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57th Annual Meeting in Miami, FL
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Highlights of the 57th Annual Meeting of the American Academy of Neurology
Movement Disorders
Robert A. Hauser, M.D., M.B.A.
Parkinson’s Disease and Movement Disorders Center
Professor of Neurology, Pharmacology and Experimental Therapeutics
University of South Florida
Tampa General Healthcare
Theresa A. McClain, M.S.N., ARNP, B.C.
Parkinson’s Disease and Movement Disorders Center
University of South Florida
Tampa General Healthcare
PARKINSON’S DISEASE (PD)
Parkinson’s disease: Genetics
Mutations in the LRRK2 (Leucine-rich repeat kinase 2) gene (PARK8) on chromosome 12 have recently been identified as a cause
of autosomal dominant parkinsonism. Patients with such mutations, exhibit clinical features similar to Parkinson’s disease
(PD) but the underlying pathology can include Lewy body and Tau inclusions. Mata et al. (1) evaluated the LRRK2 gene in affected
probands from 100 PD families with an autosomal dominant pattern of inheritance. They identified 6 novel gene mutations including
3 amino acid substitutions. In this study, 6% of autosomal dominant, late-onset, levodopa-responsive PD was caused by mutations
in the LRRK2 gene. How common these mutations might be in sporadic PD is not yet known, but will be examined.
Toft et al. (2) identified 13 affected probands with a LRRK2 mutation (6055A>G) from families with autosomal dominant parkinsonism.
Seven families were from
Norway, 3 from the US, 2 from Ireland, and 1 from Poland. Twenty-one additional family members were found to carry the mutation
and the mutation segregated with disease in affected families. Clinical disease prevalence increased with increasing age and
was evident in >80% of mutation carriers older than 65 years. Although the families were from various European populations,
they were found to share an ancestral haplotype indicative of a common founder, and the mutation appears to be ancient.
Taylor et al. (3) reported that mutations in the LRRK2 gene may alter kinase activity, leading to phosphorylation of alpha-synuclein
and tau, thereby triggering disease pathogenesis. This suggests that therapies to prevent phosphorylation might be developed
to slow or stop disease progression.
Parkinson’s Disease: Imaging
Recent studies that have used ß-CIT SPECT or 18F-Dopa PET imaging to assess progression of dopamine neuron loss in PD have
found that approximately 10-15% of subjects thought to have early PD as diagnosed by clinical criteria have normal scans.
These individuals have been termed subjects with scans without evidence of dopaminergic deficit (SWEDDs). It is not clear
if these patients have “very early” PD, some previously unrecognized form of PD, or do not have PD. Understanding
this situation has implications regarding the sensitivity of such imaging studies to diagnose early PD and our ability to
accurately diagnose early PD using clinical criteria. Marek et al. (4) reported the 4-year follow-up study of a cohort from
the ELLDOPA-CIT study. Patients whose initial scans demonstrated a dopaminergic deficit (non-SWEDDs) showed a progressive
decline in ß-CIT uptake, as expected. At baseline, 9, 18, 36, and 48 months, putamenal ß-CIT uptake was 40%, 39%, 37%, 35%,
and 31%, of normal age-matched controls. In contrast, for SWEDD subjects, ß-CIT uptake was normal at baseline and remained
normal through the study. At baseline, 9, 18, 36, and 48 months, SWEDD subjects had putamenal ß-CIT uptake of 111%, 105%,
105%, 110%, and 112% of normal, age-matched controls. This suggests that patients with a baseline SWEDD comprise a distinct
population, and probably do not have PD. It was therefore suggested that dopaminergic imaging should be considered as an inclusion
criteria for future studies to assess progression of disease in early PD. An analysis of the videotapes of SWEDD subjects
is underway to determine if SWEDD subjects can be distinguished from non-SWEDD subjects at baseline based on clinical features.
Parkinson’s Disease: Medication Treatment
Korczyn et al. (5) reported results of a 10 year follow-up of patients who participated in the 5-year 056 study in which patients
were randomized to initial treatment with ropinirole or levodopa. Upon completion of the 056 study, patients could be treated
in any way the investigator thought best (open, naturalistic study). Approximately 25% of the patients initially randomized
in the 056 study were followed through 10 years. At 10 years, significantly fewer patients initially randomized to ropinirole
(regardless of current treatment) (52.4%) developed dyskinesias compared to the levodopa group (77.8%) (p=.046). Time to develop
dyskinesias was significantly longer in the ropinirole group (median, 8.6 yrs) compared to the levodopa group (7.0 years)
(p=0.007). Although the ropinirole group experienced less disabling dyskinesia, this difference was not statistically significant
(p=0.27). Unified Parkinson Disease Rating Scale (UPDRS) motor and ADL scores were comparable in both groups. These findings
extend those from the original randomized study and suggest that potential benefit of reduced dyskinesia in patients initially
treated with a dopamine agonist is maintained long term.
Isaacson et al. (6) retrospectively evaluated use of dopamine agonists in elderly PD patients using the Ali Project database.
They identified 339 patients over age 70, including 132 over age 80, who were treated with a dopamine agonist. They found
that lower UPDRS scores and improved postural reflexes were common. In addition, many patients were able to lower their levodopa
doses, and had less motor fluctuations. They found that if the dopamine agonist was titrated slowly, side effects were not
a significant problem. Patients tolerated QD or BID dosing better. This retrospective study suggests that dopamine agonists
may be useful and well tolerated when titrated slowly in the elderly. Age may be a less important factor in choosing therapy
than current consensus guidelines suggest.
The TEMPO study (7) found that patients with early PD randomized to treatment with the MAO-B inhibitor, rasagiline, for one
year experienced less worsening of total UPDRS scores than subjects randomized to placebo for 6 months followed by rasagiline
for 6 months (delayed start). Hauser et al. (8) presented results of the long-term open label extension of the TEMPO study.
One hundred-seventy-seven subjects of the original 404 were still being followed for at least 4.5 years (and up to 6.5 years)
from TEMPO start. All patients were receiving 1mg of rasagiline per day, and other antiparkinsonian medications were administered
as appropriate. Results showed that patients who received rasagiline from the beginning maintained better (lower) UPDRS scores
than the group that received placebo for the first 6 months (delayed start). The mean difference in total UPDRS over time
was 2.42 units (p=0.02). These results support those previously reported after 1 year. They suggest that rasagiline might
provide long-term neuroprotective or disease modifying effects in addition to a symptomatic benefit. Additional studies are
required.
Castillo et al. (9) suggested that continuous subcutaneous infusion of apomorphine may be a valid alternative to deep brain
stimulation (DBS). They studied 5 PD patients with a mean age of 73.4 years (range 56-86) who were experiencing severe motor
complications. All had been excluded from treatment with subthalamic nucleus (STN) DBS: 2 older than 70, 1 previous STN DBS
failure, 2 refused surgery. All had a positive response to an apomorphine subcutaneous injection test. A programmable pump
was used to infuse apomorphine and infusion rates were adjusted as needed. At a mean of 10.7 months, daily apomorphine doses
were 48-50 mg/day. Results demonstrated that OFF time was reduced 70%, and dyskinesias were reduced in duration (86%) and
severity (40%). Daily levodopa doses were reduced by approximately 50%. Side effects included skin nodules at the infusion
site in all patients, and one had severe eosinophilic panniculitis. This study demonstrates the potential efficacy of medication
infusion therapy. Further work is necessary to determine if troublesome side effects can be avoided.
Parkinson’s Disease: Surgical Treatment
Okun et al. (10) reviewed 41 cases referred from elsewhere for DBS failure over 2 years. They evaluated reasons why DBS failed
and whether outcomes could be improved. Reasons identified for failure included problems in patient selection, lead placement,
and programming. One important issue was misdiagnosis. Pre-operative diagnoses were PD (31), essential tremor (ET) (9), and
dystonia (1). Based on expert evaluation, actual diagnoses were PD (26), ET (5), Parkinson’s disease dementia (PDD)
(3), PD/ET (1), multiple system atrophy (MSA) (2), corticobasal ganglionic degeneration (CBGD) (1), progressive supranuclear
palsy (PSP) (1), dystonia (1), and myoclonus (1). This is important because response to DBS would not be expected in atypical
parkinsonism (MSA, CBGD, PSP) or myoclonus. Twenty-seven percent of patients had not seen a movement disorder specialist prior
to surgery, 12% had had an inadequate medical trial, and 12% had significant cognitive dysfunction prior to implantation.
Forty-six percent had misplaced leads, 37% were inadequately programmed, and 17% had no or poor access to follow-up care.
Seven leads (17%) were replaced with good improvement and 3 (7%) with partial improvement. Fifteen patients (37%) were reprogrammed
with good improment and 6 (15%) with partial improvement. Once proper management was completed, 21 (51%) of the patients had
good outcomes and 14 (34%) did not improve. This study highlights the importance of proper diagnosis and pre-operative evaluation,
expert surgical and programming teams, and the need for follow-up care and medication adjustments.
Ahn et al. (11) presented results of intravenous stem cell transplantation in a rat model of Parkinsonism. Rats were lesioned
unilaterally with 6-OHDA and 3 weeks later received intravenous transplantation of human neural stem cells (HB1.F3 and HB1.F3.Nurrl
cells). The rats were sacrificed at 3, 6, and 9 weeks. Results showed that transplanted human neural stem cells migrated to
diverse brain areas, but much more to the side of the lesioned striatum and substantia nigra than the normal side. The transplanted
stem cells were differentiated into mostly astrocytes and a few neurons. Evidence of differentiation into dopaminergic neurons
(TH immunoreactivity) was not detected. This study reflects both the promise and difficulty of stem cell transplantation.
It was demonstrated that intravenous delivery does allow stem cells to reach the brain, but none were observed to differentiate
into dopaminergic neurons.
CERVICAL DYSTONIA (CD)
Yablon et al. (12) examined the rate of neutralizing antibody formation with botulinum toxin type A (BoNTA) in botulinum toxin-naïve
patients being treated for neuromuscular disorders. They obtained data from 6 studies of patients receiving injections of
Botox for conditions including cervical dystonia, headache, and post-stroke spasticity. Antibody serum samples were obtained
at baseline, prior to each treatment, and at study end. Exposure to Botox ranged from 20-500U per treatment and the number
of treatments ranged from 1 to 14. The presence of neutralizing antibodies was assessed using the mouse protection assay (MPA).
Of the 895 samples analyzed, 887 (99.2 %) were negative, 4 (0.4%) were inconclusive, and 4 (0.4%) were positive. Of the 4
patients who had a positive MPA test, 3 were CD patients who had received injections of 100-400U per treatment and had received
between 1 and 8 treatments. One of these patients developed a positive MPA after a single treatment of 300U. In addition,
1 patient with spasticity developed a positive MPA test after 1 treatment with 200U. This study suggests that neutralizing
antibody formation with Botox is rare but can happen after a single exposure.
Hung et al. (13) presented the results of long-term follow-up of 8 patients with cervical dystonia who underwent globus pallidus
internus (Gpi) deep brain stimulation (DBS). The patients were operated on between February 2000 and February 2004. One patient
had CD secondary to spinocerebellar ataxia 3 (SCA 3) while the rest had idiopathic CD. Benefit was evaluated using the Toronto
Western Spasmodic Torticollis Rating Scale (TWSTRS). Results showed that the patient with SCA 3 had substantially less benefit
so the 7 patients with idioapathic CD were evaluated separately. In these patients, mean follow-up was 23.6 months. The mean
TWSTRS severity score was reduced 46% (p=0.0005), the TWSTRS disability score was reduced by 71% (p=0.0007), and the TWSTRS
pain scale was reduced by 63% (p=0.0006). These results suggest that Gpi DBS is an effective treatment for idiopathic CD.
RESTLESS LEGS SYNDROME (RLS)
Kushida et al. (14) evaluated the burden RLS places on health-related quality of life (HRQL). They compared scores on the
SF-36 Health Survey (HRQOL) in RLS patients to norms from patients with type-2 diabetes, depression, osteoarthritis (OA),
and the 1998 general U.S. population. The total RLS HRQOL burden was greater than that for type-2 diabetes and similar to
depression and OA. RLS affected both physical and mental aspects of HRQOL including physical, role, and social functioning,
vitality, pain, emotional well-being, and overall perceptions of health.
Bogan et al. (15) presented results of a 12-week double-blind, placebo-controlled, flexible dose study of ropinirole as a
treatment for moderate or severe RLS. Ropinirole was introduced at a dose of .25 mg 1-3 hours prior to bedtime and could be
titrated up to 4.0 mg. The mean ropinirole dose at endpoint was was 2.15 mg. Compared to placebo, ropinirole significantly
reduced International RLS (IRLS) scale scores (-3.7, p<0.0001). The proportion of patients who were much or very much improved
was significantly higher in the ropinirole group (p=0.0006). Onset of action occurred by the end of week 1. Adverse events
included nausea, headache, and somnolence. The rates of withdrawals were similar in both groups (ropinirole 3.7% and placebo
4.7%).
Garcia-Borreguerro et al. (16) presented the results of two 52-week, open-label trials of ropinirole for RLS. Common adverse
events (AEs) included nausea (37.1%), headache (18.5%), and arthralgia (13.5%). The majority of AEs were mild or moderate
and occurred in the first 12 weeks of treatment. Few patients withdrew due to AEs (8.7%). Augmentation was uncommon (3.9%).
Improvement in IRLS scores occurred quickly and was maintained throughout the studies. More than 74% of patients in both studies
were reported to be much or very much improved at 52 weeks.
Allen et al. (17) evaluated whether age-at-onset affected clinical response to ropinirole. Early-onset RLS (<45 years) is
slowly progressive and usually familial, whereas late-onset RLS is rapidly progressive and usually not familial. Using pooled
data from 3 twelve-week, placebo-controlled studies of ropinirole, these investigators found that clinical response and doses
of ropinirole were similar in early- and late-onset phenotypes.
Ott et al. (18) reported results of a 6-week, double-blind, placebo-controlled, flexible dose study of pramipexole as a treatment
for RLS. Subjects were treated with pramipexole at doses of 0.125 to 0.75 mg per day. CGI-Severity response, defined by an
improvement of at least 2 levels, was significantly more common in the pramipexole than placebo group (50.0% vs. 21.9%, p<0.0001).
Most AEs were mild to moderate, and included headache (13%), nausea (12.2%), and fatigue (9.1%). Only one patient withdrew
from the study due to an AE.
References
1) Mata I, Kachergus J, Hulihan M, Aasly J, Payami H, Lynch T, Wiley J, Czyzewski K, Stycznska M, Nutt J, Gibson M, Krygowska-Wajs
A, Hauser R, Wszolek Z, Farrer M. LRRK2 mutation screening in 100 families with autosomal dominant Parkinson’s disease.
Neurology 2005;64 (Suppl 1):A88-A89.
2) Toft M, Mata I, Kachergus J, Hulihan M, Aasly J, Gibson M, Ross O, Lynch T, Wszolek Z, Maraganore D, Czyzewski K, Styczynska
M, Payami H, Nutt J, Farrer M. Identification of a novel LRRK2 mutation, linked to autosomal dominant parkinsonism in families
from several European populations; evidence for a common founder. Neurology 2005;64(Suppl 1):A147.
3) Taylor P, Lincoln S, Pielsticker L, Farrer M. Molecular characterization of
Lrrk2, the gene responsible for autosomal dominant PARK8. Neurology 2005;64 (Suppl 1):A88.
4) Marek K, Jennings D, Seibyl J. Long-term follow-up of patients with
scans without eividence of dopaminergic deficit (SWEDD) in the ELLDOPA
study. Neurology 2005;64 (Suppl 1):A274.
5) Korczyn A, DeDeyn P, Rascol O, Lang A. Incidence of dyskinesia in a 10-yr
follow-up of patients with early parkinson’s disease (PD) initially receiving ropinirole compared with L-dopa. Neurology
2005;64 (Suppl 1):A396.
6) Isaacson S, Isaacson R, Kreitzmann D. Dopamine agonist treatment of
parkinson’s disease in the elderly. Neurology 2005;64 (Suppl 1):A107.
7) Parkinson Study Group.A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol
2004;61:561-566.
8) Hauser R, Lew M, Hurtig H, Ondo W, Wojcieszek J. Early treatment with Rasagiline is more beneficial than delayed treatment
start in the long-term management of Parkinson’s disease. Neurology 2005;64 (Suppl 1):A107.
9) Castillo V, Burkhard P, Pot C. Is subcutaneous infusions of apomorphine a valid alternative to STN-DBS in advance Parkinson’s
disease. Neurology 2005;64 (Suppl 1):A108.
10) Okun M, Tagliati M, Pourfar M, Fernandez H, Rodriguez R, Alterman R,
Foote K. Management of referred DBS failures: a retrospective analysis
from two movement disorders centers. Neurology 2005;64 (Suppl 1):A279.
11) Ahn S, Kim J, Kwon S, Kim S, Jeon B. Stem cell therapy in a parkinson’s
disease model. Neurology 2005;64 (Suppl 1):A109.
12) Yablon S, Daggett S, Brin M. Toxin neutralizing antibody formation with botulinum toxin type A (BoNTA) treatment in neuromuscular
disorders. Neurology 2005;64(Suppl 1):A72.
13) Hung SW, Piboolnurak P, Poon, Y, Lang A, Lozano A, Miyasaki J, Molnar G, Moro E. Bilateral pallidal deep brain stimulation
in cervical dystonia: long term follow-up. Neurology 2005;64 (Suppl 1):A279.
14) Kushida CA, Martin M, Nikam P, Blaisdell B, Ferini-Strambi L, Ware J. Restless legs symdrome places a substantial burden
on the health-related quality of life of US patients. Neurology 2005;64 (Suppl 1):A41.
15) Bogan C, Connolly MG, Rederich G. Ropinirole is an effective, well-tolerated treatment for moderate or severe RLS: results
of TREAT RLS US, a 12-week, randomized, double-blind, placebo-controlled US trial. Neurology 2005;64 (Suppl 1):A27.
16) Garcia-Borreguerro D, Lee D, Ball E. Ropinirole is well tolerated and effective for the long-term treatment of RLS. Neurology
2005;64 (Suppl 1):A42.
17) Allen RP, Tidswell P, Ritchie S. Clinical efficacy of ropinirole for RLS is unaffected by age-at-onset phenotype: pooled
analysis of three clinical trials. Neurology 2005;64 (Suppl 1):A41-A42.
18) Ott E, Schwingenschuh, P, Katschnig R. Beneficial effect of pramipexole on overall disease severity in restless legs syndrome
(RLS) is not disturbed by treatment emergent side effects. Neurology 2005;64 (Suppl 1):A42-A43.
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