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The 56th annual meeting of the american academy of neurology
The 56th Annual Meeting
of the American Academy of Neurology
Lawrence M. Prescott, PhD
More than 8,000 neurologists, neurosurgeons,
newly diagnosed epilepsy, restless legs syn-
research scientists, and other health care profes-
sionals from around the world met in San Fran-
immunotherapeutic combination for multiple
cisco, California, from April 24 to May 1, 2004, to
sclerosis; demonstration of improved behav-
hear the latest developments in the prevention,
ioral symptoms in Alzheimer’s disease (AD)
treatment, and control of neurological diseases.
with a well-known drug used to treat AD; and
Major areas of interest included new approaches with
the development of novel agents for the treatment of AD
established drugs for the treatment of musician’s dystonia,
Donepezil Therapy in Alzheimer’s Disease
The randomized placebo cohort included 121 patients who
Jeffrey Cummings, MD, Professor of Neurology,
received donepezil monotherapy only during the 20-week
Department of Neurology, University of California, Los Ange-
study period. After 20 weeks of monotherapy, statistically sig-
les, School of Medicine, Los Angeles, California.
nificant improvements from baseline were observed in theNPI-12 scores, (of –8.2 and a relative change of 27.6%) and in
Therapy with donepezil (Aricept®, Pfizer) has been found
NPI-10 scores (of –7.2 and a relative change of 28.7%). Statis-
to significantly improve behavioral symptoms in patients with
tically significant differences in both the CGI–S and CGI–I
mild-to-moderate Alzheimer’s disease (AD). A 20-week study
measures were observed from baseline to the end of the 20
was designed primarily to compare the efficacy and safety of
the antidepressant sertraline (Zoloft®, Pfizer) with placebo in
The BEHAVE–AD scores, as well as two items on the
patients already receiving donepezil therapy. The patients
CMAI–C, also improved significantly. Cognition, as measured
were not depressed but were exhibiting substantial behavioral
by the MMSE and ADAS–Cog, was maintained at or above
symptoms, with Neuropsychiatric Inventory (NPI) total scores
baseline values at the end of the study.
above 5 at screening and NPI severity scores in at least two
Overall, donepezil was well tolerated. Adverse drug events
(ADEs) led to discontinuation in 10.8% of patients receiving
The patients received open-label donepezil 5 mg daily for
donepezil monotherapy. The most common side effects
four weeks, followed by four weeks of donepezil 10 mg daily
involved the digestive and nervous systems.
in an open-label fashion. At the eighth week, patients receiv-ing donepezil were randomly assigned to receive placebo or
Memantine Monotherapy in Mild-to-Moderate
sertraline 25 to 200 mg/day, in addition to the open-label
Steven G. Potkin, MD, Professor of Psychiatry and
Human Behavior, and Director of the Brain Imaging Center,University of California at Irvine, Irvine, California.
• 10-item and 12-item NPI scores.
• Clinician’s Global Impression Scale for Improvement
Memantine (Namenda™, Forest) monotherapy has been
(CGI–I) and Severity (CGI–S) subscales.
shown to be effective and safe for the treatment of mild-to-mod-erate AD and superior in efficacy to placebo on measures of
The secondary efficacy measures included:
cognition, global status, and behavior.
A total of 403 patients were enrolled into a randomized, dou-
• behavioral symptoms, as assessed by the Behavioral
ble-blind, parallel-arm, placebo-controlled phase III clinical
Pathology in Alzheimer’s Disease Rating Scale (BE-
trial at 42 U.S. centers. These patients, all of whom had mild-
HAVE–AD) and the Cohen–Mansfield Agitation Inven-
to-moderate AD, were randomly assigned to receive meman-
tine 10 mg twice daily or placebo for six months. The two
• cognition, as assessed by the Alzheimer’s Disease Assess-
primary outcome measures were the ADAS–Cog and the Clin-
ment Scale–Cognition subscale (ADAS–Cog) and the
ician’s Interview-Based Impression of Change–Plus version
Mini-Mental State Examination (MMSE).
(CIBIC–Plus). Secondary outcomes included:
• daily functioning, as assessed by the Alzheimer’s Disease
Dr. Prescott is a medical, health, and science writer based in SanDiego, California, and a former medical microbiologist and clinical
Cooperative Study–Activities of Daily Living Inventory
pathologist for the World Health Organization.
450 P&T® • July 2004 • Vol. 29 No. 7
Meeting Highlights: American Academy of Neurology
• behavior, as assessed by the 12-item NPI.
instrumentalists. Their mean age was 45.9 years, and the mean
• safety, as measured by the incidence of ADEs and
duration of symptoms was 10.6 years.
changes in laboratory parameters, electrocardiograms,
As a group, the musicians subjectively rated their playing
ability as significantly improved following botulinum toxin Atreatment. In a self-rating of treatment response, 69% of the
Overall, 394 patients were included in the intent-to-treat
musicians indicated improvement and 45% rated the benefit as
(ITT) population. As assessed by the ADAS–Cog, patients
sufficient to improve their performance. Twenty-four musi-
receiving memantine monotherapy maintained their cogni-
cians received ongoing treatment for an average of 36 months;
tive abilities above baseline values for the entire 24 weeks of
another six patients showed long-lasting benefits without the
the study. In contrast, patients receiving placebo exhibited a
progressive decline during the study, and the difference
Three patients with embouchure
dystonia (of the lips and
between the two treatment groups was statistically significant.
facial muscles) had a poor response. Overall, 30 of the 84
Patients who took memantine had significantly better global
musicians either experienced persisting improvement or con-
status than did those taking placebo, as measured by the
tinued to benefit from ongoing injections for an average of
A pilot study of positron emission tomography (PET) to
evaluate memantine’s action on brain metabolism in a subset
Topiramate in Newly Diagnosed Epilepsy
of 10 patients from the phase III trial demonstrated a statisti-
Elinor Ben-Menachem, MD, PhD, Professor,
cally significant increase in glucose metabolism in several re-
Department of Neurosciences, Sahgrenska Academy at Göte-
gions of the brain associated with language and attention in
borg University, and Director, Clinical Pharmacology and
these patients. In contrast, the placebo patients showed
Epilepsy, Department of Clinical Neurosciences, Sahlgrenska
metabolic declines in these same regions.
University Hospital, Göteborg, Sweden.
With regard to safety, the incidence of treatment-related
ADEs was similar in the memantine and placebo patients.
Findings from two studies indicate that topiramate (Topa-
Somnolence was reported in more than 25% of patients taking
max®, Johnson & Johnson) 100 mg/day is an effective dose
memantine than in those taking placebo. By the same criteria,
in patients with newly diagnosed epilepsy; is at least as
more than 25% of patients in the placebo group reported upper
effective as the traditional first-line agents carbamazepine
respiratory infection and depression.
(Tegretol®, Novartis) and valproate (Depacon®, Abbott) forpreviously untreated patients with epilepsy; and is better
Botulinum Toxin Injections in Musician’s Dystonia
Stephen U. Schuele, MD, Consulting Neurologist,
A dose-controlled study enrolled 470 adults and children
Department of Neurology and Medicine, The Cleveland Clinic
with epilepsy that was characterized by partial-onset or primary
generalized tonic–clonic seizures. The patients were randomlyassigned to take topiramate 50 mg or topiramate 400 mg daily,
Results of an outcome survey of musicians with focal task-
titrated at 50 mg from the first week to 400 mg at the sixth
specific dystonia (FTSD) treated with injected botulinum toxin
week. The significant between-group difference in time until
A (Botox®, Allergan) suggest that this approach can offer
the first seizure favoring the higher dose confirmed topira-
long-term benefit, independent of the musical instrument used.
mate’s efficacy as monotherapy. Furthermore, the significant
Because FTSD in musicians often leads to the end of their
difference between 100 mg/day and 25 mg/day during the
careers, a study was performed to evaluate the initial and long-
dose-escalation phase identified topiramate 100 mg/day as an
term benefits of the toxin. Between 1995 and 2002, musicians
effective dose and an appropriate target dose for initial therapy
with FTSD at the Institute of Music Physiology and Musicians
Medicine at the University of Music and Drama in Hanover,
In a comparative monotherapy study, 613 adults and children
Germany, received botulinum toxin A injections. The initial
with epilepsy, with no seizure type excluded, were randomly
average injected dose was 51.2 units, and the final dose was
40.1 units. A minimum of 2.2 and a maximum of 3.4 injectionswere administered.
• topiramate 100 mg/day (median duration, 544 days)
Using telephones and a chart review, investigators surveyed
• topiramate 200 mg/day (median duration, 378 days)
88 of 225 musicians with FTSD after treatment. Of the 88 musi-
• carbamazepine 600 mg/day (median duration, 434 days)
cians, 84 responded to the survey. Assessments included a rat-
• valproate 1,250 mg/day (median duration, 304 days)
ing of severity; an estimate of playing ability before and afterinjection, in percentages; and a rating of treatment response,
Double-blind treatment continued until six months after the
from worse to none to mild to moderate to marked to remis-
last patient was assigned to a therapy regimen or until a
sion. Initially, the investigators observed muscle involvement
decision was made to change therapy by altering the dose or
while the musicians were playing and then reported their find-
medication or by discontinuing the study medication entirely.
The primary endpoint was the time to exit from the study
A total of 74 men and 10 women participated in the study
(when a patient left). The secondary endpoints were (1) free-
group. The group included 25 woodwind players, 25 guitarists,
dom from seizures during the last six months of the study and
20 keyboard players, 12 bowed-string musicians, and two brass
Vol. 29 No. 7 • July 2004 • P&T® 451
Meeting Highlights: American Academy of Neurology
There was no significant difference in efficacy between top-
The high efficacy of zolmitriptan nasal spray was not
iramate 100 mg/day and 200 mg/day, as measured by the
affected by the presence of rhinitis. Two-hour pain-free rates
time until the first seizure. At most time points, however, the
for each 90-day period ranged from 54.4% to 56.6% for attacks
cumulative number of study exits was lower with topiramate
treated in the presence of rhinitis.
than with carbamazepine or valproate. Median retention timeswere longer with topiramate than with either of the compara-
Levetiracetam for Transformed Migraine
tor drugs. Topiramate 100 mg/day was better tolerated than
Alan M. Rapaport, MD, Co-Director of the New
topiramate 200 mg/day, carbamazepine 600 mg/day, or val-
England Center for Headache, Stamford, Connecticut, and
proate 1,250 mg/day. Patient discontinuation rates were 19%
Clinical Professor of Neurology, Columbia University College
with topiramate 100 mg/day, 28% with topiramate 200 mg/day,
of Physicians and Surgeons, New York.
25% with carbamazepine 600 mg/day, and 23% with valproate1,250 mg/day.
A prospective, open-label study shows that the antiepileptic
agent levetiracetam (Keppra®, UCB Pharma) significantly
Zolmitriptan Nasal Spray for Long-Term
reduces the frequency and impact of headaches in patients with
Treatment of Migraine
transformed (chronic, daily) migraine.
Andrew Dowson, MD, Director of the Headache
Overall, 36 patients (26 women, 10 men; average age, 46.5
Clinic, Kings College Hospital, London, United Kingdom.
years) were enrolled into a prospective, open-label study oflevetiracetam for the preventive treatment of refractory trans-
Six-month follow-up results from a large-scale phase III
formed migraine. All the participants had previously been
clinical study demonstrate that zolmitriptan nasal spray
unresponsive to one, but not more than three, preventive drugs
(Zomig®, AstraZeneca) 5 mg is safe, well tolerated, and reli-
and had taken no more than one antiepileptic drug. Eleven
ably effective when used for the long-term acute treatment of
patients were not using other preventive drugs at the time of
multiple migraine attacks. High pain-free rates have been
After a baseline evaluation, patients received levetiracetam
To assess the spray’s long-term safety and tolerability as well
250 mg/day and increased the dose by 250 mg every fifth day,
as its efficacy at 5 mg, investigators enrolled 538 patients aged
up to a dose of 1,000 mg daily. After the first month, doses could
18 to 65 years of age with a diagnosis of migraine, as defined
be further increased to 3,000 mg/day in two divided doses. The
by the International Headache Society. This open-label, non-
treatment phase lasted three months.
comparative study was conducted in 52 centers in Canada,
The primary endpoint was headache frequency. Secondary
Finland, Germany, South Africa, Sweden, and the United King-
dom. The patients had endured at least three migraine head-aches per month in the previous three months.
• the number of days during which patients experienced
Patients with headache of any baseline pain intensity—mild,
moderate, or severe—were given zolmitriptan nasal spray and
• Migraine Disability Assessment (MIDAS) scores.
a second dose of trial medication; patients with persistent or
• patients’ scores on the Headache Impact Test (HIT).
recurrent headache could take an “escape” medication at morethan two hours after the initial dose.
These primary and secondary endpoints were assessed at
The study population of 538 patients had treated themselves
for more than one migraine attack, for a total of 20,717 treated
The median headache frequency at baseline was 24.9 days
attacks. There was a high rate of treated attacks; 43.9% of
of headaches per month. Three months of treatment with
patients treated a mean of three or more attacks per month for
levetiracetam reduced this number by 35%—to 16.2 days of
at least six months. Over the course of the 20,717 attacks
headaches per month. The average number of moderate or
treated, ADEs were reported in 85.3% of patients; however,
severe days of headache decreased by 42%, from 16.8 days per
patients reported only 32.8% of the attacks.
month to 9.7 days per month, after three months of levetira-
The most commonly reported ADEs were unusual taste in
19% of patients and paresthesias in 6.8% of patients. Overall,
After three months of levetiracetam treatment, MIDAS
only 24 patients withdrew from the study because of ADEs.
scores were also significantly reduced by 35% (from 62.8 to
Patients used a second dose of zolmitriptan nasal spray
40.8) and HIT scores declined by 6.0% (from 63.4 to 59.4).
5 mg at least two hours after the initial dose to treat 5,101
Fifteen patients reported drug-related ADEs. Eight patients
attacks. The use of two 5-mg doses to treat an individual
dropped out of the study because of side effects, although no
attack did not change the type, frequency, or maximum inten-
As for efficacy, 53.8% of the 20,717 treated attacks were
Interferon Beta-1b and Azathioprine Combination
recorded as pain-free at two hours following treatment. This
for Multiple Sclerosis
outcome was maintained throughout the study, and the pain-
Peter A. Calabresi, MD, Associate Professor of
free rates at two hours were consistent over the four 90-day
Neurology, Department of Neurology, The Johns Hopkins
periods of the study: 51.2% for days 0 to 90; 52.7%, for days
University School of Medicine, and Director of the Johns Hop-
91 to 180; 55.8% for days 181 to 270; and 55.7% for days 271
kins Multiple Sclerosis Center, Johns Hopkins Hospital, Balti-
452 P&T® • July 2004 • Vol. 29 No. 7
Meeting Highlights: American Academy of Neurology
Combination therapy with interferon beta-1b (Betaseron®,
Helsinki, Finland, and Director of Rinnekoti Research Centre,
Berlex/Schering AG) and azathioprine (Imuran®, Prome-
theus) is safe and effective at reducing inflammatory diseaseactivity in most patients who have multiple sclerosis (MS)
Pramipexole (Mirapex®, Pfizer/Boehringer Ingelheim), a
with “breakthrough activity” who are receiving interferon beta
dopamine agonist indicated for the treatment of Parkinson’s
disease, offers rapid relief of restless legs syndrome (RLS).
Several previous studies have documented the potential
Typical symptoms include motor restlessness, nocturnal wors-
benefit of interferon beta plus azathioprine, but because results
ening of RLS, and sleep disturbances.
have been variable, an attempt was made to determine the
To determine the optimal dose of pramipexole in patients
parameters that might guide optimal dosing.
with idiopathic RLS, researchers enrolled 109 patients with RLS
In an open-label, baseline-versus-treatment study, 15 MS
in a double-blind, placebo-controlled, single-center, compre-
patients with breakthrough activity on relapse received azathio-
hensive polysomnographic study. The patients were randomly
prine, added in a dose-titrated manner to 325 mcg of interferon
assigned to receive pramipexole 0.125 mg/day, 0.25 mg/day,
beta-1b subcutaneously every other day for up to six months.
0.5 mg/day, or 0.75 mg/day or placebo. All of the pramipex-
ADEs, blood counts, and serum chemistry profiles were used
ole groups were started at 0.125 mg/day, and the doses were
increased stepwise for the higher levels of drugs adminis-
The primary endpoint was a decrease in inflammatory dis-
ease activity, as measured by a reduction in contrast-enhanced
For patients receiving 0.25 mg, the final dose was reached
lesions. Secondary measures of safety and efficacy included:
on the fifth day; for patients receiving 0.5 mg, the final dose wasreached on the ninth day; and for patients receiving 0.75 mg,
the final dose was reached on the 13th day. The total study
• scores on the Kurtzke Expanded Disability Status Scale
The primary endpoint was a reduction in limb move-
• MS Functional Composite (MSFC) scores.
ments, as assessed by the Periodic Limb Movement Index
• gadolinium-enhanced lesion counts: three at two months,
(PLMI) during time in bed. Secondary endpoints included
at one month, and at baseline with monotherapy, and
changes on (1) the Restless Legs Symptom Rating Scale
three at four months, at five months, and at six months
(RLSRS) and (2) the CGI–I. The mean age of the patients
was 57 years, and 74% were women. The mean duration ofRLS was 4.74 years.
Optimization of dosing was evaluated according to the white
Pramipexole showed excellent efficacy over the entire dose
blood cell (WBC) count nadir and per 6-mercaptopurine lev-
range of 0.125 to 0.75 mg/day within three weeks of therapy.
els, an active metabolite of azathioprine, from red blood cell
A statistically significant difference in the reduction of periodic
limb movements during time in bed was observed with
Three of the 15 patients who received combination therapy
pramipexole compared with placebo (P
discontinued treatment prematurely because of ADEs or non-
The responder rate, defined as greater than a 50% reduction
compliance. Of the 12 patients who completed six months of
on the RLSRS, increased from more than a 60% reduction with
therapy, gastrointestinal toxicity was the most common clini-
pramipexole 0.125 mg to approximately 78% with 0.5 mg, and
cal ADE. Liver function test abnormalities occurred in five of
to 75% with 0.75 mg. At three weeks, CGI–I scores showed
the 12 patients, but this ADE was resolved in all patients with
“very much” to “much” improvement in 60% of patients taking
0.125 mg, up to approximately 85% with 0.5 mg, and 83% with
There was a statistically significant 63% reduction in con-
trast-enhancing lesions after combination therapy compared
From the results of the high responder rates and high scores
with monotherapy. From the baseline evaluation to the sixth
on the CGI–I, it is obvious that the severity of the RLS symp-
month, EDSS and MSFC scores remained stable in the group
toms was significantly reduced by pramipexole treatment.
as a whole. As predicted, neither active metabolite levels of
Clinical efficacy was most prominent in the patients receiving
azathioprine nor WBC levels were correlated with doses of
0.5 and 0.75 mg/day. Furthermore, safety and tolerability were
azathioprine. However, WBC and lymphocyte counts were
favorable at all dose levels, with no serious ADEs occurring
strongly correlated with the reduction in the number of
gadolinium-positive lesions, as detected with magnetic reso-nance imaging.
Fluphenazine for Tourette Syndrome
It should be noted that careful monitoring of liver func-
Yavuz S. Silay, MD, Research Coordinator, Parkin-
tion tests and WBC counts is necessary to prevent toxicity.
son’s Disease Center and Movement Disorders Clinic, Depart-
Azathioprine should be titrated upward to the highest toler-
ment of Neurology, Baylor College of Medicine, Houston,
ated dose, and the WBC count should be used to help guide
Fluphenazine (e.g., fluphenazine, Geneva; Proloxin®, Novar-
Pramipexole for Restless Legs Syndrome
tis) appears to be safe and effective in the long-term treatment
Markku Partinen, MD, Associate Professor of
of tics in patients with Tourette syndrome (TS).
Neurology, Department of Neurology, University of Helsinki,
To provide data on the long-term safety and efficacy of
Vol. 29 No. 7 • July 2004 • P&T® 453
American Academy of Neurology
continued from page 453
fluphenazine, investigators enrolled 1,348 patients with a diag-nosis of TS, as defined by criteria formulated by the TouretteSyndrome Classification Study Group, between December 14,1981, and March 24, 2004. A total of 272 patients were randomlyselected for further analysis and were grouped into one ofthree categories:
• patients who had never been treated with fluphenazine• patients who had tried fluphenazine but discontinued it
• patients who had taken fluphenazine for at least one year
Responses to fluphenazine, the main outcome measure,
were rated on a clinical rating scale of 1 to 5, with 1 repre-senting a marked reduction in tics and improved function and5 representing a worsening of tics or a deterioration in func-tion.
The investigators assessed 63 patients; the mean age of
those with TS symptoms was 8.3 + 7.2 years (range, 1.2–60years). The mean age at initiation of fluphenazine therapy was15.6 + 9.9 years (range, 5.7–60 years). These patients receivedfluphenazine for a mean of 3.9 + 3.3 years, and their responsewas rated as 1 or 2 ( i.e., marked to moderate improvement)in 84.1% of patients. The mean daily dose of fluphenazine was3.9 + 2.7 mg/day.
Although tardive dyskinesia did not affect any patients, 23
patients discontinued the study because of (1) the study
medication’s lack of efficacy, (2) the occurrence of side effects,
(3) the achievement of better results with botulinum toxin, or(4) other reasons.
While acknowledging the limitations of a retrospective analy-
sis, these findings represent the long-term clinical experiencein a large number of patients. On the basis of these longitudi-nal findings of a high degree of efficacy and a relatively lowfrequency of ADEs, fluphenazine is now considered to be thefirst-line pharmacotherapy for treating tics at the MovementDisorders Clinic at Baylor College. Although other neuro-leptic agents have been reported to cause tardive syndromesin patients with TS, tardive dyskinesia was not encountered inthis study. This is a major consideration because tardive dys-kinesia is one of the most feared side effects of chronic neuro-leptic therapy. It still is prudent for patients to be monitoredcarefully so that any potentially serious side effects might bedetected as early as possible.
460 P&T® • July 2004 • Vol. 29 No. 7
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