Parkinson’s disease who were taking levodopa. Efficacy assessment was based on the reduction in percentage of average daily “off” time during waking hours compared with baseline reports from patient/caregiver–completed diary cards. Safety and tolerability analyses were based on the incidence of adverse effects, along with findings on routine laboratory tests, vital signs, physical examinations, electrocardiography, and oropharyngeal examinations.

Results from patients treated with selegiline ODT for longer than six months and for one, two, three, and four years indicate sustained long-term efficacy, with a mean reduction from baseline in actual daily “off” time of 1.4 hours among patients in the prior selegiline ODT groups. Reduction from baseline in percentage daily “off” time was 9.4% in the prior selegiline ODT patients and 6.0% in the prior placebo group.

LONG-TERM EFFICACY OF INFB-1b

Sixteen-year outcomes from the pivotal INFB-1b trial indicate that the drug has been safe and well tolerated in patients with relapsing forms of MS, reported George C. Ebers, MD, Action Research Professor of Clinical Neurology, University of Oxford, United Kingdom.

“Though all analyses provided are strictly exploratory in nature and hypothesis-generating, results from this 16-year long-term follow-up study will give some context for clinicians wishing to assess the long-term safety and efficacy of INFB-1b,” Professor Ebers commented. “No other immunomodulatory treatment has been used for this length of time.”

The 16-year, long-term follow-up is a multicenter, open, observational study in patients with relapsing forms of MS. Cross-sectional data are being collected from patients who participated in the original trial and will be compared with well-characterized natural history data. The collected data include survival, disease status, relapse rate, Expanded Disability Status Scale (EDSS) score, adverse events, MRI measures, and others.

As of September 15, 2005, of the 372 participants in the original trial, 331 (89%) had been identified, with 297 still alive. In this cohort of identified patients, the median time since diagnosis was 19 years. “The patient population took different routes to reach the 16-year point and analysis will be complex, but ascertainment of nearly 90% of the original cohort has already exceeded previous standards and there may be more to come,” Professor Ebers told Neurology Reviews.

Preliminary results, said Professor Ebers, showed that EDSS progression appears to be low across all groups compared with natural history predictions. However, because it was a relapsing-onset group of patients, adjustment needs to be made for poor early outcomes because these patients were not eligible to participate in the trial. There was a higher death rate in the group starting out on placebo and this is being further explored, he said. Strong cross-sectional univariate associations between EDSS scores and MRI parameters were also observed. INFB-1b is safe and well tolerated over the long term as indicated by the minimal adverse events and by the adherence to therapy, Professor Ebers and his colleagues concluded, and efforts are being made to follow up all patients and to proceed with more detailed analyses.

IMPROVING COGNITIVE FUNCTION IN BIPOLAR DISORDER

Olanzapine or lithium treatment results in improved cognitive function in nonrelapsing patients with bipolar disorder, with improved attentional capacity seen in the olanzapine-treated patients and improved organizational capacity and immediate recall demonstrated in lithium-treated patients, reported Deborah A. Yurgelun-Todd, PhD, Associate Professor, Harvard Medical School Department of Psychiatry, Cambridge, Massachusetts, and Director of Cognitive Neuroimaging and Neuropsychology, Brain Imaging Center, McLean Hospital, Belmont, Massachusetts.

“Results from the current investigation underscore the importance of examining discrete cognitive domains following pharmacologic treatment in patients with bipolar disorders,” she said. “Future investigations are needed to determine the effects of clinical heterogenicity and duration of illness on differences in neuropsychological tests administered.”

A number of studies have proposed that cognitive performance may play a role in the onset of bipolar disorder, while additional studies have highlighted the importance of neurocognitive ability in treatment outcome. A double-blind, 52-week, multisite international study was conducted to prospectively examine neurocognitive performance and clinical outcome in patients with bipolar disorder. Initially, a total of 431 patients were enrolled in a clinical trial and randomized to double-blind maintenance therapy to olanzapine 5 to 20 mg/day or lithium 0.6 to 1.2 mEq/L for 52 weeks. A total of 320 patients completed neurocognitive testing and ratings of clinical symptoms.

Patients were categorized by both treatment and relapse status to identify the changes in cognitive processing ability associated with drug type in patients with nonrelapsing bipolar disorder. Nonrelapsing was defined as never achieving a score greater than 15 on either the 21-item Hamilton Depression Rating Scale (HAM-D) or the Young Mania Rating Scale (YMRS) during the trial.

Although relapse-free treatment subgroups did not differ significantly on HAM-D or YMRS change scores, they did demonstrate a number of significant changes on cognitive performance. The lithium-treated group showed a significantly greater improvement on recall of the first word list and a trend for improved total recall on the Rey Auditory Verbal Learning Test; they also demonstrated greater improvement on number of categories completed in the Wisconsin Card Sorting Test and in the Immediate Recall of the Key Complex Figure Test. The olanzapine group showed a greater improvement on the Wechsler Memory Scale-Revised Digit Span Test.

ESZOPICLONE RECOMMENDED FOR CHRONIC INSOMNIA

Eszopiclone, a new nonbenzodiazepine sleep agent, offers long-term efficacy in the treatment of patients with primary chronic insomnia, according to Andrew D. Krystal, MD, Associate Professor of Psychiatry and Behavioral Sciences and Director of the Sleep Laboratory, Insomnia Clinic, and Quantitative EEG Laboratory, Duke University Medical Center, Durham, North Carolina.

“Our study results were consistent with previous 12-month data and indicate that in this study, nightly use produced consistent and sustained improvements across all sleep and daytime parameters,” Dr. Krystal pointed out. “In addition, eszopiclone was well tolerated with no pharmacologic tolerance, withdrawal, or rebound insomnia.”

In an attempt to evaluate the long-term efficacy of eszopiclone and the long-term safety, quality of life, and discontinuation effects with this drug, 830 patients with a diagnosis of chronic primary insomnia and an average total sleep time of six hours or less per night and/or sleep latency greater than 30 minutes were randomized in a 2:1 fashion to eszopiclone 3 mg or placebo nightly for six months, followed by a two-week placebo run-out period. Patient-reported end points included sleep efficacy, latency, sleep duration measured by total sleep time, maintenance measured by wake after sleep onset, quality of sleep, and daytime function including alertness, daytime sleepiness, ability to concentrate, and physical well-being.

At all monthly assessment points, eszopiclone was effective in inducing and maintaining sleep, as shown on the scales measuring total sleep time and wake time after sleep onset. It was also effective in improving sleep quality and daytime function measures, the researchers found. This efficacy was sustained for six months of nightly use, without evidence of tolerance. Furthermore, the drug proved to be safe and well tolerated.

NR

—Lawrence M. Prescott, PhD

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