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Thus, anticoagulation may be resumed safely in some patients after ICH.
M-1. “Real World” Results of Carotid Endarterectomy
in High-Risk Patients
Manish Kapadia, Ramesh Madhavan, Maysaa Mehri-Basha,
and Seemant Chaturvedi; Detroit, MI
M-3. Effect of Levodopa on Recovery from Post
Stroke Aphasia
Anna Czlonkowska, Marika Litwin, Tomasz Litwin,
Marcin Lesniak, and Joanna Seniow; Warsaw, Poland
Background: Some carotid stenting trials have relied on historical controls due a paucity of data on carotid endarterectomy
(CEA) in patients considered high-risk for surgery (HRP).
Objective: To document the complication rate of CEA in
Methods: A retrospective study of CEA operations performed
in 2003-4 at a single hospital. Medical data were obtained and
in-hospital outcomes recorded. Comparisons between HRP
and low-risk patients (LRP) were performed using Fisher’s exact test.
Results: 51 patients (mean age 71.3 years) had a CEA. All had
a history of HTN, 39.2% had DM and 61% had heart disease. 33 (65%) were classified as HRP, mainly due to age ⬎80
or reduced ejection fraction. The perioperative stroke rate in
HRP was 12.1% (4/33) and it was 5.6% in LRP (p⫽0.64).
The rates of MI and combined stroke/MI were 9.1% and
21.2% in HRP and 5.6% and 5.6% in LRP (p⫽1.0 and
Conclusions: We found a markedly elevated major complication rate in HRP. Although we did not have sufficient
power to document a difference between HRP and LRP,
our data suggest that less invasive approaches such as medical therapy or carotid stenting should be studied further in
this population.
Objective: The purpose of this prospective, randomized,
double-blind placebo-controlled study was to determine
whether small doses of levodopa improve aphasia recovery.
Methods: Patients with post-stroke aphasia, 2-8 weeks after
stroke were enrolled in the study. During 3 weeks, 30 minutes before speech and language therapy, 20 patients received 100 mg of levodopa, and 19 placebo. 45 min therapeutic sessions were provided 5 times per week (15 in
total). For aphasia assessment Boston Diagnostic Aphasia
Examination (BDAE) was used. This test was performed
before enrollment and after 3 weeks of training.
Results: After 3 weeks, improvement in the range of all
language abilities was observed both in the levodopa and
the placebo group. Nevertheless, there were considerable
differences in improvement rate in favour of the levodopa
group vs. placebo in the following verbal functions: fluency
in controlled association (p⫽0,011), repeating phrases and
sentences - high frequency (p⫽0,028) and repetition of
words (p⫽0,05 -tendency).
Conclusions: Levodopa in addition to traditional speech
and language therapy improves recovery from post stroke
aphasia, especially in patients with frontal language structure lesions.
M-2. Reinitiating Anticoagulation after WarfarinAssociated Hemorrhage
Daniel O. Claassen, Alexander Y. Zubkov,
Edward M. Manno, Eelco F. M. Wijdicks, and
Alejandro A. Rabinstein; Rochester, MN
M-4. Estimating Diffusion-Perfusion Mismatch Using
the NIHSS-Plus
Rebecca F. Gottesman, Jonathan T. Kleinman,
Cameron Davis, Jennifer Heidler-Gary, Melissa Newhart, and
Argye E. Hillis; Baltimore, MD
Background: Anticoagulation is often withheld after
Warfarin-related intracerebral hemorrhage (ICH) due to
perceived risk of ICH recurrence. We reviewed patients
who were re-started on anticoagulation after Warfarinrelated ICH.
Methods: Retrospective analysis of consecutive patients
with Warfarin-related ICH between 2001 and 2005. Inclusion criteria were INR ⱖ 1.5, current Warfarin therapy,
radiologically documented ICH, and re-initiation of Warfarin within 3 months of ICH. Outcome was assessed at
time of death or last follow-up.
Results: Of 88 patients with Warfarin associated ICH, 20
(23%) were re-started on warfarin within 3 months of
ICH, including 18 (85%) who were restarted within 2
Indication for anticoagulation was mechanical valve (55%),
atrial fibrillation (25%), and deep vein thrombosis (20%).
Mean age upon ICH was 71.5 years (range 65 – 81). Average ICH volume was 16.7cm3 and location was deep in
45%, lobar in 40%, and infratentorial in 15%. During a
mean follow up of 2.7 years, only 1 patient (5%) had recurrent ICH after restarting warfarin. Two other patients
(10%) had bleeding complications from trauma.
Conclusions: Recurrent anticoagulation-associated ICH after reinitiating warfarin is uncommon in our experience.
Diffusion-perfusion (DWI/PWI) mismatch is assessed in
acute stroke patients to determine the difference between
infarcted brain tissue and surrounding dysfunctional area at
risk for infarction. Presence of a mismatch may lead to further stroke intervention, including tPA or endovascular
treatment. However, this technology is neither available at
all hospitals nor feasible in all patients. We hypothesized
that we could estimate DWI/PWI mismatch by combining
actual DWI volume with estimated perfusion abnormality,
using clinical tests. We studied 87 consecutive acute nondominant hemispheric stroke patients with DWI/PWI and
cognitive testing. We have previously described the NIHSSplus, with additional points for errors on line cancellation
and visual extinction tasks. Using this scale, we calculated
predicted PWI (pPWI) volume with a linear spline regression model. Compared to DWI volume, we calculated percent radiographic mismatch (PWI-DWI/DWI *100) and
clinical mismatch (pPWI-DWI/DWI *100), and coded
these each as presence (⬎20%) or absence of mismatch.
Having an estimated mismatch had 90% sensitivity in prediction of actual mismatch. Specificity was 36%, and the
area-under-the-curve (for ROC analysis) was 0.63. The
high sensitivity means most patients with an actual mismatch will be identified clinically, indicating potential benefit from intervention to restore blood flow.
Program and Abstracts, American Neurological Association
M-5. Gene Expression in Blood of Humans Following
Subarachnoid Hemorrhage, Intracerebral Hemmorhage
and Ischemic Stroke
Frank R. Sharp, Huichun Xu, Dongwoo J. Chang,
Christi DeLemos, Piero Verro, Aigang Lu, Art Pancioli,
Jane C. Khoury, Laura R. Sauerbeck, Janice A. Carrozzella,
Judith Spilker, Joseph F. Clark, Kenneth R. Wagner,
Edward C. Jauch, and Joseph P. Broderick; Sacramento, CA;
and Cincinnati, OH
Acute stroke is a neurological emergency and differential
diagnosis largely relies on CT and MRI scans. However, it
may be difficult to obtain these in a timely manner. Recently our group showed that ischemic stroke changes RNA
levels in whole blood as early as 2 – 3hr after onset. In this
study we examined 15 acute ischemic stroke patients, 5
subarachnoid hemorrhage and 2 ICH intracerebral hemorrhage patients at 24, 48 and 72h. Whole blood was processed on Affymetrix human HU133 plus2 microarrays. Although many genes are co-regulated following ICH, SAH
and ischemic stroke versus controls, there are groups of
genes that are only regulated by each condition. At 24h
after the onset, 758 genes are regulated between ICH and
ischemic stroke; 564 genes between SAH and ischemic
stroke; and 652genes between ICH and SAH. Cluster analyses confirmed that expression profiles for the same diagnosis were similar to each other, whereas profiles for different diagnoses were different. Iischemic stroke, ICH and
SAH have unique expression profiles in whole blood. RNA
expression changes in blood can potentially provide surrogate markers for the differential diagnosis of acute stroke.
Study supported by NIH and NINDS.
M-6. Statins in Ischemic Stroke – Just LDL Lowering
or More?
Lekshmi Vaidyanathan, Gautam Kumar, David L. Nash,
Fernanda M. Bellolio, Rachel M. Gilmore, Sailaja Enduri,
Rahul Kashyap, Robert D. Brown, Jr., and Latha G. Stead;
Rochester, MN
Hypothesis: Daily statin intake improves functional outcome following an acute ischemic stroke despite ideal LDL
Methods: The cohort included patients having an acute
ischemic stroke. Lipid profile measured between 15 days
before the stroke to 17 days after (Mean 0.79 days) was
abstracted. The functional disability was determined using
modified Rankin scale (mRs, 0 – 2 good outcome, 3 – 6
bad outcome) at discharge. Pearson’s chi square test was
utilized for analysis.
Results: Of 508 patients, 207 presented with an LDL of £
100 mg/dL. They were divided based on whether they were
on a statin on admission (n⫽100) or not (n⫽107). There
was no significant difference in admission stroke severity
(NIHSS) (p⫽0.18), age (p ⫽ 0.31) and gender (p⫽0.06)
between the groups. Patients on a statin were significantly
more likely to have a good functional outcome, (OR 0.5;
95% CI 0.29-0.95; p⫽0.033). Adjusting for age and
NIHSS, statin intake still predicted a better functional outcome (p⬍0.0001).
Conclusion: Daily statin intake appears to result in a better
functional outcome following an ischemic stroke despite
ideal LDL levels (⬍100) and similar admission stroke severity. Pleiotropic effects of statins may play a role.
Annals of Neurology
Vol 62 (suppl 11)
M-7. Prophylactic Anticonvulsivants Therapy in
Intracranial Hemorrhage: To Treat or Not To Treat?
Retrospective Study
Zack Hakma, Martina Vendrame, Zulfi Haneef,
Jacobson P. Mercedes, and S. Ausim Azizi; Philadelphia, PA
It is controversial whether patients with non-traumatic
intra-cranial hemorrhage (ICH) should receive antiepileptic
drug prophylactic therapy (AEDP). In this study we retrospectively analyzed 123 cases of ICH admitted to Temple
University NICU over a one-year period. Clinical and radiological presentation, intervening complications, incidence of new onset seizures and length of NICU stay were
analyzed. In 78 (63.4%) ICH was related to hypertension
only. Clinical presentation included coma, confusion,
hemiparesis, headache and aphasia. ICH site included basal
ganglia and thalamus (51.2%), temporal/parietal lobes
(41%), cerebellum (2.5%), and pons (3.8%). Only 2 of the
78 subjects (2.5%) had seizures on admission. Both had a
prior history of epilepsy and were treated with antiepileptics. Of the remaining 76 subjects, 23 (30.2%) received
AEDP, 53 (69.8%) did not receive AEDP. None of nonAEDP experienced seizures during their hospital stay.
However, there was a significant difference on length of
ICU stay between AEDP (6.2 days) and non-AEDP subjects (10.6 days) (F ⫽ 5.52, p ⫽ 0.022). These data show
that seizure prophylaxis in patients with ICH without cerebral cortical involvement is not indicated and may be associated with increased morbidity.
M-8. Effect of Pre-Stroke Use of Antihypertensives,
Antiplatelets, and Statins on Ischemic Stroke Severity
and Early Outcome
Amy Y. X. Yu, Mark R. Keezer, Bin Zhu, Christina Wolfson,
and Robert Côté; Montreal, QC, Canada
Background: Some studies have suggested that treatment
with antihypertensives (AHT), antiplatelets (APL), or statins (STAT) decreases ischemic stroke severity, whereas
others have not. We examined the effect of pre-stroke use
of these medications on initial severity and early outcome
of ischemic stroke.
Methods: We reviewed the charts of 364 acute ischemic
stroke patients. Severe stroke was defined as a Canadian
Neurological Scale score ⱕ7. Poor early outcome was determined by a modified Rankin score ⬎3 at 10 days poststroke. Unconditional multivariable logistic regression analysis was used with adjustment for age, diabetes, coronary
disease, hypertension, atrial fibrillation, hyperlipidemia, initial blood pressure, and stroke severity (for early outcome).
Results: In three separate analyses, we compared the prestroke use of AHT, APL, or STAT with untreated patients.
None of these medications showed a significant protective
effect. However, APL therapy resulted in a trend with better early outcome [OR⫽0.66(95%CI, 0.36-3.00)], as did
STAT treatment [OR⫽0.63(95%CI, 0.29-1.36)].
Conclusions: Although none of the medications showed a
significant protective effect, the point estimates suggested
that better outcomes may be associated with pre-stroke use
of antiplatelets or statins.
M-9. Atrial Fibrillation as an Independent Predictor
of Poor Outcome after Ischemic Stroke
M. Fernanda Bellolio, Lekshmi Vaidyanathan,
Rachel M. Gilmore, Sailaja Enduri, Rahul Kashyap,
David L. Nash, Wyatt W. Decker, Robert D. Brown, and
Latha G. Stead; Rochester, MN
OBJECTIVE: To investigate if patients presenting to the
Emergency Department (ED) with acute ischemic stroke
(AIS) and concurrent atrial fibrillation (AF) had an increased
risk of poor outcome and death.
METHODS: Study population: 954 consecutive patients
who presented to the ED with AIS between Dec/2001-Jun/
2005 and had an ECG performed within 24 hours. We recorded demographic information, NIHSS, TOAST and
functional status (modified Rankin scale, mRS) at hospital
dismissal and death.
RESULTS: There were 510 men (53.5%). The mean
age⫾SD was 72.8⫾14.1 (range: 17-101 years). The median
NIHSS at presentation was 5, with a mean of 9.3. A good
mRS (ⱕ 2) at dismissal occurred in 382 patients (40.3%). A
total of 141 patients had AF on the first ECG recorded.
In the linear regression model we found that the presence of
AF concurrent with the stroke predicted a worse mRS after
adjusting for age and NIHSS (p⬍0.0001). There is a statistically different survival between those with and without AF
at presentation (p⬍0.0001).
CONCLUSION: Patients presenting with ischemic stroke
and concurrent AF had an increased risk of poor functional
outcome and death after adjusting for stroke severity and
age. Study supported by Emergency Department, Mayo
Clinic College of Medicine, Rochester, MN.
M-10. High Risk of Both Cardiac and
Cerebrovascular Events in Patients with Symptomatic
Intracranial Atherosclerosis
Neepa Patel, and Seemant Chaturvedi; Detroit, MI
Background: The cardiac risk for patients with symptomatic
intracranial atherosclerosis (SIA) is not well defined.
Objective: To document the vascular outcomes in patients
with SIA.
Methods: Retrospective study of patients seen in a University
stroke clinic.Past medical history was obtained. Outcome
events were documented from either direct patient contact or
medical records. Statistical comparisons were done with Fisher’s exact test.
Results: 27 patients (mean age 61.1 years) were identified.
The frequency of HTN was 81.5% and 63.0% had DM.
51.9% were African American (AA) and 59.3% were smokers. During a mean follow-up of 4 years, 10/27 (37.0%) patients had a stroke or TIA (11.1% with stroke). In this period, 9/27 (33.3%) had angina or a myocardial infarction
(MI)(14.8% with MI). The frequency of stroke or MI did
not differ in AA patients vs. whites (29% vs. 23%, p ⫽1.0).
The frequency of stroke/MI was 28% in patients less than 65
years and 22% in patients over age 65 (p⫽1.0).
Conclusions: Individuals with SIA have significant mid-term
risks of not only recurrent stroke but also for cardiac events.
Screening for heart disease may be advisable in these patients.
M-11. Neuroserpin Polymorphisms and Stroke Risk in
a Biracial Population: The Stroke Prevention in Young
Women Study
John W. Cole, Adam C. Naj, Jeffrey R. OConnell,
Oscar C. Stine, Braxton D. Mitchell, John D. Sorkin,
Marcella A. Wozniak, Barney J. Stern, Manuel Yepes,
Daniel A. Lawrence, Dudley K. Strickland,
Laurie J. Reinhart, and Steven J. Kittner; Baltimore, MD;
Atlanta, GA; and Ann Arbor, MI
Background: Neuroserpin, primarily localized to CNS neurons, inhibits the adverse effects of tissue-type plasminogen
activator (tPA) on the neurovascular unit and has neuroprotective effects in animal models of ischemic stroke. We
sought to evaluate the association of neuroserpin polymorphisms with stroke risk among young women.
Methods: A population-based case-control study of stroke
among women aged 15-49 identified 224 cases of first ischemic stroke (47.3% African-American) and 211 agecomparable control subjects (43.1% African-American).
Neuroserpin single nucleotide polymorphisms (SNPs) chosen
through HapMap were genotyped in the study population
and assessed for association with stroke.
Results: Of the five SNPs analyzed, the A allele (frequency;
Caucasian ⫽ 0.57, African-American ⫽ 0.44) of a SNP located in intron 1 was associated with stroke under a dominant
model (AA and AT vs. TT) among Caucasians but not
African-Americans in models adjusting for other risk factors.
Haplotype analyses demonstrated significant association with
stroke in both races involving the same region within the gene.
Conclusions: This study provides the first evidence that neuroserpin is associated with early-onset ischemic stroke among
women. Study supported by Department of Veterans Affairs,
Baltimore, Office of Research and Development, Medical Research Service, and Stroke Research Enhancement Award Program.
M-12. The Relative Intensity of Physical Activity and
the Risk of Stroke: A Meta-Analysis
Lien B. Diep, AeRang Kim, Lori Jordon, Jon Sevransky,
Mona Duggal, Shilpa Bhardwaj, Tsilidis Konstantinos, and
Joseph Kurantsin-Mills; Baltimore, MD; and Washington, DC
Context: The protective effect of physical activity (PA) on
stroke remains controversial due to lack of insight into the
sources of heterogeneity between studies. We performed a
meta-analysis of published studies to quantify the relationship between intensities of PA and the risk of stroke. Methods: A systematic literature search of MEDLINE and EMBASE (1986-2005) was conducted. Risk estimates (RR) and
95% confidence intervals (CI) were used to assess the association of stroke incidence/mortality with low, moderate or
high PA. Study-specific risk estimates were pooled using random effects models. Results: Twelve of 991 identified articles satisfied the inclusion criteria. Summary statistics showed
reduction in RR of stroke with moderate-high PA (RR 0.89;
95% CI, 0.85 - 0.94). Data-units stratification revealed gender differences. Stroke associated with moderate vs. low PA
was 0.88 (95% CI, 0.82 - 0.94) for men and 0.99 (95% CI,
0.83 - 1.00) for women. Stroke associated high vs. low PA
yielded RR of 0.81 (95% CI, 0.75 - 0.87) for men and 0.76
(95% CI, 0.64 - 0.89) for women. Conclusion: Moderate to
high physical activity resulted in a significant relative risk reduction of stroke. Study supported by NIH Multidisciplinary Clinical Research Career Development K12 Award.
Program and Abstracts, American Neurological Association
M-13. Serum Magnesium as a Predictor of Stroke
Rahul Kashyap, M. Fernanda Bellolio, Sailaja Enduri,
David L. Nash, Lekshmi Vaidyanathan, Rachel M. Gilmore,
Anjali Bhagra, Robert D. Brown, Wyatt W. Decker, and
Latha G. Stead; Rochester, MN
OBJECTIVE: To investigate whether serum magnesium at
Emergency Department (ED) presentation for acute ischemic
stroke (AIS) impacts acute stroke severity, functional outcome or death.
METHODS: Study cohort comprised 509 consecutive patients who presented to the ED with AIS and had Mg measured within 48 hours. Demographics, NIH Stroke Scale,
ischemic stroke subtype, modified Rankin score (mRS) at
hospital discharge, and death at 90 days were prospectively
assessed; mRS was considered good if ⱕ 2.
RESULTS: The mean Mg⫾Standard deviation was 1.96⫾0.22
mg/dL. The median NIHSS at presentation was 5. Over a third
of the cohort had a good mRS at discharge, while another third
died during follow up.
Higher serum magnesium was correlated with a lesser stroke severity as measured by the NIHSS at presentation (p⫽0.014).
This relationship remained statistically significant after adjusting
for age in the linear regression model (p⬍0.0001).
Serum magnesium levels did not demonstrate a statistically significant relationship with functional outcome at hospital discharge (p⫽0.10) or death at 90 days (p⫽0.25).
CONCLUSION: Higher serum levels of Mg during AIS are
related to lower NIHSS at presentation, but not with better
short term function or mortality.
M-14. Higher Early Post-Ischemic Stroke
Rehospitalization Rates in US Minorities
Judith H. Lichtman, Norrina B. Allen, Emi Watanabe,
Yun Wang, and Larry B. Goldstein; New Haven, CT; and
Durham, NC
Objective: Evaluate the effect of race/ethnicity on 1-month
post-ischemic stroke rehospitalization rates among the elderly
in the United States.
Methods: One-month rehospitalization rates following hospital discharge for ischemic stroke (ICD-9 433, 434, 436) was
determined among all fee-for-service Medicare beneficiaries in
2002. Differences by race (White, Black, Hispanic, Other)
were compared using Cox proportional hazards models that
censored for deaths and adjusted for demographic factors, past
medical history, comorbidities, and prior hospital events.
Results: Among 366,688 ischemic stroke patients (mean age
78 years; 56% Women), 85% were White, 10% Black, 2%
Hispanic, and 3% Other groups. The unadjusted 1-month readmission rate was highest for Blacks (19.3%), followed by
Hispanics (18.3%), Other groups (14.6%), and Whites
(13.8%; p⬍0.001) with the relationship persisting after riskadjustment (Blacks: Risk Ratio [RR] 1.37, 95% Confidence
Interval [CI] 1.134-1.41; Hispanics: RR 1.28, 95% CI 1.201.36; Other groups: RR 1.07, 95% CI 1.01-1.13) as compared with Whites.
Conclusion: Elderly race/ethnic minority populations are
more likely to be rehospitalized within one month following
ischemic stroke than Whites. Additional research is needed to
identify factors that may be contributing to this difference.
Study supported by NINDS.
Annals of Neurology
Vol 62 (suppl 11)
M-15. Higher One-Month Post-Ischemic Stroke
Mortality in US Women
Judith H. Lichtman, Norrina B. Allen, Emi Watanabe,
Yun Wang, and Larry B. Goldstein; New Haven, CT; and
Durham, NC
Objective: Evaluate the effect of gender on 1-month postischemic stroke mortality among the elderly in the United
Methods: One-month mortality rates following hospital discharge for ischemic stroke (ICD-9 433, 434, 436) were determined among all fee-for-service Medicare beneficiaries
65⫹ years of age in 2002. Gender differences in mortality
rates were compared using logistic regression with adjustment for demographic factors, past medical history, comorbidities, and prior hospital events.
Results: Among 366,688 ischemic stroke patients (mean age
78 years; 56% Women, 85% White, 10% Black, 2% Hispanic, 3% Other), women were older (mean 79 vs 77 years),
had a lower prevalence of comorbid conditions (MI, COPD,
diabetes), but a longer mean length of stay (5.3 vs 4.7 days).
The unadjusted 1-month mortality was higher (12.3% vs
9.4%, p⬍0.001) among women with the difference persisting after risk-adjustment (Odds Ratio 1.06, 95% Confidence
interval [CI] 1.04-1.08).
Conclusion: This analysis of US national data found that
elderly women are more likely than men to die within one
month of ischemic stroke, even after adjustment for other
potential contributing factors. Understanding the reasons for
this discrepancy may lead to interventions to reduce strokerelated mortality in women. Study supported by NINDS.
M-16. Role of Caveolins in Cerebral Ischemic Injury
Samit Malhotra, Jean-François Jasmin, Manjeet S. Dhallu,
Isabelle Mercier, Michael P. Lisanti, and
Daniel M. Rosenbaum; Brooklyn, NY; Philadelphia, PA; and
Bronx, NY
Caveolins (Cav), the principal structural proteins of the
caveolar domains, have been implicated in the pathogenesis
of ischemic injury. However, the role of Cav-1 in the pathogenesis of cerebral ischemia remains unknown. Analyses of
rat brains subjected to middle cerebral artery occlusion revealed marked increases in endothelial Cav-1 and Cav-2 protein levels. The effects of cerebral ischemia in caveolin-1
knockout (KO) mice showed a marked increase in cerebral
volume of infarction, as compared to wild-type (WT) and
Cav-2 KO mice. Immunofluorescence analyses showed an
increased number of proliferating endothelial cells in WT
ischemic brains, as compared to Cav-1 KO ischemic brains.
Immunoblot analyses of WT ischemic brains showed an increase in eNOS protein levels. Conversely, the protein levels
of eNOS remained unchanged in Cav-1 KO ischemic brains.
TUNEL analysis also showed increased apoptotic cell death
in Cav-1 KO ischemic brains, as compared to WT ischemic
brains. In conclusion, cerebral ischemia induces a marked increase in endothelial Cav-1 and Cav-2 protein levels. Genetic
ablation of the Cav-1 gene in mice results in increased cerebral volume of infarction. Mechanistically, Cav-1 KO ischemic brains showed impaired angiogenesis and increased apoptotic cell death. Study supported by NIH/NEI RO1
EY11253 (DMR).
M-17. Cerebral Sinus Thrombosis Masquerading as
Subarachnoid Hemorrhage
Marlon S. Mathews, Kenneth G. Meng, Binh V. Nguyen,
and Fong Y. Tsai; Orange
Clinical presentation of patients with cerebral sinus thrombosis
varies widely. Headache, focal cerebral signs, including motor or
sensory deficits, dysphasia, and mental changes are commonly
seen. Rarely patients may present with intracerebral hemorrhage.
Here we report subarachnoid hemorrhage as a rare initial manifestation of cerebral venous thrombosis in five patients. Presenting symptoms and risk factors for dural sinus thrombosis were
variable. Two patients were poly-substance drug abusers. One
patient demonstrated a clear history of cranial trauma resulting
in a right transverse sinus thrombosis and presented with a
headache and non-focal mental status changes. One patient had
serum hyperviscosity (monoclonal gammopathy), and one was
pregnant in the 1st trimester. All of the patients had at least one
risk factor for dural sinus thrombosis. In all five cases, the patients presented with subarachnoid hemorrhage along the sulci
of the convexities, while one patient also had blood in the interpeduncular cistern.
Reaching the diagnosis of dural sinus thrombosis is complicated in the setting of subarachnoid hemorrhage. Without specific consideration for sinus thrombosis as the cause of subarachnoid hemorrhage, the appropriate work up may be
delayed, leading to a poor outcomes.
M-18. A Controlled Study of Cognitive Outcomes
after Coronary Artery Bypass Surgery
Ola A. Selnes, Maura A. Grega, Maryanne M. Bailey,
Scott Zeger, Luu Pham, and Guy M. McKhann;
Baltimore, MD
INTRODUCTION: Cardiopulmonary bypass has been implicated in the late neurocognitive decline that has been reported after coronary artery bypass grafting (CABG).
METHODS: We compared longitudinal changes in cognitive performance from baseline to 3 years in 152 on-pump
CABG patients and three control groups: 72 off-pump patients; 99 with medically treated coronary artery disease; and
69 without coronary artery disease risk factors. Neuropsychological test performance was evaluated by standardized measures in 8 cognitive domains.
RESULTS: Compared to baseline, none of the groups had
significantly lower performance at 36 months for any cognitive domains. Comparing the on- and off-pump groups, we
found no statistically significant differences in the degree of
change from 12 to 36 months. There was a trend towards
mild decline in some cognitive domains, but differences
among groups in degree of change were not significant.
CONCLUSION: We found no significant differences in the
degree of late cognitive decline after on-pump compared with
off-pump surgery, but a mild non-significant trend towards decline for all groups with coronary artery disease. These findings
suggest that previously reported late decline after surgery may
not be specific to the use of cardiopulmonary bypass. Study supported by NIH.
M-19. Superior Sagittal Sinus Involvement in Cerebral
Venous Sinus Thrombosis Increases Risk of
Hemorrhagic Infarct and Seizures
Srikanth Muppidi, Farhan Siddiq, Kiwon Lee, David G. Brock,
Carissa C. Pineda, and Rodney D. Bell; Philadelphia, PA
Objective: This study seeks to determine the relationship
between hemorrhagic infarct, seizures and the location of
cerebral venous sinus thrombosis(CVT).
Methods: We retrospectively reviewed the medical records,
MRI/MRVs of all patients presenting with CVT from January 2000 to January 2007 at our institution. We excluded
patients with deep venous sinus thrombosis. Patients fulfilling the inclusion criteria were divided into groups based on
the location of thrombus. Superior Sagittal Sinus(SSS)
Group included patients presenting with SSS thrombosis
alone or with other sinuses involvement. Non-SSS Group
included patients without SSS involvement. We identified
the patients who had hemorrhagic infarct and seizures. Chisquare test was used for statistical analysis.
Results: Fifty-four patients were identified with CVT during the study period. Twenty-four patients were included
in SSS group and twenty in Non-SSS group. Fourteen patients in SSS group had hemorrhagic infarct compared to
only four patients in Non-SSS group (p⫽0.01;RR2.92;
95%CI:1.14-7.46). Nine patients in SSS group had seizures
compared to only two patients in Non-SSS group (p⫽0.03;
Conclusions: Our data suggests that the involvement of
SSS in patients with CVT may increase the likelihood of
hemorrhagic infarct and seizures.
M-20. S100: Marker for Acute Ischemic Stroke(AIS),
Systematic Review
David L. Nash, and Latha G. Stead; Rochester, MN
Background: Studies show S100 as a possible acute ischemic
stroke (AIS) marker.
Objectives: Determine (1)whether S100 serum concentrations correlate with stroke symptom onset, infarction volume, stroke severity, functional outcome, or length of hospital stay; (2)whether S100 serial measurements are useful
markers for ongoing brain ischemia, and (3)whether S100
levels at various time intervals are significantly higher in AIS
patients than controls.
Methods: All relevant reports identified by literature searches
were assessed.
Results: Eighteen studies (1202 patients) satisfied entry criteria. S100 peaks from symptom onset between 24 – 120 hrs
with significantly raised values measured from 0 – 120 hrs.
Higher S100 values indicate larger infarction volumes, more
severe strokes, and worse functional outcome with significance. One study found no correlation between S100 and
functional outcome. There was a significant difference in
S100 levels between AIS patients and controls.
Conclusion: Peak values after stroke onset varied. S100 was
significantly increased after stroke onset with significantly
higher values in AIS patients than controls. S-100 correlates
with infarction volume, stroke severity, functional outcome,
and is a possible marker for ongoing ischemia. S100 shows
promise as a marker for AIS; further studies are needed to
determine its clinical use.
M-21. Unusual Etiology of Recurrent Refractory
Paroxysmal Vértigo. Experience with 15 Cases
Ricardo A. Rangel-Guerra, and Alberto Garcia de la Fuente;
Monterrey, NL, Mexico
INTRODUCTION: Purpose is to present unusual etiology
of recurrent and refractory type of paroxysmal vertigo, not
reported previously.
MATERIAL AND METHODS: From March 2004 to December 2005, we collected 15 patients with recurrent, refractory paroxysmal vertigo. There were 7 males and 8 females
with ages ranged from 18 to 80 years-old with a medium of
Program and Abstracts, American Neurological Association
28.7 yrs. All patients showed thrombosis of intracraneal venous sinuses.
RESULTS: All patients showed paroxysmal vertigo refractory
to conventional treatments. Only pts #7 and #11 showed
alterations in the prothrombotic factors (Decreased Protein
“C” and protein “S”). MRI with MRA (venous phase) were
performed in all patients and in all, venous thrombosis was
demonstrated. All patients were treated with antiaggregants.
Super selective thrombolysis with Tirofiban or r-tPA was
used in 3 patients an endovascular prosthesis (STENT) in
the affected vein was applied.
All patients responded satisfactorily with this type of treatment and the VERTIGO disappeared.
DISCUSSION: The correction of the obstructed venous
outflow from the inner ear, relieved the intraendolymphatic
pressure with the clearing of VERTIGO.
CONCLUSION: We present an unusual etiology of PAROXYSMAL REFRACTORY VERTIGO, not previously reported, and the excellent results obtained with the treatments
used in these 15 patients.
M-22. The Canonical Cyclin Dependent Kinase
Inhibitor P21 WAF1/CIP1 Mediates the Protective
Effect of Histone Deacetylase Inhibitors on DNA
Damage-Induced but Not Oxidative Neuronal Death
Brett Langley, Melissa D’Annibale-Tolhurst, Issam Ayoub,
M. Flint Beal, and Rajiv Ratan; White Plains, NY; and
New York, NY
Histone deacetylase inhibitors (HDACi) are in human trials
as cancer drugs, yet also improve behavioral outcomes and
survival in numerous neurological disease models. The mechanism(s) by which HDACi retard tumor growth but also
prevent death in neurons are poorly understood. HDACi induce the tumor suppressor gene p21 waf1/cip1(p21) in cancer cells, a gene with known prosurvival properties. Here we
demonstrate that HDACi significantly reduce damage associated with permanent MCA occlusion. This protection is
associated with induction of p21. Similarly, we show that a
two hour pulse of an HDACi after the onset of oxidative
stress or DNA damage can signfiicantly protect cultured cortical neurons and upregulate p21 for 24 hours. While p21
upregulation is not required for HDACi mediated protection
from oxidative death, it is required for full protection from
DNA damage-induced death. Our findings suggest that the
broad therapeutic potential of HDACi relates to their ability
to upregulate a cassette of adaptive genes, including the tumor suppressor p21, that each confer stimulus specific protection. Study supported by NINDS. New York State Department of Health. Burke Foundation.
M-23. Small Molecule and Peptide Activators of
Adaptive Gene Expression to Hypoxia Provide Novel
Strategies for Neuroprotection in Acute and Chronic
Neurodegenerative Diseases
Ambreena Siddiq, Leila Aminova, Brett Langley,
Juan Chavez, and Rajiv Ratan; White Plains, NY
Hypoxia-inducible factor (HIF) prolyl 4-hydroxylases are a
family of iron- and 2-oxoglutarate dependent dioxygenases
that negatively regulate the stability of several proteins that
have established roles in adaptation to hypoxia or oxidative
stress. These proteins include the transcriptional activator
HIF-1␣. We report that structurally diverse low molecular
weight or peptide inhibitors of the HIF prolyl-4 hydroxylases
stabilize HIF-1␣ and upregulate HIF-dependent target genes
Annals of Neurology
Vol 62 (suppl 11)
(e.g., vascular endothelial growth factor or erythropoietin) in
cortical neurons in vitro or adult rat brains in vivo. We also
show that inhibitors of the HIF prolyl 4 hydroxylases prevent oxidative apoptotic death in vitro and ischemic injury in
vivo when added after the onset of the injury stimulus. We
identified more than a dozen FDA-approved drugs that can
activate the HIF pathway and facilitate neuroprotection
and/or neural repair in disease models. Taken together these
findings define HIF prolyl-4 hydroxylase inhibitors as novel
therapeutic candidates for stroke, spinal cord injury, multiple
sclerosis, Alzheimer’s disease, and Parkinson’s disease. The
established safety of some of these inhibitors in humans
should accelerate their testing in clinical trials. Study supported by National Institute of Health. New York State Department of Health. Adelson Foundation for Neuroprotection and Neural Repair.
M-24. Abnormal Visual Evoked Flow Response
Suggests Decreased Vascular Reactivity in Humans with
Cerebral Amyloid Angiopathy
Eric E. Smith, Madhu Vijayappa, Lauren Wendell,
Jonathan Rosand, and Steven M. Greenberg; Boston, MA
Background/Objective: We sought to determine whether
stimulus-induced vascular reactivity is reduced in humans
with cerebral amyloid angiopathy (CAA).
Methods: Evoked flow velocity in the posterior cerebral artery (PCA) was measured by transcranial Doppler ultrasound
during 10 epochs of a flashing checkerboard visual stimulus
alternating with a blank screen. CAA was diagnosed, using
validated criteria, based on biopsy (n⫽4) or multiple lobar
intracerebral hemorrhages on gradient-echo MRI (n⫽7).
Results: There were 11 CAA (7/11 male, age 73.5⫾7.4) and
9 controls (7/9 male, age 70.9⫾7.9). CAA subjects had a
lower peak PCA velocity, expressed as percent change from
baseline averaged over the 10 epochs (CAA 8.0⫾6.1%, control 17.4⫾5.7%, p⫽0.002). Baseline PCA pulsatility index
(PI), before visual stimulation, was higher in CAA (CAA
1.35⫾0.35, control 1.04⫾0.14, p⫽0.03). Subjects with
higher baseline PCA PI had lower peak PCA velocity (r⫽0.49, p⫽0.03).
Conclusions: Abnormal visual evoked flow in CAA suggests
dysfunction of the neurovascular unit and may be caused by
abnormal vascular reactivity, abnormal neuronal activation,
or both. The elevated PCA PI, and correlation with peak
PCA evoked flow response, suggests pathology of the distal
resistance vessels in CAA.
M-25. Acute Monoplegia Secondary to Epidural
Venous Engorgement in Pregnancy
Martina Vendrame, Zulfi Haneef, Mercedes P. Jacobson,
Luo J. Jin, and S. Ausim Azizi; Philadelphia
A 20-year-old 33 week pregnant woman presented with
2-day history of back pain and leg extremity weakness. Examination was remarkable for left leg paresis and brisk reflexes bilaterally. T2-weighted MRI of thoracic and lumbar
spine revealed prominent epidural and paravertebral venous
collaterals within lower thoracic and nearly entire lumbar
spine consistent with venous congestion. Signal abnormality
within the conus was observed and attributed to edema. MR
angiography of the abdomen yielded loss of signal of the left
common iliac vein and compression of the inferior vena
cava. Post-delivery the left limb paresis resolved. On repeated
MRI there was normal signal within the conus and normalappearing paraspinal arterial and venous system, ruling out
Foix-Alajouanine syndrome. Radiculopathy associated with
inferior vena cava obstruction and epidural venous enlargement have been described (Paksoy et al., 2004), but not in a
transient fashion nor in association with pregnancy. Epidural
venous engorgement with myelopathy has to be considered
in the differential diagnosis when acute limb paresis occurs
during pregnancy. MRI and angiography are essential in
confirming the diagnosis and providing reassurance for a
good post-delivery outcome.
M-26. Loss of Intermediolateral Nucleus Sympathetic
Neurons in the Upper Thoracic Cord Increase Risk of
Sudden Cardiac Arrest in ALS
Hirohide Asai, Makito Hirano, Fukashi Udaka,
Takao Kiriyama, and Satoshi Ueno; Kashihara, Nara, Japan;
and Osaka, Japan
ALS exclusively involves motor neurons, however, accumulating evidence suggests involvement of sympathetic neurons,
as in other diseases including Parkinson’s disease and multiple system atrophy. In these diseases increased risk of sudden
cardiac arrest is established, while that in ALS remains uncertain. We retrospectively studied 20 sporadic ALS patients
who received no assisted ventilation. Among them, two patients died of sudden cardiac arrest. Changes in QTc interval
and dispersion, indices of sympathetic activities obtainable by
routine electrocardiograms, were evaluated at the early stage
and the terminal stage. Pathologically, intermediolateral nucleus (IML) sympathetic neurons in the upper thoracic cord
were examined. The QTc intervals and dispersion were significantly increased at the terminal stage compared with that
at the early stage (p⬍0.01). The numbers of IML neurons
were significantly lower in ALS patients than in controls
(p⫽0.017), and had linear inverse correlation with the rate
of increases in maximum QTc interval and QTc dispersion
(p⫽0.01, r⫽-0.915 and p⫽0.02, r⫽-0.884). Notably, two
patients with sudden cardiac arrest showed longer QTc interval, larger QTc dispersion, and lower number of IML
neurons than most of others.
M-27. Sphingolipid Transport and Lipid Raft
Morphology in the Neuronal Ceroid Lipofuscinoses and
Implications for Therapy
Elena Rusyn, Talal Mousallem, Dixie-Ann Persaud-Sawin,
Sara Miller, and Rose-Mary N. Boustany; Durham, NC; and
Beirut, Lebanon
Increased apoptosis, trafficking defects and endosomal inclusions are present in the neuronal ceroid lipofuscinosis or Batten disease. Juvenile neuronal ceroid lipofuscinosis (JNCL) is
caused by mutations in the CLN3 gene. CLN3 protein
(CLN3p) recycles from Golgi to lipid rafts (LR) via Rab4
and Rab11-recycling endosomes. CLN3p has a structural
galactosylceramide (GalCer) LR binding domain. In CLN3p
deficient cells, GalCer and mutant CLN3p are barely visible
at the surface and are retained in Golgi. Reintroduction of
CLN3p rescues the GalCer deficit at LR. GalCer is decreased
in LR and retained in Golgi suggesting that CLN3p is involved in transport of GalCer from Golgi to LR. JNCL LRs,
as well as LRs of CLN1-, CLN2-, CLN6-, CLN8- and
CLN9-deficient cells have small vesicular structures by electron microscopy. These structural changes probably reflect
altered sphingolipid composition documented in NCL LRs.
Knockdown of galactosylceramide transferase with siRNA,
leads to decreased cell growth and increased apoptosis suggesting the deficit in GalCer is related to the wellbeing of the
cell. Addition of GalCer restores growth. Abnormal LR function due to altered sphingolipid stoichiometry may be a
common theme for all NCLs.
M-28. The Neuronal Ceroid Lipofuscinoses: Defects in
Different Proteins but a Common Pathway
Dixie-Ann Persaud-Sawin, Talal Mousallem, Christine Wang,
Adam Zucker, Eiki Kominami, and Rose-Mary N. Boustany;
Durham, NC; Tokyo, Japan; and Beirut, Lebanon
Six of nine Neuronal Ceroid Lipofuscinoses or NCL genes
(CLN1-CLN9) are identified. They are grouped together because the NCLs exhibit progressive blindness, seizures, motor/cognitive decline, and early death. Most variants manifest
apoptosis and dysregulated sphingolipid metabolism, therefore, the culprit proteins may interact in one pathway. NCL
patient-derived cells exhibit growth and apoptotic defects
that reverse upon transfecting the wild-type gene. CLN1/
CLN2/CLN3/CLN6-deficient cells grow slowly and CLN8deficient mouse cells grow fast. Transfecting CLN3-deficient
cells with CLN2/CLN3/CLN6/CLN8 corrects growth/apoptosis; Transfecting CLN6-deficient cells with CLN2/
CLN3/CLN6/CLN8 corrects growth/apoptosis; Transfectin
CLN8-deficient mouse fibroblasts with CLN2/CLN3/
CLN6/CLN8 corrects growth/apoptosis.
Membrane-bound CLN3/CLN6/CLN8 proteins complement each other as do CLN1/CLN2 proteins, with respect
to growth/apoptosis. CLN1/CLN2-deficient growth defects
are not corrected by CLN3/CLN6/CLN8 proteins. CLN2/
CLN3/CLN6/CLN8 proteins co-immunoprecipitate and colocalize to early and/or recycling endosomes and lipid rafts.
CLN2p/CLN1p co-immunoprecipitate. These NCL proteins
bind sphingolipids. NCL proteins may interact: from ER,
proteins may traffic to Golgi via COPII-positive vesicles.
CLN2p/CLN3p may interact within Golgi, early recycling
endosomes, and lipid rafts. CLN6p/CLN8p recycle via endosomes and appear in lipid rafts. CLN1p/CLN2p reside in
lysosomes where they may interact, with CLN1p acting
downstream of other NCL proteins.
M-29. Epidemiology of Falls in Amyotrophic Lateral
Sclerosis Patients: Analysis of Cross-Sectional and
Prospective Cohorts in the ALS CARE Registry
Benjamin Rix Brooks, Joyce Li, Wei Huang,
Frederick A. Anderson, Robert G. Miller, Hiroshi Mitsumoto,
and ALS CARE Study Group; Madison, WI; Worcester, MA;
San Francisco, CA; and New York, NY
Objective: Determine prospectively the monthly occurrence
of falls in ALS CARE Registry.
Background: Annual occurrence of at least one fall is 62% –
Parkinson’s disease, 57% – fainting patients, 48% – polyneuropathy and 12% – epilepsy [J Neurol. 2004 251(1):79-84].
Design/Methods: Analysis of 4817 ALS patients entered in
ALS CARE Registry during the decade 1996 – 2005.
Results: Falls occurred prior to enrollment in 32% of ALS
patients [age – 61yr, time from onset – 2.4yr and time from
diagnosis – 1.5yr]. Onset in falls patients was 47% lumbar,
27% cervical, 21% bulbar and 5% thoracic. A prospective
longitudinal cohort of ALS patients demonstrated 32% falls
– 6 months [5.3 falls/month per 100 patients], 27% falls –
12 months [4.5 falls/month per 100 patients] and 29% falls
– 18 months [4.8 falls/month per 100 patients].
Conclusions/Relevance: The observed rate of falls in ALS
Program and Abstracts, American Neurological Association
patients provides a benchmark for future clinical studies and
safety analyses for clinical trials. The observed rate is higher
than the rate for polyneuropathy and Parkinson’s disease patients. The role of site of ALS onset, time to develop leg
weakness and time to develop impaired postural reflexes in
the pathophysiology of falls requires further study. Study
supported by Sanofi Aventis grant to Center for Outcomes
M-30. Real-Time State – Level Public Health
Surveillance of Amyotrophic Lateral Sclerosis (ALS) in
Regional Environmental Public Health Tracking System
(EPHTS) and National Electronic Disease Surveillance
System (NEDSS): Practical Geographic Implications of
Wisconsin ALS Mortality Experience
Benjamin Rix Brooks, Mark A. Werner,
Marni Y. V. Bekkedal, Marty S. Kanarek, and
Henry A. Anderson; Madison, WI
Background: Governmental health and environmental data
are largely not collected to support surveillance efforts for
chronic conditions likely caused by environmental factors.
Design/Methods: Mortality data were analyzed to summarize death relationship and to determine the degree to which
geographically-specific estimates of environmental hazards
could account for decedent exposure.
Results: From1989 – 1998, ALS deaths increased from 72
to 116 per annum. Among 1047 deaths, ALS was primary
cause in 179 deaths (17.1%) and underlying cause of death
(UCOD) in 508 deaths (48.5%). In 360 ALS cases (34.4%),
respiratory arrest, pneumonia and death due to inhalation of
food or vomitus were most commonly reported as the
UCOD. Among the 658 deaths reported as occurring outside hospital, 280 (42.6%) were classified as occurring in
nursing homes rather than the place of residence.
Conclusions/Relevance: Investigations of the role of environmental hazards in ALS incidence require patient-level information about residential history, and adds to the impetus
to develop statewide ALS registries for real-time localization
of incident ALS patients for environmental association studies. Study supported by Center for Disease Control and Prevention, Department of Veterans Affairs, Wisconsin Department of Health and Family Services.
M-31. Transcriptome Analysis in Friedreich’s Ataxia
Identifies Potential Biomarkers Related to Treatment
Giovanni Coppola, Ryan Burnett, Maren Engelhardt,
Matthew N. Suberlak, Susan Perlman, Joel M. Gottesfeld,
and Daniel H. Geschwind; Los Angeles, CA; and
La Jolla, CA
Background and Objective: No therapy is currently available
for Friedreich’s ataxia (FRDA). Some HDAC inhibitors have
recently been shown to increase frataxin levels in vitro (Herman et al, Nat Chem Biol 2006). We aimed at characterizing
the gene expression changes induced by these compounds, and
their effect on the transcriptional profile related to frataxin deficiency.
Patients and Methods: We studied with microarrays RNA
from lymphocytes of 5 FRDA patients and 5 matched heterozygous controls, before and after treatment with three compounds that had shown efficacy in raising frataxin levels in
Results: More than 2,000 genes showed expression changes
after treatment with 2 out of 3 compounds, suggesting that
Annals of Neurology
Vol 62 (suppl 11)
the drugs act on the same pathways. We were able to identify
gene expression changes highly correlated with changes in
frataxin levels, and identified a subset of genes affected by
frataxin deficiency and reversed after drug treatment.
Conclusions: This pilot study shows potential applications in
evaluating candidate drugs for FRDA, identifying the genes
and pathways underlying the mechanism of action, and allowing the selection of a peripheral biomarker panel, a potentially
valuable tool in follow-up and clinical trials.
M-32. Functional Genomic Analysis of Friedreich’s
Ataxia Pathogenesis In Vivo and In Vitro
Giovanni Coppola, Maren Engelhardt, Matthew N. Suberlak,
Eric M. Wexler, Manuela Santos, Carlos J. Miranda,
Sahar Al-Mahdawi, Mark Pook, Massimo Pandolfo, and
Daniel H. Geschwind; Los Angeles, CA;
Montreal, QC, Canada; Uxbridge, United Kingdom; and
Brussels, Belgium
Background and Objective: We aimed at characterizing
tissue-specific gene expression changes associated with early
deficiency of frataxin using microarrays.
Methods: We studied RNA from heart and skeletal muscle in
knock-in/knock-out (KIKO) and YAC-transgenic FRDA
mouse models. We verified our data on cellular models of
frataxin deficiency using shRNA on C2C12 and HL1 cell
Results: We detected ⬃200 genes with tissue-specific changes
or showing differential expression across all the frataxindeficient tissues in the KIKO model. A significant proportion
of these genes was shared with those changing in the YAC
model. Heart samples showed changes in structural proteins,
while skeletal muscle showed no evidence of myopathy, but
rather changes involving lipid metabolism and insulin-related
pathways. We were able to confirm a significant percentage of
changes in vitro using shRNA-mediated frataxin knockdown.
We also identified a set of transcripts showing a temporal pattern of expression closely matching the frataxin knockdown,
suggesting a causal relationship.
Conclusions: These studies contribute to both identifying genes
with a pathogenic role in FRDA-related cardiomyopathy and
diabetes, and beginning to define potential biomarkers that may
be useful in follow-up and drug trials. Study supported by Dr.
Miriam and Sheldon G. Adelson Medical Research Foundation.
Friedreich’s Ataxia Research Alliance (FARA).
M-33. Global Proteomics: A Shorter and Safer Path to
Pharmacodynamic Biomarkers
Paul Kearney, Nathan L. Currier, Dan Chelsky,
Clarissa Desjardins, Patrice Hugo, Joanna Hunter,
Eustache Paramithiotis, Marc Riviere, Olivier Maes,
Howard M. Chertkow, and Hyman M. Schipper;
St-Laurent, QC, Canada; and Montreal, QC, Canada
Disease and drugs can modulate the concentration of hundreds of proteins in the blood which can be accurately measured using contemporary proteomic methods. Nevertheless,
it is common practice to represent the plurality of disease
and drug effects by a few proteins for the purposes of immunoassay development. The vast majority of putative biomarkers discovered by this reductionist approach never
reach the clinic for two reasons: the prohibitive time and cost
of assay development and the acute risk of a reduced protein
panel failing when validated on a broader cross-section of the
Global Proteomics is an alternate methodology where all
blood proteins modulated by disease or drug are used to resolve pharmacodynamic questions without the time, cost,
and risk of developing an immunoassay. The Global Proteomic approach is applied to an Alzheimer study where it is
demonstrated that a large panel of plasma proteins is predictive of disease severity (as measured by the Mini Mental
State Examination). Furthermore, a subset of this panel is
shown to be modulated by disease treatment (donepezil)
thereby providing a means to quantify response to treatment.
Study supported by Caprion Pharmaceuticals.
M-34. Tumefactive Demyelinating Lesions: A
Diagnostic Challenge – Case Series
Aria Fallah, Sarfaraz M. Banglawala, John Erik Paulseth,
and Neilank K. Jha; Hamilton, ON, Canada
OBJECTIVE AND IMPORTANCE: Multiple sclerosis and
other related demyelinating diseases may present clinically
and radiologically similar to brain tumors and are difficult to
differentiate at times. It is important to identify these lesions
as it influences the treatment options. Erroneous diagnosis of
a brain tumor can lead to unnecessary surgical resection on
viable brain tissue.
We present three cases of such lesions that were difficult to
distinguish between a brain tumor versus a demyelinating
process based on symptomatology and radiological findings.
The nature of the lesion was determined to be demyelinating
by a brain biopsy in two of these cases and by resection in
the other case.
CONCLUSION: In order to avoid invasive procedures for
the eventual diagnosis of a demyelinating lesion, physicians
often require the aid of alternative testing to characterize the
lesion. There are important subtle features on neuroimaging,
histopathology and laboratory markers that may help distinguish brain tumors from demyelinating disease.
M-35. Autonomic Dysfunction and Peripheral
Neuropathy in Chromosome16q22.1-Linked Autosomal
Dominant Cerebellar Ataxia
Yoshiko Furiya, Makito Hirano, Masami Nomura,
Hirohide Asai, Takao Kiriyama, and Satoshi Ueno;
Kashihara-shi, Nara, Japan; and Kaifu-gun, Aich, Japan
A new type of ADCA, named chromosome16q2.1-linked autosomal dominant cerebellar ataxia (16q-ADCA), was recently reported to be caused by a heterozygous C-T substitution in the 5’ non-coding region of puratrophin-1 gene.
We searched for this mutation in168 patients from 129 families with ADCA and found it in 6 patients; they all showed
late-onset pure cerebellar ataxia, but two had mild axonal
neuropathy and orthostatic hypotension (OH). The results
of nerve conduction studies revealed reduced compound
muscle action potentials with slightly or mildly decreased
nerve conduction velocities, indicating axonal sensorimotor
neuropathy. On head-up-tilt test, increased plasma argininevasopressin concentrations and renin activity suggested that
their OH was not due to involvement of the central autonomic nervous system. In one of two patients, abnormal
QTc intervals and dispersion suggested involvement of the
cardiac post-ganglionic sympathetic nervous system, which
was supported by the abnormal findings of 123I-MIBGscintigraphy. Our findings are inconsistent with those previously reported in 16q-ADCA, but agree with those found in
many other types of ADCA. Collectively, although only
small numbers of patients have been studied available evi-
dence suggests that 16q-ADCA may also involve nervous systems other than the cerebellum.
M-36. Comparison between QSART and 123I-MIBG
Scintigraphy for Differential Diagnosis of PD and MSA
Hidenori Hara, Yoshimasa Kuzumoto, Mitsuaki Shioyama,
Yohei Inatsugi, and Susumu Kusunoki; Osaka, Japan
Recently, it has been reported that cardiac uptake of 123Imetaiodobenzylguanidine (MIBG) is decreased in patients
with Parkinson disease (PD), but not in patient with multiple system atrophy (MSA). Also, MSA patients have more
often disturbance of sudomotor function than PD patients.
Therefore, we performed both of MIBG and quantitative sudomotor axon reflex test (QSART) in eight PD and eight
MSA patients and compared them. There was no significant
difference in disease duration (PD: 93.6⫾20.2 months,
MSA: 83.3⫾18.7 months, mean⫾S.E.) and in the grade of
Hoehn and Yahr (2.9⫾0.3 and 3.4⫾0.2). The severity of
MIBG abnormality was rated by heart-mediastinum (H/M)
ratios and that of QSART by the sudomotor subscore of the
Composite Autonomic Scoring Scale (CASS-sud). As a result, MIBG H/M ratios for PD and MSA were 1.432⫾0.028
and 2.147⫾0.057, respectively. CASS-sud scores were
0.4⫾0.2 and 2.4⫾0.2. There was significant difference between them in each modality. For differential diagnosis of
PD and MSA, QSART is useful as well as MIBG. However,
QSART is superior to MIBG in the point of cost and exposure to radiation.
M-37. Mutant ALADIN Impairs Selective Nuclear
Import and DNA Repair in Triple A Syndrome
Makito Hirano, Yoshiko Furiya, Hirohide Asai,
Takao Kiriyama, Akira Yasui, and Satoshi Ueno;
Kashihara, Nara, Japan; and Sendai, Miyagi, Japan
Triple A syndrome is a rare autosomal recessive neuroendocrinological disease. The causative gene encodes ALADIN, a
component of nuclear pore complex (NPC). We identified a
novel mutant ALADIN (I482S) that fails to target NPC in a
patient with adult-onset motor neuron disease-like phenotype, and investigated the consequences of mistargeting using
fibroblasts (I482Sf) from the patient. This mutation selectively decreased nuclear accumulations of aprataxin (APTX),
a DNA repair protein causative for cerebellar ataxia, and of
DNA ligase I, another repair protein, in I482Sf. I482Sf were
hypersensitive to oxidative stress created by a glutathione depleting agent with increased DNA damage, but became resistant by transfection with both APTX and ligase I. Collectively, this study suggests that oxidative stress increased DNA
damage beyond the limited capacity of decreased nuclear
DNA repair proteins, culminating in cell death.
M-38. A Cell Model for Abnormal Hepatocyte Copper
Transporting in Wilson Disease
Guoqing Hou, Chunhua Zeng, Xiulin Liang, Rong Chen,
and Zhenwen Yan; Ann Arbor, MI; and
Guangzhou, Guangdong, China
Wilson disease (WD) is characterized by exclusive defect
copper transportation in the liver, brain and other organs,
caused by mutations in ATP7B, which putatively encodes
copper transporting P-type ATPase, ATP7B protein. In this
paper, we set up a copper transportation hepatocyte model,
in order to evaluate the effect of copper transporting P-type
Program and Abstracts, American Neurological Association
ATPase on hepatocyte’s copper metabolism and pathogenesis
of Wilson disease (WD), When hepatocytes were cultured,
higher copper load, vanadate (antagonist of P-type ATPase)
and ATP were added into the incubation medium to mimic
copper cumulation in WD patients. Copper uptake and excretion in different hypatocyte organelles were assayed. The
results indicated that there exited ATP-dependent copper
transporting in microsomes (mainly consisting of endoplasmic reticulum and Golgi apparatus) and plasma membrane
of hepatocytes, and the antagonist of P-type ATPase obviously inhibited copper transporting of microsomes and
plasma membranes. As of WD patients, we found prominent
decrease of ATP dependent copper transport in their hepatocytes organelles comparing with controls.
Copper transporting P-type ATPase plays an important
role in hepatocytic copper metabolism. Dysfunction of hepatocytic copper transporting P-type ATPase is one of the most
important pathogenesis of WD.
M-39. Green Tea-Containing Food Delays Progression
Wobbler Mouse Neuromuscular Disease
Ken Ikeda, Osamu I. Kano, Konosuke Iwamoto, and
Yasuo Iwasaki; Tokyo, Japan
Background: Japanese green tea (GT) contains epigallocatechin gallate, serine and multi-vitamins A, B1, B2, C, E.
Those substances have protective effects on motor or dopamine neurons. Our purpose is to evaluate whether GT can
retard progression of motor symptoms and spinal motoneuron degeneration in wobbler mice.
Methods: Wobbler mice fed regular food or five kinds of food
mixed with 2.0 % GT (2.0 g/kg/day), 0.36 % catechins,
0.028 % theanin, 0.054 % caffeine or combination of catechins/theanin/caffeine. Such doses of catechins, theanin and
caffeine correspond to 2.0 % GT. Diet therapy (each total
n⫽15) started from disease onset (3-4 weeks of age) for 4 or 8
weeks. Motor function of the forelimbs was assessed weekly
for 8 weeks (each n⫽10). Neuropathologic changes were compared among six groups (each n⫽5) after 4 weeks treatment.
Results: GT treatment extended forelimb motor function for 4
weeks (p⬍0.01), whereas other foods-treated mice lost motor
function of the forelimbs at 11-12 weeks of age. GT-feeding
mice suppressed denervation muscle atrophy in the biceps
muscle (p⬍0.01) and attenuated C5-6 motoneuron degeneration (p⬍0.01).
Conclusion: Our data indicate that 2.0 % GT rescues spinal
motoneurons from wobbler mouse neuromuscular disease.
Abstract Withdrawn
M-41. Low Molecular Weight Chitosans as Cheleators
of Cu (II) In Vitro and In Vivo Decreased
Neurotoxicity of Amyloid ␤-Peptide Bound with Cu
Zhao-Feng Jiang, Jie-Min Geng, and Han-Yi Yang;
Beijing, China; and Changchun, Jilin, China
The interaction of amyloid ␤-peptide (A␤) with Cu (II) in
Alzheimer’s disease (AD) brain leads to the formation of reactive oxygen species, and neurotoxicity. And low molecular
weight chitosans have a potential to bind Cu (II). Here we
demonstrated in vivo and in vitro that (i) Cu (II)A␤1-40 had
the activity to produce hydrogen peroxide and hydroxyl free
radicals and had neurotoxicity to neurons in culture and in
rat hippocampus by injected the complexes; (ii) low molec-
Annals of Neurology
Vol 62 (suppl 11)
ular weight chitosans had a stronger activity in adsorbing Cu
(II) from the Cu (II)A␤1-40 and formed Cu (II)-chitosan
complexes, and the complexes had a lower activity to produce
hydrogen peroxide and hydroxyl free radicals than Cu
(II)A␤1-40; (iii) the Cu (II)-chitosan complexes as Cu (II) chelators decreased the neurotoxicity of Cu (II)A␤1-40 to neurons in culture and in rat hippocampus when the complexes
injected after Cu (II)A␤1-40 complexes. these findings suggest
that low molecular weight chitosans may be as chelators for
treatment of AD in someway. Study supported by grants from
the Technology Development Program of the Beijing Education Committee and from the Key Program of the Beijing
Narutal Science Foundation(No. KZ200311417015).
M-42. Changes in the Progression of Diagnostic
Interval and Pathway in Amyotrophic Lateral Sclerosis
in Japan
Osamu Kano, Ken Ikeda, Keisuke Arasaki, and
Yasuo Iwasaki; Tokyo, Japan
After the revised criteria of the El Escorial (REE), whether
survival and progression of amyotrophic lateral sclerosis
(ALS) are altered remains unclear. Our purpose is to compare diagnostic pathway and interval from onset to physician
or special neurologist visit between previous El Escorial (EE)
and REE criteria. A total of 160 patients were divided into
two groups; historical group (n⫽117) of definite and probable cases using EE (1990-1999) and contemporary group
(n⫽43) of definite, probable and probable-laboratorysupported cases using REE (2000-2006). Diagnostic interval
from onset (SD) was 12.4 (8.2) months in historical group
and 14.5 (10.5) in contemporary group. Those of limb onset
were statistically longer in both groups, as compared to bulbar onset (p⬍0.05). The first consultation to physicians or
neurologist delayed markedly in limb onset patients of the
contemporary group. Mean interval from general practitioner
to neurologist was longer in historical group [8.5 (5.9)
months] than contemporary group [21.3 (12.0)]. Diagnostic
interval is longer in patients diagnosed by REE, predominantly in limb onset patients. Thus, REE with electromyography fails to shorten the diagnostic interval of ALS.
M-43. Transglutaminase Modulates Expression of
Genes Involved in Compensation for Mitochondrial
Dysfunction in Huntington’s Disease Models
Stephen McConoughey, Arthur Cooper, Juan Chavez,
Flint Beal, and Rajiv R. Ratan; White Plains, NY; and
New York, NY
Pharmacological inhibition or molecular deletion of transglutaminase (tgase), a cross-linking enzyme, can ameliorate pathology and behavior in Huntington’s disease (HD) models.
The mechanisms by which tgase confers these salutary effects
remains unclear. Here we report that tgase can act directly at
promoters of genes such as PGC-1␣ (a coactivator) and cytochrome c to repress the ability of transcription factors to
recruit the basal transcription factor machinery. Using a
chromatin immunoprecipitation assay, we demonstrate that
tgase is bound to a complex of proteins that interact directly
with the promoters of these target genes. Inhibition of tgase
activity using pharmacological inhibitors or siRNA knockdown leads to increased promoter activity, mRNA levels and
protein levels of PGC1␣ or cytochrome c. Finally, inhibition
of tgase leads to robust protection of HD cell lines or pimary
neurons from the mitochondrial toxin, 3 nitroproprionic
acid. Together these studies suggest that tgase inhibition
overcomes mitochondrial dysfunction in HD by faciliating
the expression of genes involved in mitochondrial biogenesis
and function and host defense. Study supported by NIA.
M-44. Clinical Features in a Patient with Late-Onset
Sporadic VV1 Subtype Creutzfeldt-Jakob Disease
Rebecca H. Reiser, Steven S. Chin, Peirluigi Gambetti, and
Norman L. Foster; Salt Lake City, UT; and Cleveland, OH
The subtype of sporadic Creutzfeldt-Jakob disease (sCJD),
that includes patients who are homozygous for the valine
codon 129 of the prion protein gene, and have the abnormal
prion protein type 1 (sCJDVV1) is the least common of the
six molecular subtypes, accounting for 1-2%. Previously reported cases had prominent psychiatric symptoms, unusually
long disease duration, young age at onset (median age 44-47,
range 19-72) without EEG periodicity. We evaluated an 80year-old man with a 4-month disease course of progressive
gait instability and word finding difficulties. Because of rapid
neurological deterioration, CJD was suspected early but dismissed because of an unremarkable EEG and misinterpretation of his MRI scan. Brain biopsy confirmed sCJD VV1.
This case extends the known age-of-onset of VV1 sCJD and,
because his symptoms and course are typical for sCJD, raises
the possibility that age may modify the clinical features of
this subtype. Because of the much higher prevalence of other
neurodegenerative diseases, patients with CJD in this age
group may be under-recognized and deserve full evaluation
with immunohistochemical analysis and histopathological examination with molecular subtyping because of the familial
and public health implications of this disorder.
M-45. Progranulin Plaques Correlate with A␤ Burden
in Dementia with Lewy Bodies
Gonzalo J. Revuelta, Andrea Rosso, and Carol F. Lippa;
Philadelphia, PA
OBJECTIVE: To report the presence of progranulin
(PGRN) plaques in dementia with Lewy Bodies (DLB), and
begin to characterize pathological processes associated with
its accumulation.
BACKGROUND: Recent studies demonstrated that the loss
of PGRN expression play a role in some CNS neurodegenerative diseases. However, PGRN aggregates have not been
reported in synucleinopathies.
METHODS: We determined immunoreactivity for PGRN
in medial temporal lobe (MTL) structures in seven cases of
DLB. Similar data was collected for ␤-amyloid (A␤) burden.
Blinded investigators used a 0-3 scale, where zero represented
no pathology, and six represented the greatest number of aggregates. We used Western blot analysis in four DLB cases
and four controls to compare the level of expression.
RESULTS: PGRN plaques occurred throughout the MTL
in all DLB cases (mean scores 0.78 and 1.78 for PGRN and
A␤ respectively). We identified a significant positive correlation (r⫽0.861, p⬍0.01) between A␤ and PGRN plaque
burden. There was an appreciable increase in PGRN expression in DLB compared with control cases.
CONCLUSIONS: PGRN plaques are present throughout
MTL structures in DLB. A␤ correlates with PGRN plaque
formation, implying that these two aggregates are likely associated.
M-46. Motor Neuron Protection by VEGF:
Implications for Amyotrophic Lateral Sclerosis
Stacey A. Sakowski, J. Simon Lunn, and Eva L. Feldman;
Ann Arbor, MI
Amyotrophic Lateral Sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by progressive degeneration of motor neurons (MN) resulting in weakness, paralysis
and subsequent death. Familial ALS accounts for 10% of
ALS cases, 20% of which are associated with mutations in
Cu2⫹/Zn2⫹ superoxide dismutase (SOD1) with G93ASOD1 being the best characterized mutation. We use
NSC34 cells and rat primary MN cultures transfected with a
G93A-SOD1 adenoviral vector as our model of ALS. Transfected cells exhibit morphological and biochemical responses
characteristic of cell death such as caspase-3 activation. Vascular endothelial growth factor (VEGF), an angiogenic and
neuroprotective growth factor that can increase axonal outgrowth, block neuronal apoptosis and promote neurogenesis,
may prevent these effects on MN. G93A-SOD1 transgenic
mouse spinal cords contain decreased levels of VEGF
mRNA, as well as decreased mRNA levels of VEGF
receptor-2 (VEGFR2). VEGF treatment leads to the activation of PI3K/Akt and MEK/ERK signaling pathways via
VEGFR2, and addition of VEGF to the G93A-SOD1 transfected cells is protective against the morphological and biochemical changes that represent ALS-like injury. These studies validate the efficacy of VEGF treatment for ALS and
provide insight into the mechanisms involved. Study supported by National Institutes of Health (NS38449 and
NS36778) and the Program for Neurology Research and
M-47. Correlation of Magnetisation Transfer Ratio
Histogram Measures with Clinical Disease Severity in
Inherited Prion Disease
Durrenajaf Siddique, Stephen J. Wroe, Harpreet Hyare,
Thomas E. F. Webb, Suvankar Pal, John Collinge,
Sarah Walker, Tarek Yousry, and John Thornton;
London, United Kingdom
In Inherited prion diseases (IPD), conventional MR neuroimaging is often unremarkable. We investigated global and
regional cerebral MR magnetisation transfer ratios (MTRs)
in IPD. Twenty-three patients, recruited into the MRC
PRION-1 Trial, underwent MTR and conventional MR imaging. For each patient, whole-brain MTR histogram mean
(AVMTR), peak height (PH), peak location (PL), and MTR
at the 25th, 50th and 75th percentile (MTR25%, MTR50%,
MTR75%) were calculated together with mean MTR for bilateral caudate, putaminal and pulvinar regions of interest
(ROI). A clinician’s assessment of disease severity (GIC), clinician’s dementia rating (CDR), Alzheimer’s disease assessment scale (ADAS-COG), activities of daily living (ADL),
brief psychiatric rating scale (BPRS), mini mental score examination (MMSE) and Rankin scores were evaluated. Significant (p⬍0.01) bivariate Spearman rank correlations were
found between AVMTR and Rankin (p⫽0.008), CDR
(p⫽0.002) and ADAS-COG (p⫽0.004); PH and Rankin
(p⫽0.002); MTR25% and Rankin (p⫽0.001), CDR
(p⬍0.001), ADAS-COG (p⫽0.008) and GIC (p⫽0.006);
and MTR50% and Rankin (p⫽0.004). Mean ROI MTRs
did not correlate with clinical scores, and conventional MR
imaging was normal. Whole-brain MTR histogram measures
may provide valuable indices of IPD disease severity for future therapeutic trials. Study supported by Medical Research
Council, UK.
Program and Abstracts, American Neurological Association
M-48. Identification and Characterization of
Neuroprotective Agents for HIV-Dementia
Joseph P. Steiner, Daniella Asch, Norman J. Haughey,
Justin C. McArthur, and Avindra Nath; Baltimore, MD
There are severe neurological complications that arise from
HIV infection, ranging from peripheral sensory neuropathy
to cognitive decline and dementia. The HIV proteins secreted from infected macrophages and astrocytes, gp120 and
Tat, are cytotoxic to the surrounding neuronal cells. Mechanistically, this neurotoxicity may be mediated via HIV
protein-induced oxidative stress. Recently, we have established a high throughput functional assay in primary rat hippocampal cultures to quantitate neurotoxicity following oxidative damage. We have screened over 2000 FDA approved
drugs and natural products for protective efficacy at a single
dose (10 uM) and have generated a short list of potential
neuroprotective compounds. We have confirmed their neuroprotective activities and potencies in vitro. A few representative compounds include the antioxidants resveratrol and
epicatechin, estrogens, such as b-estradiol, antidepressants,
such as imipramine and fluoxetine, and statins, such as pravastatin. Initial testing of these compounds demonstrates neuroprotective efficacy in the low micromolar range and subsequent neuroprotection against HIV Tat and gp120. Thus,
compounds like these and their derivatives, may provide new
avenues by which neuroprotective treatment(s) may be derived and used to treat patients with HIV-Dementia. Study
supported by P30MH075673 to JPS, AN, NJH and JCM,
R01NS43990 & R01NS039253 to AN, and AG023471 &
MH068388 to NJH.
M-49. The Antioxidant Response as a Therapeutic
Target in Diabetic Neuropathy
Andrea M. Vincent, Koichi Kato, Lisa L. McLean,
Carey Backus, and Eva L. Feldman; Ann Arbor, MI
Hyperglycemia produces acute oxidative stress in dorsal root
ganglion (DRG) neurons that initiates mechanisms leading
to diabetic neuropathy. This stress occurs primarily in the
mitochondria and the resulting energy crisis activates apoptosis. We proposed that increased antioxidant potential in
DRG neurons would prevent glycemic injury. Moderate oxidative stress (10 ␮M H2O2) significantly increases TUNEL
positive staining and caspase 3 activation in DRG cultures
similar to hyperglycemic injury. However, 1 ␮M H2O2 does
no injure neurons, but prevents injury by subsequent 10 ␮M
H2O2 or 20 mM added glucose. Botanical compounds
known to activate the antioxidant response in non-neuronal
cells (10 ␮M resveratrol or 10 ␮M sulphoraphane) also prevent injury caused by hyperglycemia or 10 ␮M H2O2. DRG
neuron protection is associated with increased translocation
of the antioxidant enzyme transcription factor Nrf-2 from
the cytoplasm to the nucleus within 1 h. The pre-treated
DRG neurons generate more reduced glutathione and display increased expression and activity of glutathione
S-transferase and NQO-1. Thus, natural compounds that activate the antioxidant response improve the innate ability to
withstand fluctuations in glycemia and are an attractive therapeutic strategy against this common and severe complication of diabetes. Study supported by the Program for Understanding Neurological Diseases (PFUND), the Juvenile
Diabetes Research Foundation Center for the Study of Complications in Diabetes, and grants from the National Institutes of Health (NIH RO1 NS36778, and NIH RO1
Annals of Neurology
Vol 62 (suppl 11)
M-50. Knowledge, Attitudes and Beliefs as Regards
Causes and Management of Epilepsy among Road
Transport Workers in Nigeria
Babawale Arabambi; Lagos, Nigeria
Epilepsy commonly has various misconceptions leading to
negative attitudes toward sufferers of this disorder. The aim
of this study is to ascertain the knowledge, attitudes and beliefs of road transport workers at Mushin Local Government
Area, Lagos state, Nigeria as regards the causes and management of epilepsy.
The most common manifestation of epilepsy proffered was
convulsions (85%) followed by falling down (63%). Inheritance (53%) was the most implicated cause, brain injury and
brain infection were less common responses, chosen by 16%
and 11% of the respondents respectively. Overall, 84% had
at least fair knowledge about the disorder.
Overall, 63% of the respondents have a positive attitude towards persons with epilepsy. The people who believed that
epilepsy was contagious were more likely to exhibit negative
attitudes compared to those who do not (␹2 ⫽ 37.1, df ⫽ 1,
p ⬍ 0.01). It can be concluded that the belief that epilepsy
is contagious is a major determining factor for the negative
attitudes. Therefore, public awareness campaigns are recommended to improve the knowledge and attitudes of the society about the disorder and to people suffering from it respectively.
M-51. Diagnosis Workup and Final Etiologies in
Children Presenting with First Time Seizure
Sailaja Enduri, M. Fernanda Bellolio, David L. Nash, and
Stead G. Latha; Rochester, MN
OBJECTIVE: Characterize the diagnostic workup and final
diagnosis in children presenting to the pediatric emergency
department (PED) with a first time seizure.
METHODS: Study population: 111 consecutive patients
with a first time seizure over a 24 month period. Information on the ED visit, demographics, diagnostic workup and
final diagnosis was collected. Statistical analyses were performed using JMP 6.0 (SAS Institute)
RESULTS: Of the 111, 44% were girls. The mean
age⫹/-SD was 35 ⫹/- 44 months (range 8 days-15 years).
Diagnostic workup consisted of laboratory analyses (56%),
urinalysis (18%), head CT (43%), lumbar puncture (15%),
and EEG (47%).
Under 1/3 of the cohort was admitted. The median length of
hospital stay was 1 day (range 1-8 days).
A total of 43% had a final diagnosis of febrile seizure, while
25% had a diagnosis of epilepsy.
Older children presenting with first time seizure were more
likely to have epilepsy (p⫽0.004) while those younger were
significantly more likely to have febrile seizures (p⫽0.009).
There was no difference between gender with regard to final
CONCLUSION: Age at presentation appears to be a predictor of first time seizure etiology, in this pediatric emergency
department cohort.
M-52. Severe Neonatal Status Epilepticus and Stress
Prematurely Terminate the Depolarizing GABAA-ergic
Signaling in Male Hippocampus: Implications for an
Altered Brain Development, but Not Necessarily
Aristea S. Galanopoulou; Bronx, NY
Depolarizing GABAA receptor signaling is critical for normal
early brain development; its switch to hyperpolarizing signaling occurs following region-specific patterns. Pathological reemergence of depolarizing GABAA-ergic signaling is a key
feature of the adult epileptic hippocampus. Although neonates develop mild functional sequelae from status epilepticus (SE), they are relatively resistant to epileptogenesis. To
test whether this is linked to GABAA-ergic signaling, 3
kainate-induced SE were induced at postnatal days PN4, 5,
and 6 (KA456 group) on male Sprague-Dawley rats. Controls were naive (CON) or maternally separated (SS456)
male rats. Both KA456 and SS456 had earlier appearance of
hyperpolarizing GABAA-ergic signaling in CA1 pyramidal
neurons (gramicidin-perforated patch clamp). Susceptibility
to lithium-pilocarpine seizures at PN19 (seizure onset, severity, and hippocampal neurodegeration) was unchanged. No
spontaneous seizures occurred in adulthood. Conclusions:
Severe neonatal SE and separation stress induce precocious
arrest of GABA-related hippocampal differentiation, which
may contribute to long-term functional deficits. The resistance of the SE-exposed immature hippocampus to maintain
depolarizing GABAA-ergic signaling is associated with, and
could potentially contribute to, its relative resistance to epileptogenesis. Study supported by NIH NINDS grants
NS45243 and NS20253; RSRF (Rett Syndrome Research
Foundation) grant; My salary is largely supported by the
above NIH NINDS grant (NS45243). The research included in this abstract is supported by all above grants.
M-53. Protein Misfolding and Degradation of the
GABA-A Receptor Alpha 1 Subunit Produces a
Monogenic Juvenile Myoclonic Epilepsy
Martin J. Gallagher, and Robert L. Macdonald;
Nashville, TN
A nonconservative missense mutation (A322D) in the
GABA-A receptor alpha 1 subunit causes an autosomal dominant form of juvenile myoclonic epilepsy (ADJME). Previously, we demonstrated that with coexpression in mammalian heterologous cells of wild type alpha 1, heterozygous
alpha 1/alpha 1(A322D) or homozygous alpha 1(A322D)
subunits with beta 2 and gamma 2S subunits, the alpha
1(A322D) mutation reduced GABA-evoked peak current
amplitudes, reduced both total and surface alpha 1 subunit
expression, and caused residual alpha 1(A322D) subunit to
be localized in the endoplasmic reticulum. Here we determined the mechanistic basis for these findings. We demonstrated that because the A322D mutation increased the alpha
1 subunit’s M3 transmembrane domain’s polarity, M3 inefficiently inserted into the membrane lipid bilayer. We then
showed that the misfolded alpha 1(A322D) subunit was degraded rapidly through the ubiquitin-proteasome system and
thus with heterozygous expression resulted in a posttranslationally haploinsufficient phenotype. These findings identified ADJME as a protein misfolding disease caused by an
alteration of alpha 1 subunit transmembrane topology and
suggested that alpha 1 haploinsufficiency can cause the ADJME clinical phenotype. Study supported by United States
Public Health Service Grants NS33300 and NS39479 (to
R. L. M.) and NS44257 and a grant from the Milken Family Foundation / American Epilepsy Society (to M. J. G.).
M-54. Magnetic Resonance Imaging (MRI)
Abnormalities in Status Epilepticus (SE) and Frequent
Repetitive Seizures (FRS)
Mahmut E. Gurol, Toshio Moritani, and Erik K. St Louis;
Iowa City, IA
Purpose: To identify periictal MRI findings and evaluate
their relationship with clinical and EEG features. Patients/
Methods: Eleven patients (5 SE and 6 FRS, mean age 40, 7
females) had at least one MRI within 24 hours after onset of
EEG-confirmed SE/FRS. Two-to-four MRIs performed in
each subject included FLAIR/T2, diffusion-weighted imaging (DWI), apparent-diffusion-coefficient (ADC) and postcontrast T1 sequences. MRI lesion location and appearance,
clinical, and EEG findings were recorded for each subject.
Results: All patients had focal DWI changes, 8 had
FLAIR/T2 abnormalities, 2 had contrast-enhancing lesions.
Thalamic DWI/ADC lesions were found in 4/5 SE patients,
but only 1/6 with FRS. Two SE and 3 FRS patients had
hippocampal lesions. Focal cortical lesions were seen in 3 SE
and 3 FRS cases. One refractory SE patient had generalized
vasogenic brain edema. Two patients with splenial ADC
changes had psychiatric manifestations. Focal lesions did not
respect a vascular territory, they correlated well with focal
postical deficits and EEG findings. Most lesions resolved on
repeat imaging. Conclusions: MRI lesions are commonly
found in the acute phase of SE and FRS and they colocalize
with clinical and EEG findings.
M-55. Bisphosphonates in the Treatment of
Antiepileptic Drug Induced Osteoporosis
Zulfi Haneef, Mercedes P. Jacobson, Navid Mostofi, and
John O. Elliott; Philadelphia, PA; Washington, DC; and
Columbus, OH
RATIONALE: Osteoporosis is an important complication of
long-term Anti-Epileptic Drug (AED) treatment. Calcium/
vitamin D supplementation is traditionally used to prevent
this. Although bisphosphonates are approved for treatment
in post-menopausal osteoporosis and in males with osteoporosis, there is scant evidence measuring their efficacy in males
with AED-induced osteoporosis.
METHODS: A retrospective chart review identified men
with chronic AED-induced osteoporosis. Bone Mineral Density (BMD) improvement among those treated with bisphosphonates was assessed using serial DEXA bone scans.
RESULTS: Fifty-nine males on AEDs had serial DEXAs.
The initial scan identified 10 osteoporotic (mean age 45.1)
and 15 osteopenic (mean age 45.3) subjects. Seven of the 10
osteoporotics were on bisphosphonates, and the BMD improved in 6. Two of the 15 osteopenics took bisphosphonates; 1 improved.
Overall, among 9 subjects taking bisphosphonates, 7 improved/stabilized and 2 worsened. Among 16 not on
bisphosphonates, 10 improved/stabilized and 6 worsened.
CONCLUSIONS In men with AED-induced osteoporosis,
there was no statistically significant BMD improvement between those on or not on bisphosphonates. Larger trials
should address whether bisphosphonates benefit AEDinduced osteoporosis as it did post-menopausal osteoporosis.
Some of the improvement in the bisphosphonate-naive subjects in this study may be secondary to calcium/vitamin D
Program and Abstracts, American Neurological Association
M-56. Treatment of SE Does Not Always Correlate
with Better Outcome
Henry Hasson, Mimi Kim, and Solomon L. Moshé;
Bronx, NY
M-58. Cortical Hypoperfusion during Postictal Todd’s
Marlon S. Mathews, Wade S. Smith, William P. Dillon, and
Devin K. Binder; Orange, CA; and San Francisco, CA
Status Epilepticus (SE) is common in children yet the efficacy and consequences of standard treatments are unknown.
Methods: Postnatal day 9 (P9), 15(P15) and 21(P21) rats
were exposed to 1-hour long status epilepticus (SE) induced
by kainic acid (KA) or lithium pilocarpine (PI) and then
treated with varying doses of pentobarbital (PB) or diazepam
(DZ). If left untreated seizures continue for 24 hours. Rats
were monitored with EEG to assess efficacy of treatment.
Results: At P9, neither drug stopped SE and both increased
mortality over non treated rats. At P15, DZ 20mg/kg
stopped SE in most rats and did not increase mortality. Although higher doses were more efficacious, they increased
mortality in the KA model. PB 50mg/kg stopped SE and did
not increase mortality. Lower doses decreased mortality but
did not stop SE. At P21, DZ ⬎20mg/kg was required to
stop SE and did not increase mortality. PB was dose dependent but was not associated with improvements in mortality.
Conclusions: These results indicate that DZ and PB can stop
prolonged SE in an age dependent fashion. They are ineffective in very young rats. Controlling SE was not associated
with improvements in mortality. Study supported by NIH
NINDS grants K12-NS048856 (NSADA) (HH) and R01NS20253 (SLM).
Postictal (“Todd’s”) paralysis, or “epileptic hemiplegia,” is
an established complication of epileptic seizures. However,
it is unclear whether the pathophysiology of Todd’s paralysis is related to alterations in cerebral perfusion. We report
CT perfusion findings in a 62-year-old woman presenting
with postictal aphasia and right hemiparesis. A noncontrast
head CT demonstrated no acute hemorrhage. Left hemispheric ischemia was suspected, and the patient was considered for acute thrombolytic therapy. MR imaging revealed subtle increase in signal intensity involving the left
medial temporal, hippocampal, and parahippocampal regions on both T2-weighted FLAIR and diffusion-weighted
sequences. The CT perfusion study and CT angiogram
demonstrated dramatic reduction in cerebral blood flow
and blood volume involving the entire left hemisphere, but
with relative symmetry of mean transit time, ruling out a
large vessel occlusion. No significant stenosis or occlusion
of the intracranial arteries was seen. Clinical resolution of
the aphasia and hemiparesis occurred within a few hours,
and correlated with normalization of perfusion to the left
hemisphere (detected by MR perfusion). The transient nature of the clinical paralysis correlated with the transient
perfusion deficit, suggesting that Todd’s paralysis may be a
cerebrovascular phenomenon related to functional cortical
M-57. Emergent Network Topology at Seizure Onset
in Humans
Mark A. Kramer, Eric D. Kolaczyk, and Heidi E. Kirsch;
Boston, MA; and San Francisco, CA
Epilepsy — the world’s most common serious brain disorder
— is defined by recurrent unprovoked seizures resulting
from complex interactions between distributed neural populations. Summary measures of these complex interactions are
needed to define patterns of seizure onset and propagation to
target focal therapy for partial epilepsy. In this study, macroscopic characteristics of emergent ictal networks were examined using intracranial ictal recordings from four patients.
For each seizure, a simple measure of linear coupling was
applied to all electrode pairs (⬎2400) to define networks of
interdependent electrodes during preictal and ictal time intervals. Network analysis was used to identify statistically significant global and local changes in network topology; at seizure onset global changes indicated diffuse breakdown in
coupling, and local changes indicated increased throughput
of specific cortical regions. A simple computational model of
the network suggests that preictal and ictal states correspond
to bursting and traveling wave activity, respectively. This
study demonstrates that network analysis techniques yield
summary measures of emergent coupling of highdimensional voltage changes at seizure onset. These measures
can identify discrete brain regions that may facilitate seizures,
and may therefore be potential targets for focal therapies.
Study supported by NINDS Career Development Award
K23 NS 047100 to HEK. ONR award N00014-06-1-0096
to EDK.
Annals of Neurology
Vol 62 (suppl 11)
M-59. Acute Clinical and EEG Responses to
Intravenous Benzodiazepines Predict Subsequent
Outcomes in Suspected Nonconvulsive Status
Allan Krumholz, Ana Sanchez, George Hart, and
Jennifer Hopp; Baltimore, MD
Although many patients with Nonconvulsive Status Epilepticus (NCSE) benefit from aggressive antiepileptic (AED)
treatment, not all recover even with the most aggressive therapies. We assessed acute responses to intravenous (IV) benzodiazepines (BDZ) for predicting subsequent outcome in
suspected NCSE.
We included all patients referred with suspected NCSE
tested with an acute IV BDZ protocol and correlated the
clinical and EEG responses to this BDZ test with their subsequent outcomes.
We identified 62 patients with suspected NCSE who received test doses of IV BDZ. 22 (35%) had a clinical response of improvement in consciousness, and 40 (65%) were
nonresponders. Of the clinical nonresponders 14 (35%) recovered consciousness, 22 (55%) survived, and 59% of survivors had poor functional outcomes. In contrast, all the
clinical responders (100%) survived, recovered consciousness,
and had good functional outcomes (p⬍.001). EEG improvement was also a predictor of subsequent recovery of consciousness and functional outcome (p⬍.05), but not of survival.
We demonstrate that acute clinical and EEG responses to IV
BDZs are predictive of subsequent outcome and survival in
patients with suspected NCSE and may be helpful for guid-
ing the management of such patients. Study supported by
Rosen Foundation for Clinical Neurological Research.
M-60. The Accumulation of 7S SNARE Complexes
(7SC) and Increase of SV2 in Hippocampal
Synaptosomes from Kindled Rats Is Blocked in
Levetiracetam-Treated Animals
Elena A. Matveeva, Thomas C. Vanaman,
Sidney W. Whiteheart, and John T. Slevin; Lexington, KY
The fusion of vesicle and plasma membranes, which mediates neurotransmitter release, is initiated by the formation
of a stable, ternary complex of attachment proteins,
SNAREs, that spans the two bilayers. Entorhinal kindling
is associated with an increase of 7SC that begins early in
the process and achieves a peak with full kindling; the increase is limited to the ipsilateral hippocampus despite progression to generalized seizures. Amygdalar, entorhinal, and
septal kindling are all associated with this accumulation of
7SC measured 30 days following completion of kindling.
The asymmetry is present 1 year post-amygdalar kindling,
suggesting that accumulation of 7SC is an altered molecular process associated with epileptogenesis that is permanent
and occurs regardless of stimulation pathway. Of eight
SNARE regulators measured 1 month post-kindling only
SV2, the primary binding protein in brain for the anticonvulsant levetiracetam (Lev), and NSF show significant alterations. Treatment with Lev but not its inactive enantiomer prevented kindling-induced SV2 accumulation.
Furthermore, Lev retarded the electrical and behavioral
concomitants of amygdalar kindling coincident with a
break in the accumulation of 7SC. Study supported by
UCB Pharma. Department of Veterans Affairs. National
Institutes of Health (HL56652).
M-61. Increased Seizure Sensitivity in Mice Lacking
the Regulatory Peptide Prokineticin 2
Alex G. Lee, Wang-Ping Hu, Chong-Wei Wen, Jia-da Li,
Michell Y. Cheng, and Qun-Yong Zhou; Irvine, CA
Prokineticin-2 (PK2) is a cysteine-rich neuropeptide that
has been shown to serve versatile functions, including modulation of neuronal excitability. Here we demonstrate that
PK2 and its receptor (PKR2) mRNA are dramatically induced after pilocarpine-induced seizure. Transient induction and upregulation were observed throughout the cortices, amygdala and hippocampus. Behavioral and EEG
monitoring indicated that mice deficient in PK2 displayed
lower latency time for seizures evoked with pilocarpine. We
also observed that PK2-deficient mice reached a faster kindling state after PTZ injection. In the amygdala, PKR2 receptor is partially co-localized with GABA-A receptor, suggesting a possible interaction between the GABA and the
PK2 system. Using electrophysiological studies, we found
that exogenous PK2 attenuated GABA-A receptor-evoked
currents. Taken together, our data indicate that PK2 may
play a physiological role in seizure induction, as well as
epileptogenesis, possibly through modulation of the
GABAergic system. Study supported by UC Discovery program.
M-62. Cerebrospinal and Serum Cytokine and
Chemokine Profiles in Idiopathic Intracranial
Samish Dhungana, Nicola M. Woodroofe, Basil Sharrack,
Peter Monk, Stephen J. Howell, and Sian Price;
Sheffield, United Kingdom
Objective: To identify cerebrospinal fluid (CSF) and serum
cytokine and chemokine profiles associated with idiopathic
intracranial hypertension (IIH).
Method: Antibody arrays were used to detect the relative expression of 42 cytokines and chemokines in the CSF and
serum of 9 IIH patients and 9 controls. The signals were
detected with a chemiluminescence imaging system and spots
in the membrane were semiquantified using Labworks software. The relative levels of cytokines were expressed as a percentage of the mean positive control value on each membrane. Results: In both patients and controls, multiple
cytokines were detected, most being present at relatively low
levels. MCP (monocyte chemotactic protein) -1, MCP-2,
MCP-3, MIP (macrophage inflammatory peptide)-1␦, MIG
(monocyte induced by gamma interferon), RANTES, IL-1␣,
leptin and IL-8 were more highly expressed. MCP-1 was increased in the CSF and MCP-2, MCP-3, IL-␣ and leptin
appeared higher in serum in IIH patients compared to controls.
Conclusion: This is the first report demonstrating differences
in cytokine expression in the serum and CSF in IIH patients
compared to controls. Since the pathogenesis of IIH is unclear, the heterogeneity of the cytokine expression reported
here may be of relevance. Study supported by Department of
Neurology, Royal Hallamshire Hospital, Sheffield, United
M-63. The Dopaminergic A11 Cell Group Affects
Neuronal Firing in the Trigeminocervical Complex –
Implications for Headache
Annabelle Charbit, Phillip R. Holland, and Peter J. Goadsby;
San Francisco, CA
Introduction: The dopaminergic A11 nucleus, located in the
posterior hypothalamus, provides the only known source of
descending dopaminergic innervation to the spinal grey matter. We investigated the effect of A11 stimulation and lesioning on trigeminovascular nociceptive transmission.
Methods Male Sprague-Dawley rats were anaesthetised with
propofol. Extracellular recordings were made in the trigeminal cervical complex (TCC), in response to electrical stimulation of the middle meningeal artery (MMA). Receptive
fields were characterised by mechanical noxious and innocuous stimulation of the ipsilateral ophthalmic dermatome. After recording baseline evoked firing the A11 was either stimulated or lesioned and the effect on TCC firing determined.
Results Stimulation of the A11 inhibited MMA (P ⬍ 0.05)
and noxious pinch (P ⬍ 0.001) evoked firing of neurons
from the TCC. This was reversed by the D2 receptor antagonist, eticlopride, for MMA (P ⫽ 0.284) and noxious pinch
(P ⫽ 0.266) inputs. Lesioning of the A11 facilitated evoked
firing of neurons from the TCC for MMA (P ⬍ 0.05) and
noxious pinch (P ⬍ 0.05), but not brush (P ⬍ 0.05) inputs.
Conclusion Neurons in the A11 may through a dopaminer-
Program and Abstracts, American Neurological Association
gic mechanism modulate trigeminovascular nociceptive traffic. Study supported by Brain Research Trust.
M-64. Migraine and Cerebral Vascular Malformations
(CVMs): A Comparative Study between Migraineurs
and Non-Migraineurs
Ken Ikeda, Ken-ichi Hosozawa, Hidetoshi Kashihara,
Kouzo Anan, Masaki Tamura, and Yasuo Iwasaki;
Tokyo, Japan
Background: It is unclear how frequent CVMs are found in
Japanese migraineurs. We studied prevalence of CVMs in
migraineurs and non-migraineurs on brain check-up (BC).
Methods: According to ICHD-II criteria, migraine with aura
(MA) or without aura (MO) was diagnosed. Brian MRI (T1,
T2, FLAIR) and MR angiography were performed in 3,954
adults on BC. Brain T2*, Gd-enhanced MRI and MR
venography were added in possible cases with CVMs.
Results: Migraine had 480 subjects (360 women and 120
men), 48 with MA and 432 with MO. A total of 2538 agematched controls without previous history of migraine were
selected. Eleven subjects (8 migraineurs and 3 controls) had
CVMs, including cavernous angioma (n⫽6), venous angioma (n⫽4) and arteriovenous malformation (n⫽1). Prevalence of CVMs (%) was higher in 1.67 in migraineurs than
0.12 in controls (p⬍0.001). Those of female (1.39) and
male (2.50) migraineurs were also higher percentage as compared to female (0.14) and male (0.10) controls (each
p⬍0.02 and p⬍0.001). MA subjects (6.25) had higher prevalence of CVMs than MO subjects (1.15) (p⬍0.01).
Conclusion: Our case-control study suggests the possibility
that CVMs is a comorbidity of migraine, especially in MA.
M-65. An Unusual Mechanism for Spinal Cord
Infarction – Case Report
Alexandra Popescu, Angela Lu, and Kathy Gardner;
Pittsburgh, PA
Epidural steroid injections are considered conservative management for intractable radicular pain. Overall, viewed as
safe and efficacious despite lack of randomized, placebocontrolled trials.
A 66 year old woman who underwent a cervical epidural
steroid injection for relief of intractable pain developed
postprocedure anterior spinal artery syndrome. Depomedrol
injection under fluoroscopy was given at C5-6. Within 45
minutes, patient developed acute onset flaccid quadriplegia
with dissociated sensory loss. No signs of blood on initial
MRI. Day 2 postprocedure MRI showed edema of the entire C-spine and restricted diffusion at C4-6 confirming the
likelihood of a cord infarct. At 3 weeks the patient remained quadriplegic with persistent hyperintensity on T2
and resolved cord swelling on MRI.
Conclusions: spinal cord infarction it is a rare but severe
complication of cervical epidural steroid injections despite
use of fluoroscopic guidance. In this case it was likely due
to an infarction of a major feeding segmental medullary
artery. Thus, the posterior placement of the needle in transforaminal injections is NOT necessarily safe despite avoiding the vertebral artery. Patients and practitioners need to
be aware that there are rare but devastating complications.
Annals of Neurology
Vol 62 (suppl 11)
M-66. Migraine in Mid-Life Predicts Brain Infarcts in
Old Age: A Longitudinal Population-Based MRI Study
Ann I. Scher, Siggi Sigursson, Larus Gudmundsson,
Gudny Eiriksdottir, Thor Aspelund, Mark van Buchem,
Vilmundur Gudnason, and Lenore J. Launer; Bethesda, MD;
Kopavogur, Iceland; Leiden, Netherlands; Raykjavik, Iceland;
and Reykjavik, Iceland
Objective: Migraine with aura has been associated with subclinical infarcts on MRI in a population-based cross-sectional
study (Kruit,2004). We consider whether mid-life migraine
predicts infarcts after an average 25 years of follow-up.
Methods: Study participants are the first 2,300 participants
in the Age Gene/Environment Susceptibility [AGES]Reykjavik Study. Migraine symptoms were assessed in the
Reykjavik study (mean age 50, mid-1970s). Migraine was
defined as three⫹ of: nausea/vomiting, unilateral, photophobia, visual disturbance during/just before headache, unilateral
numbness during/just before headache (Gudmundsson,
Brain MRI was acquired at a mean age of 76. The presence
of infarct-like lesions (cortical, sub-cortical, cerebellar, and
total) was measured by trained readers blinded to migraine
Results: Mid-life migraine prevalence was 11% (4% men,
16% women). Mid-life migraine predicted late-life cortical
infarcts (adjusted OR⫽1.84 [1.1 – 3.0]). Those reporting
symptoms of visual aura had increased risk of cortical
(OR⫽2.2 [1.2 – 3.9]), cerebellar (OR⫽1.79 [1.1 – 2.8]),
and total (OR⫽1.68 [1.1 – 2.5]) infarcts. Results were similar by sex and age (⬍⫽50, ⬎50) and after adjustment for
baseline CV risk factors.
Conclusions: Migrainous symptoms in midlife – particularly
visual disturbances – predict cortical and cerebellar infarcts
assessed an average of 25 years later. Study supported by National Institutes of Health contract N01-AG-12100, National Institute on Aging Intramural Research Program,
Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliamant).
M-67. A Randomized Trial of Mirror Therapy for
Lower Limb Phantom Pain
Brenda L. Chan, Richard Witt, Alexandra Charrow,
Robin Howard, Amanda Magee, Paul F. Pasquina,
Kenneth M. Heilman, and Jack W. Tsao; Bethesda, MD;
Washington, DC; and Gainesville, FL
Background: Mirror therapy reduces phantom limb pain
(PLP) in upper limb amputees but has not been examined in
lower limb amputees. Since the critical ingredient of mirror
therapy might be the induction of limb imagery, we conducted a sham-controlled trial of mirror versus imagery therapy for lower limb amputees with PLP.
Methods: Eighteen subjects with unilateral lower limb amputation and daily PLP were randomly assigned to three
treatment groups (n⫽6): mirror (M); covered mirror (CM);
mental visualization (MV). M and CM subjects moved their
intact foot while simultaneously imagining moving their amputated foot (15 minutes/day X 1 month). MV subjects
imagined moving their amputated foot only. Subjects reported PLP severity using a 10-cm visual analogue scale
(VAS) and episode number/duration daily.
Results: Baseline median VAS pain scores were similar in all
groups: M, 3.0cm (range: 1.5 – 9.3); CM, 3.1cm (1.5 –
5.0); MV, 4.4cm (2.2 – 7.8) (p⫽0.62). After 1 month of
therapy, median VAS pain scores were: M, 0.6cm (0 – 4.9);
CM, 3.4cm (0.4 – 6.9); MV, 5.9cm (2.3 – 7.8) (p⫽0.009).
The number/duration of PLP episodes decreased in 100%
(M), 17% (CM), and 33% (MV) of subjects.
Conclusions: Mirror therapy is highly effective for treating
lower limb PLP. Study supported by Military Amputee Research Program.
M-68. Early Treatment with Frovatriptan for
Menstrual Migraine: Improvements in Depression and
Positive Outlook Domains of the DAPOS Compared
with Patients’ Usual Care
Timothy Victor, and Richard E. White; Chadds Ford, PA
We evaluated the effectiveness of frovatriptan vs menstrual
migraineurs’ usual unspecified treatment at reducing comorbid levels of depression and anxiety, and improving positive
outlook. Subjects treated menstrual migraine (MM) with
their current/usual therapy (phase 1) and with frovatriptan
2.5 mg (phase 2) when the MM was mild (IHS grade 1).
Rescue frovatriptan was allowed. Data from the Depression,
Anxiety, and Positive Outlook Scale (DAPOS) were collected
at screening and following each phase and analyzed using
linear mixed-effects models. Mean⫾ standard deviation age
was 37.6⫾8.4 years, and patients experienced 13.5⫾6.8
MMs within the prior year. Uniformly small effect sizes and
high intraclass correlation coefficients suggest that depression, anxiety, and positive outlook scores were stable from
baseline to the end of phase 1 (all P⬎0.05; N⫽153). In
contrast, frovatriptan (N⫽145) was associated with significantly improved depression (P⫽0.008) and positive outlook
(P⫽0.028) scores relative to screening/completion of usual
care. This short-term study suggests that subjects’ emotional
status changes little with usual care, whereas early treatment
of MM with frovatriptan is effective at reducing levels of
depression while improving positive outlook. Study supported by Endo Pharmaceuticals Inc., Chadds Ford, PA;
Both authors are full-time employees of study sponsor, Endo
Pharmaceuticals Inc.
M-69. Phosphorylation of PKC␥ Kinase in Signaling
Visceral Nociception in Spinal PSDC Pathway
Jing Wu, Xuan Zhang, Qing Lin, and Li Fang;
Houston, TX; and Galveston, TX
The study is to investigate the role of phosphorylation of
PKC-␥ in processing nociceptive signaling in spinal PSDC
neurons during visceral pain. Recent clinical data indicated
that application of midline myelotomy to interrupt postsynaptic dorsal column (PSDC) pathway in clinics could effectively alleviate intractable visceral oncogenic pain. However, the role of phosphorylated PKC-␥ in visceral
nociception in spinal PSDC neurons remains unclear. By using behavioral, pharmacological, immunohistological and immunoblot approaches, we studied whether the phosphorylated PKC-␥ mediated nociceptive signaling in spinal cord
and in PSDC neurons in rats following visceral painful stimuli with intra-colonic injection of mustard oil (MO). Results
from immunoblots and immunostaining showed that MO
injection significantly activated the phosphorylation of
PKC-␥ in the lumbosacral spinal cord and in pre-labeled
PSDC neurons. Intrathecal application of an inhibitor of
PKC (NPC15473) reversed the visceral pain-induced behavioral alternations in rats. Pharmacological inhibition of PKC
activity blocked the visceral pain-induced neuronal transcription factor (phospho-c-Jun and c-fos) expression in spinal
cord. Our result suggests that the neuronal phospho-PKCtranscription factor cascades may contribute to the signal
transduction of visceral nociceptive neurotransmission in spinal PSDC pathway. Study supported by NIH.
M-70. Do Psychiatric Symptoms Have a Greater
Impact on Quality of Life in Early or Advanced
Parkinson’s Disease?
Karen E. Anderson, Ann Gruber-Baldini, R. Jake Mullins,
Paul S. Fishman, Stephen G. Reich, William J. Weiner, and
Lisa M. Shulman; Baltimore, MD
Objective: To assess the correlation between presence of psychiatric symptoms and quality of life (QoL) in early versus
advanced Parkinson’s disease (PD).
Background: Depression in PD is correlated with reduced
QoL, however the relative impact of psychiatric symptoms in
early versus advanced PD has not been studied.
Methods: Psychiatric symptoms and QoL were assessed
cross-sectionally with the Brief Symptom Inventory (BSI-18)
and the SF-12 Health Status Survey (Physical Health QoL).
Correlations between the BSI-18 and SF-12 scales were compared by Hoehn & Yahr (HY) stages, using R-to-Z transformation.
Results: 725 PD patients (64% Male, age 65.7 (⫾10.6)
years, HY 2.5(⫾1.0)) were studied. The correlation between
the severity of psychiatric symptoms and diminished Physical
Health QoL was greater in early than advanced PD, and this
achieved significance at HY stages 2, 2.5 and 5 (p⬍0.05).
Conclusions: Psychiatric symptoms have a greater impact on
quality of life in earlier than advanced stages of PD. This
may be explained by a relative shift of the impact of behavioral versus motor symptoms as PD progresses. Study supported by Rosalyn Newman Foundation; Anderson: Teva,
Boehringer-Ingelheim, Medtronic; Shulman: Teva, Kyowa,
Schwartz-Pharma, Boehringer-Ingelheim; Gruber-Balidini:
Nothing to disclose; Fishman: Pfizer, Forest, Ortho-McNeil,
Glaxo S-K, Boehringer-Ingelheim, Novartis, Allergan; Reich:
Teva, Cephalon, Guilford, GE; Weiner: EMD, Teva,
M-71. Reactivation of Research on a Family with
Perry Syndrome
Laura A. Brown, Donald B. Calne, A. J. Stoessl,
Susan M. Calne, Dennis W. Dickson, Christian W. Wider,
Willis H. Tsai, and Zbigniew K. Wszolek; Jacksonville, FL;
Vancouver, BC, Canada; and Calgary, AB, Canada
Perry syndrome is a rare neurodegenerative disorder associated with parkinsonism, depression, weight loss, and central
hypoventilation. Disease progression is rapid, with average
age of onset in the fourth decade and disease duration of 4 –
8 years. We are aware of only 9 kindreds across the world
that have been identified with this syndrome. We were fortunate to expand the family originally described by Perry et
al. (Arch Neurol 1975) and identify a new affected male
from this kindred. Clinical examination revealed significant
weight loss beginning at age 51, shortness of breath at rest,
fatigue, and loss of energy. On examination at age 53 there
was mild postural and kinetic hand tremor bilaterally, reduced arm swing on the right side, and micrographia. Polysomnography showed the presence of severe central sleep apnea and tachypnea, although there was no evidence of
significant nocturnal hypoventilation or oxygen desaturation.
It was hypothesized that there was dysfunction in the ventilatory control system resulting in dyspnea. The mechanisms
Program and Abstracts, American Neurological Association
underlying respiratory symptoms in Perry syndrome remain
unclear. Further studies are needed to better characterize this
disorder and find genetic abnormalities. Study supported by
NIH / NINDS Morris K. Udall Center of Excellence for
Parkinson’s Disease Research (P50 NS40256).
M-72. What Motor Symptoms Have the Greatest
Effect on Patient-Reported Disability in Parkinson’s
Mackenzie Carpenter, Jake Mullins, Karen E. Anderson,
Paul S. Fishman, Stephen G. Reich, William J. Weiner, and
Lisa M. Shulman; Baltimore, MD
Objective: To assess the relative contributions of cardinal
motor symptoms on disability in Parkinson’s disease.
Background Previous research has demonstrated a strong
correlation between disease severity and disability in PD.
However, the relative impact of the cardinal motor symptoms on disability is not well understood.
Methods 839 PD patients (mean UPDRS 41.7 (20.7)) completed the OARS disability scale. Disease severity was assessed with Total UPDRS. UPDRS composite subscores
were created for tremor, rigidity, bradykinesia, and gait/postural instability. Pearson’s correlations were tabulated to
compare values with significance at p ⬍ 0.01.
Results Three of the four cardinal motor symptoms correlated with severity of disability (p ⬍ 0.0001). The strongest
correlation was between disability and gait/postural instability (r ⫽ 0.720) followed by bradykinesia (r ⫽ 0.544), and
rigidity (r ⫽ 0.384). No significant correlation was found
between disability and tremor (r ⫽ 0.014, p ⫽ 0.689).
Conclusions Gait and balance impairment have the greatest
effect on disability. Bradykinesia and rigidity are also significant determinants, but tremor does not correlate with disability in PD. Study supported by The Rosalyn Newman
M-73. Late-Onset Tay-Sachs (LOTS) Disease: Scoring
Disease Severity
Deborah Elstein, Gregory M. Pastores, Ari Zimran,
Edwin Kolodny, and Isabelle Korn-Lubetzki; Jerusalem, Israel;
and New York, NY
LOTS is an ultra-rare lysosomal storage disorder. Neurologic
manifestations include progressive proximal muscle weakness,
fasciculations, dysarthria, incoordination, and tremor. Psychiatric manifestations and cognitive dysfunctioning may develop. Onset is in late teens/early adulthood but diagnosis is
often missed. Oral substrate reduction and chaperone therapy are potential options under investigation. Our purpose is
to develop a LOTS severity scale to track disease progression
and/or therapeutic interventions. Six disease-specific domains
are evaluated: cerebellar dysfunction, psychiatric disturbances, bulbar signs, upper and lower limb muscle strength,
and activities of daily living. Each domain is graded 0-5
points: 0 ⫽ normal functioning, 5 points ⫽ worst case. Total score 0 points⫽normal; 1-10 points⫽mild; 11-20⫽moderate; 21-30 points⫽severe. Twelve Ashkenazi Jewish patients were evaluated; mean age ⫽ 41.1 (range: 25-66) years;
all have genotype: G269S/4 bp insertion exon 11 (1278insTATC); all have residual hexosaminadase A levels (⬍10%
normal). Initial total Severity Score in six patients was 4-10
points (mild); five patients had 12-19 points (moderate), and
one patient had 23 points (severe). We suggest that this userfriendly scale transmits complex information useful in assessing changes in disease status.
Annals of Neurology
Vol 62 (suppl 11)
M-74. Lengthened Duration of Benefit from
Botulinum Toxin Injections for Spasticity
Chandler E. Gill, Henry M. Taylor, CaraLee R. Blair, and
David Charles; Nashville, TN
In the setting of an outcomes trial investigating the functional benefit of spasticity treatment on 20 adults with profound intellectual disability living in a public developmental
center, we report a clinical experience in which a subgroup of
patients underwent a series of regular BTX-A injections and,
after the last, had dramatically prolonged reduction in tone.
The three patients in question underwent 5.33⫾1.53 injections every three months before experiencing relief for
21.65⫾6.24 months. They were injected in different muscles
(hip adductors, finger flexors, biceps and brachioradialis) and
did not share any characteristics previously suggested to predict this response in CD/ST. Duration of spasticity
(39.0⫾1.6 years in subgroup versus 35.1⫾15.2 years for the
population, p⫽0.74), units injected per pound body weight
(3.85⫾2.08 for subgroup versus 3.92⫾1.48 for population,
p⫽0.92), and quality of physical and occupational therapy
(all patients received regular, dynamic therapy) were not different between groups. Expanded trials are necessary; in particular, analyses of existing databases of patients treated with
BTX-A for spasticity may illuminate the characteristics and
dosing strategies that result in a prolonged effect. Study supported in part by Medtronic, Inc. and Allergan, Inc.; Dr.
Charles has received honoraria, research support and consulting fees from Medtronic, Inc. and Allergan, Inc.
M-75. Leucine-Rich Repeat Kinase 2 Associates with
Lipid Rafts
Taku Hatano, Shin-ichiro Kubo, Yoshikuni Mizuno, and
Nobutaka Hattori; Bunkyo, Tokyo, Japan
Objective: We explore the localization of Leucine-Rich Repeat Kinase 2 (LRRK2) in mouse brain and cultured cells
and investigate the effects of pathogenic mutations on the
biochemical properties.
Background: Since LRRK2 is implicated in the pathogenesis
of Parkinson⬘s disease (PD) in conjunction with both
␣-synuclein and tau, characterization of LRRK2 should enhance our understanding of the pathomechanism of the nigral neuronal cell death in PD.
Methods: We performed double-labeled immunocytochemistry for both LRRK2 and several markers of intracellular organelles. For biochemical analysis, we fractionated cultured
cells into membrane and cytosolic fractions. To test whether
LRRK2 binds to lipid rafts, we solubilized cells or mouse
synaptosomes in 1% Triton X-100 at 4°C and separated the
remaining membranes on a sucrose density gradient.
Results: LRRK2 localizes to the Golgi apparatus, plasma
membrane, and synaptic vesicles. The membrane association
of LRRK2 resists solubilization by detergent, indicating its
association through lipid rafts. Unexpectedly I2020T mutant
LRRK2 does not alter its localization, and associates with
lipid rafts in a similar way to wild-type.
Conclusions: LRRK2 associates with lipid rafts and the mutations seem to interfere with its normal function on lipid
rafts. Study supported by grants from the Ministry of Education, Science, Sports and Culture of Japan. The Fund for
‘Research for the Futre’ program from the Japan Society for
the Promotion of Science.
M-76. Rotigotine Transdermal Patch Is Effective in
the Treatment of Idiopathic RLS: Results of a 6-Month,
Multicenter, Double Blind, Placebo-Controlled Trial
Wayne Hening, Richard Allen, Phiilip M. Becker,
Richard K. Bogan, June M. Fry, Joerg Keffel,
David B. Kudrow, Kurt W. Lesh, William G. Ondo,
Ervin Schollmayer, Peter Vrooman, Arthur Walters, and
John W. Winkelman; Dallas; Columbia; Lafayette Hill;
Monheim, Germany; Santa Monica; Colorado Springs;
Houston; Winston-Salem; Edison; Brighton; and Baltimore
hyposmia in PD is more robustly correlated with hippocampal than striatal dopaminergic denervation. Study supported
by NS019608.
Objective: To evaluate efficacy and safety of rotigotine transdermal patch in patients with moderate to severe idiopathic
Methods: Multicenter, randomized, double-blind, placebocontrolled, 5-arm parallel-group trial with 4 fixed doses of
rotigotine 0.5-3mg/24h (2.5-15cm2). IRLS-sum-score and
the CGI item-I are the co-primary efficacy parameters.
Results: 505 patients (52 ⫾ 13 years, 61% female) were randomized at 58 sites in the US. The mean baselines scores
were: IRLS 23.3⫾5.0 and CGI 4.7⫾0.7. Improvement net
effects versus placebo after 6 months treatment were -2.2⫾1.2,
2.3⫾1.2, -4.5⫾1.2(p⬍0.001), and -5.2⫾1.2(p⬍0.001) in the
IRLS and -0.35⫾0.19, -0.32⫾0.19, -0.65⫾0.19(p⬍0.001)
and -0.90⫾0.19(p⬍0.001) in CGI item I for rotigotine 0.5,
1, 2, and 3mg/24h, respectively.
At least 1 adverse event was reported by 88 % of patients.
Most common side effects were application site reaction(27.2%), nausea(21.5%), headache(17.6%) and somnolence(12.6%). AEs were usually mild to moderate in intensity
and transient.
Conclusion: Therapy with rotigotine transdermal patch in
doses of 2 and 3 mg/24h over a period of 6 months resulted
in a statistically significant and clinically relevant reduction in
the IRLS-sum-score and CGI item-I compared to placebo and
was well tolerated. Study supported by Schwarz Pharma INC.;
They are paid investigators.
Early efficacy of ropinirole 24-hour in patients with PD was
The EASE PD-Adjunct study (101468/169) randomized patients with PD not optimally controlled with L-dopa to adjunctive ropinirole 24-hour (n⫽202) or placebo (n⫽191),
once-daily, for 24 weeks. Initial dose: 2.0mg/day, titrated to
a maximum of 24.0mg/day. Once titrated to 8.0mg/day, and
for each subsequent increase, L-dopa dose reduction was required. Primary endpoint: mean change from baseline in
daily “off” time at Week 24 last observation carried forward
(LOCF). Also assessed: mean change in “on” time without
troublesome dyskinesia.
There was a significantly greater reduction in “off” time with
ropinirole 24-hour, versus placebo at Week 2 observed case
(OC) (adjusted mean treatment difference [AMTD]: – 0.7
hours; 95%CI:–1.1,– 0.2; p⫽0.0029) and at each visit to
Week 24 LOCF (AMTD: –1.7 hours; 95%CI:–2.3,–1.1;
p⬍0.0001). Significantly greater improvements compared
with placebo were seen with ropinirole 24-hour in “on” time
without troublesome dyskinesia at Week 2 OC (AMTD: 0.4
hours; 95%CI:0.01,0.88; p⫽0.0444) and Week 24 LOCF
(AMTD: 1.5 hours; 95%CI:0.9,2.1; p⬍0.0001).Ropinirole
24-hour demonstrated a significant treatment benefit over placebo as early as Week 2, when used as an adjunct to L-dopa.
Study supported by GlaxoSmithKline and Skye Pharma; B
Hersh has consulted for: GlaxoSmithKline, Novartis, Advisory
Board: Solstice Pharmaceuticals, Teva Neuroscience, Forest
Pharmaceuticals, Clinical Research: GlaxoSmithKline, SkyePharma. GlaxoSmithKline and SkyePharma: research support
to participate in clinical trials with ropinirole. Novartis: support for small patient education program for Parkinson’s disease; N Stover has received compensation for speaking engagement from GSK, Valeant Pharma, and Novartis and received
research support (trial grant) from Boehringer Ingelheim (BI),
GSK, Novartis, Eisai, Merck KGaA and Schwarz; L Elmer has
been a speaker for GlaxoSmithKline, Boehringer Ingelheim,
Schwarz Pharma, Novartis, Eisai, Pfizer and Valeant. He has
been a scientific advisory board member for Teva.
M-77. Selective Hyposmia in Parkinson Disease Is
More Robustly Associated with Hippocampal Than
Striatal Dopaminergic Denervation
Priyantha Herath, Satyanarayana Gedela, Larry Ivanco,
Robert Moore, and Nicolaas Bohnen; Bethesda, MD;
Pittsburgh, PA; and Ann Arbor, MI
Olfactory dysfunction is common in early Parkinson’s disease
(PD). It is unknown whether hyposmia in PD represents a
primary sensory dysfunction or a cognitive olfactory deficit.
To investigate the relationship between selective hyposmia
and nigrostriatal versus hippocampal dopaminergic denervation in patients with PD we used the University of Pennsylvania Smell Identification Test (UPSIT) and C11-␤-CFT
dopamine transporter (DAT) PET and brain MRI on 27 PD
patients - all nonsmokers, (H&Y stages I-III; 8F/19M; age
59.2⫾10.8). Regions of interest (striatum, hippocampus)
were drawn on the MR images and transferred to PET images. PD-selective hyposmia measures from the UPSIT
(UPSIT-3) and ratio between PD selective and non-selective
odors (olfactory ratio) were calculated. Correlation coefficients between the regional DAT binding potentials and the
smell measures showed that the correlation of hippocampal
DAT with total UPSIT was R⫽0.53 (P⫽0.002), with PDUPSIT-3 was R⫽0.60 (P⫽0.0007), and with the olfactory
ratio was R⫽0.67 (P⬍0.0001). The corresponding correlations of striatal DAT were R⫽0.37 (P⫽0.04) for total UPSIT, R⫽0.52 (P⫽0.005) for UPSIT-3 and R⫽0.54
(P⫽0.004) for olfactory ratio. CONCLUSIONS: Selective
M-78. Early Efficacy of Adjunctive Ropinirole 24Hour in Patients with Advanced PD
Bonnie P. Hersh, Natividad P. Stover, Lawrence W. Elmer,
and Nancy L. Earl; Boston, MA; Birmingham, AL;
Toledo, OH; and Research Triangle Park, NC
M-79. Adjunctive Ropinirole 24-Hour Leads to
Continued Improvement in “Off” Time Despite
Increasing PD Severity
Bonnie P. Hersh, Natividad P. Stover, Stuart H. Isaacson,
and Nancy L. Earl; Boston, MA; Birmingham, AL;
Boca Raton, FL; and Sanders, NC
The relationship between the efficacy of ropinirole 24-hour
and disease severity at baseline was evaluated in patients with
advanced PD.
The EASE-PD adjunct study (101468/169) randomized patients with PD not optimally controlled with L-dopa to adjunctive treatment with ropinirole 24-hour (n⫽202) or placebo (n⫽191), once daily for 24 weeks. Initial dose: 2.0mg/
day, titrated to a maximum of 24.0mg/day. At 8.0mg/day,
and at each subsequent increase, L-dopa dose reduction was
required. Primary endpoint: mean change in daily “off” time
Program and Abstracts, American Neurological Association
at Week 24 last observation carried forward (LOCF). A posthoc analysis of covariance was conducted to evaluate any relationship between the magnitude of treatment effect, in
terms of daily “off” time, and baseline UPDRS motor score
(part III).
Ropinirole 24-hour significantly reduced “off” time, versus
placebo, at Week 24 LOCF (adjusted mean treatment difference: –1.7:95%CI:–2.3,–1.1;p⬍0.0001). There was a significant interaction between treatment effect and baseline
UPDRS motor score (p⫽0.0444): the magnitude of the
treatment difference between ropinirole 24-hour and placebo
for change in “off” time increased with increasing baseline
UPDRS motor score. As patients’ PD increases in severity,
ropinirole 24-hour provides a greater reduction in “off” time.
Study supported by GlaxoSmithKline and Skye Pharma; B
Hersh has consulted for: GlaxoSmithKline, Novartis, Advisory Board: Solstice Pharmaceuticals, Teva Neuroscience,
Forest Pharmaceuticals, Clinical Research: GlaxoSmithKline,
SkyePharma. GlaxoSmithKline and SkyePharma: research
support to participate in clinical trials with ropinirole. Novartis: support for small patient education program for Parkinson’s disease. N Stover has received compensation for
speaking engagement from GSK, Valeant Pharma, and Novartis and received research support (trial grant) from Boehringer Ingelheim (BI), GSK, Novartis, Eisai, Merck KGaA
and Schwarz; S Isaacson has received grant and honoraria
support from GSK for research, consultant, and speaker activities; N Earl is an employee of GlaxoSmithKline.
M-80. Impaired Thalamic-Prefrontal Connectivity in
Patients with Idiopathic Dystonia
Leonardo Bonilha, Paulien M. de Vries, Paul S. Morgan,
Chris Rorden, Nada Besenski, Kenneth J. Bergmann, and
Vanessa K. Hinson; Columbia, SC;
Nottingham, United Kingdom; Groningen, Netherlands; and
Charleston, SC
Background: Abnormal white matter (WM) fractional anisotropy and mean diffusivity are present in patients with
idiopathic dystonia (ID) in the thalamus and prefrontal cortex. These suggest that disrupted connectivity is part of the
mechanism underlying dystonia, but does not discriminate
which tracts are affected. To test the hypothesis that impaired connectivity between the thalamus and the prefrontal
cortex is a common abnormality in ID, we employed a
three-dimensional voxel-wise analysis of MRI WM tractography, focusing on fibers from the thalamus to the middle
frontal gyrus. Methods: We reconstructed WM tracts from
the thalamus to the middle frontal gyrus from 7 subjects
with ID (5 with cervical dystonia, 2 with DYT1 negative
generalized dystonia). The statistical representation of the
thalamic prefrontal connectivity from ID patients was compared with results from 7 matched controls, with correction
for multiple comparisons (p⬍0.05). Results: ID patients exhibited less thalamic-prefrontal connections bilaterally, compared to controls. Diminished connectivity was observed to
be maximal underlying the middle frontal gyrus. Conclusion:
These results confirm that ID is related to microstructural
WM abnormalities, but expands the previous knowledge by
demonstrating that specifically thalamic-prefrontal connections are disrupted in ID.
Annals of Neurology
Vol 62 (suppl 11)
M-81. Treatment of Nocturnal Symptoms of
Parkinson’s Disease Using Rotigotine Transdermal
K. Ray Chaudhuri, Joseph Jankovic, Claudia Trenkwalder,
and Babak Boroojerdi; London, United Kingdom;
Houston, TX; Kassel, Germany; and Monheim, Germany
Transdermal delivery of rotigotine (Neupro®), provides stable 24-hour plasma levels. The effects of rotigotine treatment
on nocturnal and early morning symptoms (motor function,
overall quality of sleep, nocturia and daytime sleepiness) in
advanced-stage PD were examined in three double-blind,
placebo-controlled trials and one open-label trial.
A total of 1032 patients were analyzed (rotigotine: n⫽727,
placebo: n⫽305). Mean changes from baseline were assessed
using the 15-item PD Sleep Scale (PDSS), Epworth Sleepiness Scale (ESS) and UPDRS Part IV. In three double-blind
trials lasting up to 6 months, mean change in “off” to “on
without troublesome dyskinesia” at awakening improved in
rotigotine-treated patients by 24.1%, 15.6%, and 25.5%; in
placebo-treated patients improvement was 8%, 4.3% and
After 3 months of open-label treatment, mean change (baseline⫽9.4) in overall PDSS score (including nondopaminergic therapy responsive domains) was 11.6
(P⬍.001). ESS sum score improved from 7.3 to 6.1. Fiftyeight percent of patients with prior sleep disturbances were
symptom-free, and the frequency of nocturia decreased from
2.12 to 1.41.
Rotigotine transdermal patch improved nocturnal and earlymorning PD symptoms without increasing daytime sleepiness, likely due to beneficial effects of dopaminergic therapy
on nocturnal PD symptoms. Study supported by
SCHWARZ Pharma; Dr. Babak Boroojerdi is an employee
of Schwarz Biosciences.
M-82. Blepharospasm and the Experimental
Modulation of Cortical Excitability in Primary and
Secondary Motor Areas
Gottfried Kranz, Ejaz Shamim, Peter Lin, and Mark Hallett;
Bethesda, MD
Blepharospasm (BSP) is a common form of focal dystonia,
but the underlying pathophysiological mechanisms are still
obscure. Studying seven patients with BSP, we used repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (MC), pre-and supplementary cortex
(PMC, SMA) and the anterior cingulate (AC) in inhibitory
modes: low frequency (0.2Hz) rTMS and continuous theta
burst stimulation cTBS. Furthermore, we applied transcranial direct stimulation (tDCS). Each patient received ten different stimulation combinations. Before and after each stimulation, a blinded investigator rated BSP symptoms,
measured the blink reflex recovery curve (BRR) and the patients rated their symptoms subjectively.
The most effective combination was rTMS over the AC.
Symptoms of BSP (number of blinks, sustained eye closure,
time of eye closure) were significantly reduced, clinically by
33⫾9%, subjectively by 22⫾5% and electrophysiologically
by 9⫾5%. The inhibition of the frontal areas (AC and
PMC) was more effective than inhibition of the motor-and
premotor cortex. rTMS was more effective when compared
to tDCS and cTBS. Clinical improvement by functional inhibition of the AC suggests that hypersensitivity of the AC is
either directly or indirectly involved in the pathophysiology
of BSP. Study supported by NIH, NINDS.
M-83. How Prevalent Are Non-Motor Symptoms in
Parkinson’s Disease?
Stephanie L. Lessig, David D. Song, Evelyn S. Tecoma, and
Jody P. Corey-Bloom; San Diego, CA
We examined the prevalence of non-motor symptoms
(NMS) in Parkinson’s disease (PD) as a function of disease
severity and clinical subtype. Ninety-two veterans with a
clinical diagnosis of idiopathic PD underwent structured
evaluation, including Hoehn & Yahr (HY) staging, United
Parkinson’s disease Rating Scale (UPDRS), Epworth Sleepiness Scale (ESS), Mini-Mental State Examination (MMSE),
and NMSQuest (a 30-item self-completed non-motor symptoms questionnaire for PD). We found that NMS were
highly prevalent and increased with disease severity
(p⫽0.005). Genitourinary and gastrointestinal symptoms
predominated in this VA population; however, difficulty remembering (56%) was also highly prevalent. Statistically significant correlations were found between NMS and the UPDRS I (p⬍.001), UPDRS II (p⬍.001), UPDRS III
(p⬍.001), total UPDRS (p⬍.001), and MMSE (p⫽.012)
scores. NMS appeared to be more prevalent in PIGD as
compared to TD variants; however, this significance disappeared when controlling for disease severity. We conclude
that NMS in PD are frequent at all disease stages but increase in prevalence as motor disease progresses. In addition,
although NMS appear to be more frequent in subjects with
the PIGD clinical subtype, it may be that this increased frequency is related to advanced disease severity. Study supported by VA Medical Center.
M-84. Task Specific Influences of Parkinson’s Disease
on the Striato-Thalamo-Cortical and CerebelloThalamo-Cortical Motor Circuitries
Mechelle M. Lewis, Cara G. Slagle, Andrew B. Smith,
Young Truong, Ping Bai, Martin McKeown,
Richard Mailman, Aysenil Belger, and Xuemei Huang;
Chapel Hill, NC; and Vancouver, BC, Canada
The motor deficits in Parkinson’s disease (PD) have been
primarily associated with internally (IG), but not externally
(EG), guided tasks. The involved mechanisms underlying
this were studied in a monozygotic twin pair discordant for
PD as confirmed clinically and by SPECT. Each twin performed EG and IG right-hand finger sequential tasks. During the EG task, there were no differences between the twins
in bilateral basal ganglia-cortical (BGC: globus pallidus/putamen, thalamus, supplementary motor area, and primary
motor cortex) pathways, either basally or after levodopa,
whereas the PD-twin had relatively increased activity in the
cerebellar–cortical (CC: cerebellum, thalamus, somatosensory
cortex, and lateral premotor cortex) pathways basally that
was normalized by levodopa. During the IG task, the PDtwin had less activation than the non-PD-twin in bilateral
BGC and CC pathways. Levodopa normalized hypoactivation in the contralateral BGC pathway, but “over-corrected”
activation in the ipsilateral BGC and bilateral CC pathways.
This first fMRI study of twins discordant for PD support the
hypothesis that BGC and CC pathways are task-specifically
influenced by PD. The levodopa-induced “over-activation”
of BGC and CC pathways, and its role in long-term compensatory changes, merit further exploration. Study supported in part by NIH grants AG21491 (XH), MH058251
(AB), RR00046 (GCRC), a Parkinson’s fellowship grant
from His Excellency Sheik Abdulmohsin Al-Sheikh (MML),
a National Parkinson’s Foundation Center of Excellence
grant (MJM), and the Foundation of Hope (AB, XH).
M-85. Transdermal Rotigotine in Combination with
Levodopa in the Treatment of Advanced-Stage
Parkinson’s Patients
Peter LeWitt, Kelly Lyons, Rajesh Pahwa, and
Babak Boroojerdi; Royal Oak, MI; Kansas City, KS; and
Monheim, Germany
This trial investigated efficacy and safety of adjunctive
rotigotine (Neupro®), a transdermal D3 /D2 /D1 dopamine
agonist, in advanced Parkinson’s disease (PD).
PD subjects inadequately controlled with levodopa were
randomized to placebo or rotigotine (8mg/24h or 12mg/
24h). This double-blind, multicenter trial included a 5-week
titration followed by a 24-week maintenance phase. The primary efficacy parameter was reduced “off” time.
Of 351 randomized subjects (n⫽120 rotigotine 8mg/
24h; n⫽111 rotigotine 12mg/24h; n⫽120 placebo), 260
(74%) completed the maintenance phase. Compared to
baseline evaluations, placebo-treated subjects had an adjusted mean decrease of -0.9 hours in “off” time compared
with -2.7 hours and -2.1 hours in the 8mg/24h and 12mg/
24h rotigotine groups, respectively (P⬍0.001 and
P⫽0.003). Neither group experienced an increase in time
“on with troublesome dyskinesias”. Patient outcomes with
rotigotine were not impacted by gender, baseline H&Y
stage, age or duration of the disease. The most common
AEs with rotigotine were application site reactions, somnolence, nausea, and dizziness.
Transdermal rotigotine as adjunctive therapy to levodopa
showed clinically relevant and statistically significant reductions in “off” time. There was no increase in “on time with
troublesome dyskinesias”. Rotigotine was generally safe and
well tolerated. Study supported by SCHWARZ Pharma; Dr.
Babak Boroojerdi is an employee of Schwarz Pharma, Dr.
Peter LeWitt has received consulting fees from Schwarz
M-86. Abnormal Oscillatory Cortical Activity during
Sequential Finger Movement in Focal Hand Dystonia
Peter T. Lin, Ou Bai, Masao Matsuhashi, Yohei Tamura,
Sherry Vorbach, and Mark Hallett; Bethesda, MD
Objective: To identify electroencephalographic spatiotemporal abnormalities associated with sequential finger movement
in focal hand dystonia.
Background: Focal hand dystonia is associated with involuntary postures and impaired motor control. Deficient inhibition is a consistent pathophysiological finding. Evidence for
bilateral physiological abnormalities despite unilateral symptoms supports the concept of an endophenotypic trait. Unilateral sequential finger movements in normal subjects are
associated with task-related spectral power decreases in alpha
and beta frequency bands that are predominantly contralateral. The asymmetric activation may represent active interhemispheric inhibition of the right hemisphere during movement.
Methods: 64-channel EEG was collected from 15 focal hand
dystonia patients and 13 normal volunteers during righthanded sequential movement. Mean error rate was unchanged across groups. Subjects did not manifest dystonic
symptoms. Whereas task-related power decreases were predominantly contralateral in normal volunteers, patients with
focal hand dystonia demonstrated bilateral power decreases
with larger activation in the ipsilateral hemisphere. These
changes were specifically seen in the alpha band at 11-13 Hz.
Conclusions: The bilateral power decreases in patients with
focal hand dystonia is consistent with bilateral abnormalities
Program and Abstracts, American Neurological Association
in sensorimotor functioning and may suggest a deficit in interhemispheric inhibition during unilateral movement.
M-87. Features Associated with Parkin Mutation
Status in Probands in the Core-PD Study
Karen Marder, Lorraine Clark, Helen Mejia-Santana,
Elan Louis, Cynthia Comella, Amy Colcher, Danna Jennings,
Martha Nance, Susan Bressman, William Scott,
Caroline Tanner, Susan Mickel, Howard Andrews,
Cheryl Waters, Stanley Fahn, Janice Fraser, Llency Rosado,
Lucien Cote, Elise Caccappolo, Steven Frucht, Blair Ford,
Kevin Novak, Joseph Friedman, Ronald Pfeiffer,
Ming-Xin Tang, and Ruth Ottman; New York, NY;
Chicago, IL; Philadelphia, PA; New Haven, CT;
Minneapolis, MN; Durham, NC; Marshfield, WI;
Providence, RI; Evanston, IL; TN; and Sunnyvale, CA
Objective: To determine the features associated with parkin
mutations in PD cases in the CORE PD study. Methods:
Information on demographic and clinical features was collected on 515 cases with age at onset (AAO) ⱕ 50 at 8
centers. Mutations were detected by direct sequencing and
screening for exon deletions and duplications. Results: Current age averaged 52.4 (9.0) years, AAO 41.5 (7.2) years,
education 15.4 (3.0) years, MMSE 28.7 (2.3). 13.5% of
cases reported a first-degree family history of PD (FHPD).
86% were white, 2.1% African-American, 6.4% Hispanic
and 1.9% Asian. 61% were men. 9.1% of cases (47/515) had
mutations; 70% heterozygous. Mutation frequency was inversely associated with AAO: ⬍20 40% (4/10), 20-29
30.4% (7/23), 30-39 11.2% (15/134), and 40-50 6.0% (21/
348) (p⬍0.001). In a logistic model, mutations were also
associated with ethnicity (African-Americans: OR 6.7, 95%
CI 1.7-26.5, Hispanic: OR 4.1, 95% CI 1.4-11.5, compared
to whites) and FHPD (OR 3.1, 95% CI 1.4-6.8). MMSE,
UPDRS, and levodopa use were not associated with mutation status. Findings were similar in heterozygotes alone.
Conclusion: Among PD patients with AAO ⱕ50, AAO,
FHPD, and ethnicity are associated with parkin mutations.
Study supported by NS36630. Parkinson’s Disease Foundation, NINDS repository (
M-88. Effect of Depression Remission Status on
Physical Disability in Parkinson’s Disease: A
Longitudinal Cohort Study
Laura Marsh, and James R. Williams; Baltimore, MD
Major and non-major depressive disorders affect nearly 50%
of patients with Parkinson’s disease (PD). Despite their negative effect on physical disability, these depressive disturbances are frequently unrecognized or undertreated. Longitudinal consequences of persistent depressive symptoms have
not been studied. This study used generalized estimating
equations to determine the longitudinal effects of depression
remission status on PD-related physical disability, measured
by the Northwestern Disability Scale (NWDS), in a research
cohort of 137 PD patients followed for up to 6 years. At
baseline, mean (SD) age⫽67.1 (10.5) years and PD Duration⫽9.4 (6.9) years); there were 36 diagnoses of Symptomatic Depression (SD), 20 with Remitted (asymptomatic) Depression (RD), and 51 with No Depressive diagnosis (ND).
Compared to subjects with ND, diagnosis of SD at any
follow-up visit was associated with greater physical disability
(␤⫽-3.8, p⬍.001). There were no differences in NWDS
scores between RD and ND (␤⫽1.8, ns). Motor-related disability is greater in patients with untreated depressive distur-
Annals of Neurology
Vol 62 (suppl 11)
bances. These results underscore the importance of incorporating strategies to monitor depression remission status in
PD patients as part of routine neurological care. Study supported by NIH-P50-NS038377.
M-89. Pathological Gambling and Compulsive
Shopping in Parkinson’s Disease: Clinical Associations
Monica E. Mazda, Kathleen M. Shannon, Wenqing Fan, and
Sue E. Leurgans; Chicago, IL
Compulsive behaviors have distressing consequences in the
lives of Parkinson’s Disease patients. We investigated the frequency and associated clinical features of pathological gambling and shopping in 126 men and 74 women with Parkinson’s disease (PD). PD patients were surveyed using the
South Oaks Gambling Screen and a compulsive shopping
screen. We collected demographic, treatment and disease severity measures. Descriptive statistics, Fisher Exact test, and
univariate ordinal logistic regression (significance ␣⫽0.05)
were used to analyze the data. 6% had a lifetime prevalence
of pathological gambling and 5 subjects currently had pathological gambling. There were 4 compulsive shoppers, 2 of
whom also gambled compulsively. All pathological gamblers
were men (p⫽0.0013). Young PD onset (p⫽0.045) and
young current age (p⫽0.041) were associated with gambling
severity, but were no longer significant when gender was included in the model. There was no association with medication type (dopamine agonist or levodopa), but there was a
trend toward higher agonist dose in pathological gamblers
(p⫽0.15). Men with PD are more likely than women with
PD to be pathological gamblers and there is a trend toward
higher agonist doses in current pathological gamblers. Study
supported by Parkinson’s Disease Foundation; Consulting
fees from Valeant and Prestwick; Research funding from
Schering, Titan, Kyowa and Schwarz.
M-90. Is Depression Greater in Young-Onset or LateOnset Parkinson’s Disease?
Eric McDade, Karen E. Anderson, Jake Mullins,
Ann Gruber-Baldini, and Lisa M. Shulman;
Baltimore, MD
Objective: To compare the prevalence and severity of depression in young versus late-onset PD.
Background: Young versus late-onset PD is likely to represent different PD subtypes and to have different emotional
Methods: A cross-sectional analysis of young-onset (PD diagnosisⱕ 47yrs) and late-onset (diagnosisⱖ 75 years) patients was performed using our clinic database, comparing
prevalence and severity of depression and Global Psychiatric
Symptom Index (GSI) on the Brief Symptom Index Scale
Results: 76 patients (32 young, 44 late) were evaluated
(H&Y 2.1(0.8) and 2.8(1.0); PD duration 3.1(3.9) and
2.8(2.5) years respectively). The prevalence of depression
and global psychiatric burden was greater in late-onset PD
(41% vs 34%, 48% vs 44%). There were no significant
differences between the groups in mean depression severity
(t scores⫽ 51(8.9) vs 53(11.4) or GSI 54(8.8) vs 54(10.9).
Conclusion: Depression and psychiatric symptoms are more
common in late-onset PD, but there was no difference in
the mean severity of psychiatric symptoms in early versus
late-onset PD.
M-91. Fetal Transplant Surgery: Effect on Global
Ratings by Reviewing Baseline Video Taken 12 Months
Cynthia A. McRae, Jennifer Caspari, Emily Fazio,
Jennifer Caspari, Gina Hartsock, Dan Russell,
Linda M. Winfield, Paul Greene, and Stanley Fahn;
Denver, CO; Ames, IA; and New York, NY
A double-blind placebo surgery trial was developed to determine the effectiveness of transplantation of human embryonic dopamine neurons into the putamen of 40 persons
with advanced PD. Twelve months after surgery and before
the blind was lifted, patients were asked to rate perceived
global functioning using a scale ranging from -3 (much
worse since surgery) to ⫹ 3 (much improved since surgery).
Patients then watched a videotape of themselves before surgery and rated themselves again. The purpose of this study
was to determine: 1) whether patient perceptions of global
functioning changed after viewing the videotape; 2) what
psychological variables were related to this change; and 3)
whether there were differences in amount of change between the transplant and sham groups. Results indicated
there was a change in pre-/post-video ratings ( p ⫽ .011),
with patients rating themselves more positively after the
video. Perceived treatment, optimism, and perceived selfefficacy accounted for 34.2% of change ( p ⬍ .05). There
was a marginal difference in amount of change based on
perceived treatment ( p ⫽ .063). There was no difference
related to actual treatment received, i.e., implant or sham
surgery. Study supported by NINDS R03 NS05499201A1.
M-92. Predictors of the Placebo Effect at 12 Months
in a Double-Blind Sham Surgery Controlled Trial
Cynthia A. McRae, Emily Fazio, Gina Hartsock,
Eileen Chavez, Dan Russell, Linda M. Winfield,
Paul Greene, and Stanley Fahn; Denver, CO; Ames, IA; and
New York, NY
A double-blind sham surgery-controlled trial was conducted
to determine the effectiveness of transplantation of human
embryonic dopamine neurons into the brains of persons with
advanced Parkinson’s disease. Results indicated few differences between transplant and sham groups when the blind
was lifted at 12 months. However, based on perceived surgery, or type of surgery patients thought they received, there
were numerous differences between groups, indicating a
strong placebo effect. This study investigated predictors of
perceived treatment at 12 months among 40 patients in the
double-blind surgical trial. Information from 12 month neurological assessments as well as patient and spouse/partner
questionnaires was included in analyses. Results indicated
that a combination of UPDRS subscales (“off” medications)
was 71.8% correct in predicting perceived treatment groups
( p ⫽ .003). Patients’ reports of physical functioning quality
of life were also predictive ( p ⫽ .047), as were spouse/partner ratings of patient physical functioning ( p ⫽ .029). Predictive psychosocial variables included self-efficacy ( p ⫽ .03)
and depression ( p ⫽ .061). It appears that physical functioning as measured by medical staff, patients and spouses/partners was the strongest predictor of perceived treatment at 12
months. Study supported by NINDS R03 NS054992-01A1.
M-93. Benefit of a Dose Increase after One Year of
Treatment with the Transdermal Dopamine Agonist
Rotigotine in Early Parkinson’s Disease
Anthony Nicholas, Kenneth Sommerville, Andrea Eggert, and
Neilson Steven; Birmingham, AL;
Research Triangle Park, NC; and Mequon, WI
Rotigotine is a transdermally applied D3/D2/D1 dopamine
agonist. As with other dopamine agonists, optimal doses may
vary in individual patients based on intrinsic patient differences and disease stage. This retrospective analysis evaluates
response to rotigotine dose increase in early PD patients participating in an open-label extension of a previously conducted 24-week, double-blind, placebo-controlled trial.
Rotigotine dose was increased after 1 year of open-label
treatment (6mg/24h to 8mg/24h) at one of the first two
consecutive protocol-allowed opportunities. Mean changes
from original baseline in UPDRS(II⫹III) were calculated for
the dose-increase visit, the following visit and for the two
visits preceding the dose increase to establish the course of
disease progression.
63 subjects without confounding concomitant medications underwent the dose increase. Mean UPDRS(II⫹III)
change from baseline remained stable for the two visits prior
to dose increase (-5.0 and -5.1, respectively). The dose increase visit was coincident with symptom worsening compared to the previous two visits (mean UPDRS change of
-1.9). Following dose increase, mean UPDRS change reflected a relative symptom improvement (mean UPDRS
change of -2.8), indicating some patients can benefit from
higher rotigotine doses. Study supported by SCHWARZ
Pharma; Dr. Kenneth Sommerville and Steven Neilson are
employees of Schwarz Bioscience. Andrea Eggert is an employee of Schwarz Pharma.
M-94. Improvements in Daytime Symptoms in
Patients with Restless Legs Syndrome – 24 Months
Results from a Multinational, Open-Label Trial with
the Rotigotine Transdermal System
Wolfgang H. Oertel, Karin Stiasny-Kolster,
Diego Garcia-Borreguero, Werner Poewe, Birgit Hoegl,
Ralf Kohnen, Ervin Schollmayer, Joerg Keffel, and
Claudia Trenkwalder; Marburg, Germany; Madrid, Spain;
Innsbruck, Austria; Nuernberg, Germany;
Monheim, Germany; and Kassel, Germany
Objective: This trial is an extension of a 6-arm, doubleblind, prospective, placebo-controlled, 7 week, dose-finding
trial ongoing at 33 centers in Europe. The trial aim is to
determine safety, tolerability and efficacy of rotigotine longterm application in moderate to severe idiopathic RLS.
Methods : Rotigotine was administered with optimal dose
titration, adjustments allowed at anytime. Data are presented
assessing the 24 months follow-up
Results: A total of 295 patients entered the open-label extension trial and 191(65%) completed 2-year maintenance
period. The RLS-6 scales show reductions of 2.9⫾2.7 and
-2.4⫾2.7 for the items “severity of RLS during the day when
at rest”, and “daytime tiredness and sleepiness”, respectively.
The IRLS scores for item 5-daytime tiredness/sleepiness,
item 9-daily activities, and item 10-mood, improved by
-1.5 ⫹ 1.1, -1.5 ⫹ 0.9, and -1.4 ⫹ 0.9, respectively.
The most common adverse events (⬎10%) were application
site reactions (50%-mostly mild), nasopharyngitis (12%),
back pain (11%), and nausea (11%). Incidence of augmentation has not been observed.
Conclusion: Treatment with the rotigotine transdermal sys-
Program and Abstracts, American Neurological Association
tem was well-tolerated and showed clinically relevant improvements in RLS-daytime symptoms and were sustained
during 24-months follow-up. Study supported by Schwarz
Pharma AG; They are paid investigators.
M-95. Role of parkin in PD
Haydeh Payami, Denise Kay, Dawn Moran, Lina Moses,
Parvoneh Poorkaj, Cyrus Zabetian, Stewart Factor,
Chang-En Yu, Jennifer Montimurro, Robert Keefe,
Gerard Schellenberg, and John Nutt; Albany; Seattle; Atlanta;
and Portland
Homozygous and compound heterozygous parkin mutations
cause autosomal recessive juvenile parkinsonism. Heterozygous parkin mutations are also found in patients with Parkinson disease (PD), but it is unclear whether a single mutation in a patient is related to disease or coincidental
because parkin mutation frequency in controls is unknown.
Resolving this issue is important for the use of parkin as a
clinical test. We performed a comprehensive study where we
analyzed 617 clinic PD patients and 635 unrelated controls
for deletions/duplications, sequenced all exons in 302 PD
patients and 301 controls, and replicated the sequence findings in 2917 additional patients and controls from NeuroGenetics Research Consortium. Twelve deletions, 7 duplications, 22 point mutations and 12 polymorphisms were
detected. Five subjects were compound heterozygous for two
mutations, and all had developed PD before age 40. Heterozygous deletions/duplications were found in 3/635 controls ages 57-81 and 7/617 patients with onset ages 58-75
(OR⫽2.7, p⫽0.2). Age at onset was not earlier in heterozygous deletions/duplications than idiopathic PD (60.5⫾15.0
vs. 57.4⫾12.4). Heterozygous point mutations and polymorphisms were equally prevalent in cases vs. controls, and had
no effect on onset age. These data suggest heterozygous parkin mutations are not pathogenic. Study supported by National Institutes of Health and Michael J Fox Foundation for
Parkinson Disease Research.
M-96. Pilot Case-Control Study of Genetic &
Environmental Risk Factors for PSP
Lisa Potts, Chris Cunningham, Alex Cambon, Peter Lees,
Jennifer Adamson, Ashley Cannon, Mike Hutton, Ryan Uitti,
Zbignew Wszolek, Jorge Juncos, and Irene Litvan;
Louisville, KY; Jacksonville, FL; Atlanta, GA; and
Baltimore, MD
Progressive Supranuclear Palsy (PSP) is a sporadic tauopathy
presenting in middle to late age with postural instability,
levodopa-unresponsiveness, frontal disturbances and supranuclear vertical gaze palsy. Studies suggest a link between
the H1 tau haplotype in PSP, but the cause remains unknown. To investigate whether environmental factors and
the H1/H1 genotype are associated with and more prevalent
among PSP patients versus controls, we conducted a pilot
study to evaluate whether PSP patients responses are valid,
collect preliminary data and assess our methods. Cases, controls and verifiers were interviewed on life history, completed
dietary information through the mail and provided blood for
genetic testing. Interviewing yielded 94% responses compared to 35% from mailed questionnaires. Cases and verifiers
can provide reliable answers (case v. medical records⫽100%
agreement, verifier v. medical records⫽91% agreement).
Comparison of cases with controls revealed trends in differences in exposures to potential risk factors (pesticides⫽71%
cases v. 42% controls; pawpaw⫽33% cases v. 25% controls
Annals of Neurology
Vol 62 (suppl 11)
H1/H1 genotype⫽ 84% cases v. 62% controls), providing
the basis for a larger study. We concluded that PSP patients
can provide valid information and our study is feasible.
Study supported by Genetic and Environmental Risk Factors
for PSP: A Pilot Study. PI: Irene Litvan, M.D. UofL Grant
in Aid. Protocol # 160.04.
M-97. The Relationship between CAG Repeat Length
and Progression in Huntington’s Disease
Bernard Ravina, Megan Romer, Radu Constantinescu,
Kevin Biglan, Karl Kieburtz, Ira Shoulson, and
Michael McDermott; Rochester, NY
Objective: To examine the relationship between CAG repeat
length (CAGn) and clinical progression in Huntington’s disease (HD). Background: There are conflicting reports about
the relationship between CAGn and clinical progression of
HD. Methods: We conducted an analysis of data from the Coenzyme Q10 and Remacemide Evaluation in Huntington’s
Disease (CARE-HD) clinical trial. We modeled progression
over 30 months on the Unified Huntington’s Disease Rating
Scale (UHDRS), supplemental neuropsychological tests, and
the Hamilton Depression Inventory using multiple linear regression. The models included CAGn as the independent variable and adjusted for the baseline value of the outcome variable, age at baseline, enrolling site, and treatment assignment.
Results: Mean CAGn was 45.0 ⫾ 4.1 and mean subject age
was 47.9 ⫾ 10.5 years (N⫽335). Regression models revealed
significant associations between CAGn and worsening motor,
cognitive, and functional outcomes. Effects were clinically important; ten additional CAG repeats were associated with an
81% increase in progression on the Independence Scale. Conclusion: Age at the time of assessment is inversely related to
CAGn and positively associated with measures of progression.
Adjusting for age shows that longer CAGn is associated with
greater progression of HD. Study supported by NIH.
M-98. Quantification of Movement Using a Nintendo
Wii Remote
Anusha Sathyanarayanan, Srivatsan Pallavaram,
Robert Bodenheimer, Kevin Robinson, Benoit Dawant, and
Thomas L. Davis; Nashville, TN
Objective: To evaluate and standardize a small, portable accelerometer to quantify human motor control.
Background: The Nintendo Wii Remote controller contains
three-axes accelerometers (ADXL330) that report via Bluetooth the instantaneous motion imparted on the device.
This output can be captured and stored for later data analysis. We compared motion recordings form the Wii Remote
to that collected from a six-camera motion capture system
(Vicon, Los Angeles, CA).
Methods: Markers were affixed on the Wii Remote along
the three Cartesian axes to record the three dimensional motion of the remote. Simple periodic translations and rotations
were performed along the three axes individually. Acceleration data from the Wii Remote were captured by a personnel
computer with Bluetooth receiver. Position information was
simultaneously recorded using the Vicon.
Results: Accelerometer data from the Wii Remote was integrated twice. Sinusoidal patterns were observed for the displacement data that were consistent with the motion performed as recorded by the Vicon system (correlation
coefficient ⬎ than 0.8).
Conclusion: These results suggest that the Wii Remote can
accurately measure movement. Its simplicity and portability
offer advantages over existing systems available for research
and clinical applications in Parkinson’s disease and other
movement disorders.
M-101. Rotigotine Transdermal Patch for Better
Control of Early Morning Motor Impairment and Sleep
Disturbances in Patients with Parkinson’s Disease
Nir Giladi, and Kenneth Sommerville; Tel-Aviv, Israel; and
Research Triangle Park, NC
M-99. The EUROSCA Natural History Study:
Evaluation of the First Visit
Tanja Schmitz-Hubsch, Thomas Klockgether,
Mathieu Coudert, and Sophie Tezenas du Montcel;
Bonn, Germany; and Paris, France
This open-label, single-arm exploratory study investigated
the efficacy of rotigotine transdermal patch on early morning
motor impairment and sleep disorders in idiopathic Parkinson’s disease patients.
Fifty-four mostly advanced-stage patients with unsatisfactory
control of early morning motor impairment received rotigotine (up to 16mg/24h) over a 4-week dose-maintenance period. Motor improvement was assessed by UPDRS III and
nocturnal akinesia score, tapping rate and standing-walkingturning test; changes in sleep disturbances were rated by
Nocturnal Akinesia, Dystonia and Cramps Score, Parkinson’s Disease Sleep Scale, number of nocturias and Epworth
Sleepiness Scale.
Administration of transdermal rotigotine improved all efficacy parameters. Forty-nine percent of patients were responders in early morning motor function (ⱖ30% improvement of UPDRS III score). Nocturnal akinesia was reduced
by 56%; nocturnal dystonia, nocturnal cramps and number
of nocturias also decreased. Rotigotine improved sleep quality, reduced excessive daytime sleepiness, and appeared safe
and well tolerated. Most patients (95%) were satisfied with
transdermal rotigotine and most (82%) preferred a patch
over oral medication.
This pilot study suggests that transdermal rotigotine is efficacious in controlling early morning motor impairment and
sleep disorders. Study supported by SCHWARZ Pharma;
Dr. Kenneth Sommerville is an employee of Schwarz Biosciences.
The study was launched July 2005 to determine progression rates of spinocerebellar ataxias (SCA). 526 patients
with genetically confirmed SCA (SCA1:116,SCA2:
164,SCA3: 40,SCA6:106) are followed in yearly intervals
in 18 European centers with SARA as primary outcome
measure, UHDRS-IV functional scale and Inventory of
non-ataxia symptoms (INAS). Analyses of baseline data
show SARA increase with disease duration in all genotypes.
Furthermore data confirm close correlations of SARA and
UHDRS-IV. SARA is positively correlated with repeat
length of expanded allel in SCA2 and SCA3 and negatively
with length of normal allel in SCA1. Age is correlated with
SARA in SCA1 and SCA6 only. Regression modelling of
SARA progression rates yields different models for each genotype that have a prominent impact of disease duration in
common and explain 53% (SCA1), 35% (SCA2), 36%
(SCA3) and 36% (SCA6) of the total variance of SARA.
The number of affected extra-cerebellar systems increases
with disease duration in all genotypes and is correlated with
UHDRS-IV functional score for all genotypes, but with
SARA scores only in SCA1, 2 and 3. We here present the
evaluation of baseline data and preliminary data on oneyear follow-up. Study supported by European Union
(EUROSCA/LSHM-CT-2004-503304) and German Ministery of Education aand research (GeneMove/01 GM
M-100. Antibodies in Degenerative Ataxias
Ejaz A. Shamim, Carina Canadas, Lena Derani,
Sungyoung Auh, Fernando Pagan, and Mark Hallett;
Bethesda, MD; Washington, DC; and Dearborn, MI
Background: Reports have implicated immune dysfunction as
a possible pathology in a subgroup of patients with degenerative ataxias. Methods: We retrospectively assessed the frequency of anti-gliadin antibodies (AGA), anti-cardiolipin antibodies (ACA) and anti-thyroglobulin antibodies (ATG) in
patients who presented to our clinic with ataxia from January
2000 to May 2003. In addition, we assessed HLA DR␤1
frequencies in these patients relative to healthy individuals.
Results: A total of 89 patients had a diagnosis of ataxia: 24
had sporadic cerebellar ataxia, 21 had autosomal dominant
ataxia (ADA), 18 had multiple system atrophy (MSA), 8 had
Friedreich ataxia (FA), 6 had ataxia associated with AGA, 2
had multiple sclerosis. The remaining ten patients had a variety of other disorders. In the sporadic cerebellar ataxia
group, 63% had AGA, 53% had ACA and 22% had ATG;
in the sporadic ataxia group 77% had AGA, 40% had ACA
and 20% had ATG; in the MSA group, 82% had AGA,
77% had ACA, and 57% had ATG. Compared to racematched healthy volunteers, HLA DR␤1*16 appeared to be
a possible genetic risk factor for FA. Conclusion: All 3 antibodies were found in the different subgroups of patients suggesting a non-specific immune dysfunction. Study supported
by NINDS Intramural Research Branch.
M-102. Adjunctive Ropinirole 24-Hour Improves
Patient-Reported Outcomes of Depression, Quality of
Life and Sleep in Advanced PD
Natividad P. Stover, Stuart H. Isaacson, Lawrence W. Elmer,
and Heather M. Edin; Birmingham, AL; Boca Raton, FL;
Toledo, OH; and Research Triangle Park, NC
The effect of treatment with ropinirole 24-hour on patientreported outcomes (PROs) was evaluated.
The EASE PD-Adjunct study (101468/169) randomized patients with PD not optimally controlled with L-dopa to adjunctive ropinirole 24-hour (n⫽202) or placebo (n⫽191),
once daily, for 24 weeks. Initial dose: 2.0mg/day, titrated to
a maximum of 24mg/day. Once titrated to 8.0mg/day, and
for each subsequent increase, L-dopa dose reduction was required. Primary endpoint: mean change in daily “off” time at
Week 24 last observation carried forward (LOCF). PROs included PD Sleep Scale (PDSS), Epworth Sleepiness Scale
(ESS), Beck Depression Inventory–II (BDI-II), and PD
Quality of Life Questionnaire (PDQ-39).
At Week 24 LOCF, ropinirole 24-hour significantly reduced
“off” time, compared with placebo (p⬍0.0001). Significant
improvements were observed in BDI-II total score
(p⫽0.0130), PDQ-39 summary index score (p⫽0.001 [posthoc analysis]) and PDSS total score (p⫽0.0196). No statistically significant change was observed in daytime sleepiness,
measured by ESS total score (p⫽0.3692).
Ropinirole 24-hour significantly improves measures of depression, quality of life and sleep, with no statistically significant increase in daytime sleepiness, compared with placebo
in patients with advanced PD not optimally controlled with
L-dopa. Study supported by GlaxoSmithKline and Skye
Program and Abstracts, American Neurological Association
Pharma; N Stover has received compensation for speaking
engagement from GSK, Valeant Pharma, and Novartis and
received research support (trial grant) from Boehringer Ingelheim (BI), GSK, Novartis, Eisai, Merck KGaA and
Schwarz; S Isaacson has received grant and honoraria support
from GSK for research, consultant, and speaker activities; L
Elmer has been a speaker for GlaxoSmithKline, Boehringer
Ingelheim, Schwarz Pharma, Novartis, Eisai, Pfizer and
Valeant. He has been a scientific advisory board member for
Teva; H Edin is an employee of GlaxoSmithKline.
M-103. Daily Energy Expenditure and Physical
Activity Measured in Parkinson’s Disease Patients with
and without Weight Loss
Evangelia Delikanaki-Skaribas, Marilyn Trail,
William W. L. Wong, and Eugene C. H. Lai; Houston, TX
Background: Patients with Parkinson’s disease (PD) commonly exhibit weight loss which investigators attribute to
various factors, including elevated resting energy expenditure.
We tested the hypothesis that daily energy expenditure
(DEE) and its components, resting energy expenditure
(REE) and physical activity (PA), are elevated with weight
loss (WL) compared with weight stable (WS) PD patients.
Methods: DEE and PA was measured in 10 PD WL patients
and 10 PD WS patients using doubly labeled water (DLW),
activity monitors (waist and wrist), and activity questionnaires. We evaluated energy intake (EI) with a 3-day food
● There was no difference in DEE and PA between the
WL and WS groups measured with DLW.
● There were no differences in REE and EI between
● The WL group had significantly higher activity than the
WS group (p⬍0.042) only when measured with wrist activity monitors.
● DEE and PA, are positively related with caloric intake
(r⫽0.548, p⬍0,05; r⫽0,563, p⬍0.01).
Conclusions: Results suggest that weight loss in PD patients
cannot be explained by increased DEE but is associated with
excessive movements.
M-104. Rotigotine Transdermal Patch Is Effective in
the Treatment of Idiopathic RLS: Results of a 6-Month,
Multicenter, Double Blind, Placebo-Controlled Trial in
Claudia Trenkwalder, Heike Benes, Ray Chaudhuri,
Luigi Ferini-Strambi, Birgit Hoegl, Diego Garcia-Borreguero,
Joerg Keffel, Ralf Kohnen, Pasquale Montagna,
Markku M. Partinen, Werner Poewe, Ervin Schollmayer,
Karin Stiasny-Kolster, and Wolfgang H. Oertel;
Kassel, Germany; Schwerin, Germany;
London, United Kingdom; Milano, Italy; Innsbruck, Austria;
Madrid, Spain; Monheim, Germany; Nuernberg, Germany;
Bologna, Italy; Espoo, Finland; and Marburg, Germany
Objective: To evaluate efficacy and safety of rotigotine transdermal patch in patients with moderate to severe idiopathic
Methods: Multicenter, randomized, double-blind, placebocontrolled, 4-arm parallel-group trial with 3 fixed doses of
rotigotine 1-3mg/24h (5-15cm2). IRLS-sum-score and the
CGI-item-I are the co-primary efficacy parameters.
Results: 458 patients (58 ⫾ 11 years, 73% female) were
randomized at 49 sites in 8 European countries. The mean
Annals of Neurology
Vol 62 (suppl 11)
baselines scores were: IRLS 28.1⫾6.1 and CGI 5.0⫾0.8.
Improvement net effects versus placebo after 6 months
treatment were 5.1⫾1.3 (p⬍0.001), -7.5⫾1.3 (p⬍0.001),
and -8.2⫾1.3 (p⬍0.001) in the IRLS-sum-score and
-0.76⫾0.19 (p⬍0.001), -1.07⫾0.19 (p⬍0.001), and
-1.21⫾0.19 (p⬍0.001) in CGI-item-I for rotigotine 1, 2,
and 3mg/24h, respectively.
At least 1 adverse event was reported by 78 % of patients
on rotigotine. Most common side effects were application
site reaction(42,5%), nausea(16.4%), headache(15.8%) and
dizziness(5.8%). AEs were usually mild to moderate in intensity and transient.
Conclusion: Therapy with rotigotine transdermal patch in
doses from 1 to 3 mg/24h over a period of 6 months resulted in a statistically significant and clinically relevant reduction in the IRLS-sum-score and CGI-item-I compared
to placebo and was well tolerated. Study supported by
Schwarz Pharma AG; They are paid investigators.
M-105. Longitudinal Associations between
Instrumental Activities of Daily Living Disability,
Cognition, & Mobility in Parkinson’s Disease
James R. Williams, and Laura Marsh; Baltimore, MD
The symptoms of Parkinson’s disease (PD) often lead to disability and loss of independence. This study investigated potential causes of disability using a cohort of 141 participants
with idiopathic PD followed for up to six years. Generalized
estimating equations were used to explore the longitudinal
associations between instrumental activities of daily living
(IADL) disability measured by the Lawton scale, and motor,
cognitive, and psychiatric symptoms measured by a comprehensive test battery. IADL disability was present in 72% of
the sample at baseline and increased to 89% (n⫽54) after six
years. IADL disability progression was associated with increased axial impairment, as measured by the UPDRS, and
executive dysfunction and psychomotor slowing as measured
by the Trails Making Test parts A and B (p⬍0.001). Depressive symptoms were selectively associated with disability
in more cognitively-based activities (medications, finances,
and telephone use) (p⬍0.05). Neither UPDRS tremor, bradykinesia, and rigidity scores nor any measure of verbal
learning and memory were associated with IADL disability
progression. These findings suggest that the IADL disability
pathway in PD is multifactorial with the greatest contribution from impairments not responsive to dopaminergic therapy. Study supported by NINDS P50-NS-58377, (PI: T.
Dawson, M.D., Ph.D.), NIMH T32-MH14592 (PI: W.
Eaton, Ph.D.).
M-106. 20(S)-Ginsenoside Rg3 Attenuates DopamineInduced Apoptosis in PC12 Cells by Suppressing
Oxidative Stress
Jianxiong Yang, and Juan Wu; Xi’an, Shaanxi, China
In Parkinson’s disease, neuroprotective therapy to rescue dopamine neurons has been proposed. 20(S)-Ginsenoside Rg3,
one of the biologically active ingredients of ginseng, a chemical compound isolated from the traditional Chinese herb
ginseng, may be a candidate neuroprotective drug. In the
present study, the mechanism underlying the neuroprotection provided by 20(S)-ginsenoside Rg3 was studied against
apoptosis induced by exogenous dopamine in PC12 cells.
Pretreatment with 20(S)-ginsenoside Rg3 markedly reduced
the generation of dopamine-induced reactive oxygen species
and the release of mitochondrial cytochrome c into the cy-
tosol, and subsequently inhibited the activation of caspase-3.
In addition, 20(S)-ginsenoside Rg3 pretreatment also reduced
inducible nitric oxide (NO) synthase protein level and NO
production. These results suggested that 20(S)-ginsenoside
Rg3 may attenuate dopamine-induced apoptotic cell death
through suppression of intracellular oxidative stress, and that
it may rescue or protect dopamine neurons in Parkinson’s
disease. Study supported by Shandong Engineering Research
Center for Natrual Drugs.
M-107. Characterization of Basal Ganglia Axon
Pathfinding Using Zebrafish
Josh Bonkowsky, and Chi-Bin Chien; Salt Lake City, UT
Our objective is to characterize the development and genetic
control of basal ganglia connectivity using zebrafish. Zebrafish offers key advantages for this work, including rapid
CNS development; straightforward visualization of neurons
and axons; and the ability to economically perform largescale genetic screens. We labeled the developing zebrafish
CNS, using in situ gene markers previously shown in mice
necessary for specification of the mesodiencephalic dopaminergic (mesDA) neurons (the homolog of the primate
SNpc). This analysis revealed a complex and dynamic pattern of genes that specify mesDA neurons. Anti-sense morpholinos against nurr1 and pitx3 led to decreased dat expression, showing their requirement for mesDA neurons. Thus,
we have identified the zebrafish mesDA neurons and shown
that they appear to be genetically equivalent to the SNpc.
We generated transgenic zebrafish lines which express GFP
in subsets of the basal ganglia neurons, including dlx(mini):
GFP and foxP2-enhancerB:GFP, and have several other lines
pending analysis. Our research will allow characterization of
basal ganglia pathfinding and its genetic control, and our zebrafish model offers a rapid and powerful means for understanding the mechanisms of development, which may play a
role in diseases involving the basal ganglia. Study supported
by Child Health Research Career Development Award:
M-108. Pain on Ocular Globe Compression as a
Diagnostic Sign in Acute Meningitic Syndromes in a
Brazilian Population
Luciano Holanda, Rohit R. Das, and Neerja Agrawal;
Paraiba, Brazil; Boston, MA; and Chicago, IL
Background: Recent studies have suggested limited sensitivity and specificity for nuchal rigidity and the classical signs of
meningitis, the Kernig and Brudzinski, in the diagnosis of
acute meningitic syndromes. In the developing world, with
limited diagnostic resources, a non invasive and reliable
method is needed to diagnose acute meningitic syndromes.
Design/Methods: 80 subjects with acute meningitic syndromes and 80 controls of varying ages of both genders were
recruited, between 2000 and 2001, at the Hospital Antonio
Targino, in Brazil, where diagnostic testing was completed.
The ocular globe compression test was performed on all subjects as was testing for nuchal rigidity and for Kernig and
Brudzinski signs.
Results: In meningitic subjects 86% had nuchal rigidity,
21% positive Kernig sign and 56% positive Brudzinski sign.
Pain on ocular globe compression was present in 98.7% of
subjects; sensitivity and specificity were 97.5% and 98.8%
Conclusions/Relevance: In this study pain on ocular globe
compression proved to be a reliable test of meningitic syndromes with high specificity and sensitivity. In the developing world this sign would be helpful in arriving at an early
diagnosis of meningitic syndrome.
M-109. Long Term Prognosis of Occlusion Versus
Stenosis of a Major Intracranial Artery: A Sub-Analysis
of the WASID Study
As’ad Ehtisham, Owen B. Samuels, Scott Taylor,
Michael W. Klein, and Marc I. Chimowitz; Wichita, KS;
and Atlanta, GA
Limited data is available on the prognosis of patients with
intracranial artery occlusion versus stenosis. We here present
results from the WASID (Warfarin Aspirin Symptomatic Intracranial Disease) Study. 203 patients met inclusion criteria.
All patients presented with a transient ischemic attack or
stroke, and were treated with warfarin or aspirin. Stenosis
was calculated using [1-(Dstenosis/Dnormal)]x100 ⫽ %stenosis. 52 (25.6%) patients were diagnosed with major intracranial artery occlusion. The remaining 151 patients (74.4%)
were diagnosed with major intracranial artery stenosis. In patients with intracranial occlusion, rate of stroke was 2.8 per
100 patient years, compared to 6.8 for stenosis. Rate of myocardial infarction/sudden death was 3.7 per 100 patient years
in patients with intracranial artery occlusion, versus 6.1 for
stenosis. Rate of vascular events was also higher in patients
with intracranial stenosis (12.9 per 100 patient years) versus
occlusion (6.5 per 100 patient years). These data suggest the
risk of stroke and complications may be lower in patients
with occlusion versus stenosis of an intracranial artery. Further studies are warranted. Study supported by Emory University Hospital and Via Christi Regional Medical Center.
Study medications were provided by Bayer and DuPont.
M-110. Effect of Hypothermia Treatment (HT) and
Prognostic Value of Neuron Specific Enolase (NSE)
Level after Cardiopulmonary Arrest (CPA)
Muhammad U. Farooq; East Lansing/Lansing, MI
Background: The exact details of HT-protocol in the treatment of CPA are still not well established.
Purpose: To report the effect of HT in the 1st patient
treated with HT-protocol at Edward Sparrow Hospital, Lansing.
Method: 27-year-old male with CPA due to pulseless electrical activity. CPR was continued for 30 minutes. Initial
clinical signs and symptoms, radiological (multiple hyperintensities on DWI) and electrophysiological findings (“alpha
coma”) were suggestive of poor outcome. After return of
spontaneous circulation (30-35 minutes) the patient was still
comatose and therapeutic hypothermia (32-33 Celsius) was
instituted during the first 24 hours. NES level, drawn at 12
hours after the event, was 13.9. The same protocol was also
used in subsequent patients with CPA and NSE levels were
correlated with their prognosis.
Results: 1st patient recovered without any significant neurological deficit.
Patients with NSE levels more than 30 even with HT treatment did not show any significant recovery.
Conclusion: HT if instituted within 24 hours of CPA may
have neuroprotective effect. NSE level less than 30 if drawn
within 12-48 hours after the event can be correlated with
favorable prognosis.
Program and Abstracts, American Neurological Association
M-113. Computerized Assessment of Cognitive Fatigue
in Survivors of Paralytic Poliomyelitis
Joseph Bleiberg, Dagny E. Johnson, Sandra M. Maxwell,
Kimbra Kenney, William W. Campbell, and
Olavo M. Vasconcelos; Bethesda, MD; and Washington, DC
M-111. A Case of Fibro-Dysplasia Ossificans
Progressiva with a Novel Mutation of the Activin
Receptor Type 1(ACVR1) Gene
Hirokazu Furuya, Koji Ikezoe, Jun-ichi Kira,
Yasuyuki Fukumaki, and Naoki Fujii;
Oomuta, Fukuoka, Japan; and Fukuoka, Japan
Background: The R206H mutation of the activin A type 1
receptor gene (ACVR1) has been found in all individuals
with fibrodysplasia ossificans progressiva (FOP). Thus, this
mutation has been considered one of the most specific of all
disease-associated mutations. We reported a case of Japanese
FOP with slowly progression with a novel mutation in
ACVR1. Case presentation: A 58-year-old Japanese man developed muscular weakness and difficulty moving his shoulder due to contraction of the joint at the age of 10 years.
The symptoms in his extremities progressed slowly, and he
couldn’t walk at the age of 36 and was bedridden at 55 years
old. He also showed rigid spine, baldness, sensory hearing
loss as well as snaggle tooth and hypodactylism accompanied
with abnormal ectopic ossification. Results: Analysis of
ACVR1 cDNA revealed that the patient is heterozygous for
the G to A substitution at position 1,067, resulting in the
novel amino acid substitution (G356D). Conclusion: Our
data suggest the possibility of the multi-founder effect of this
disorder and give the clue to the relation with the mild clinical symptoms in this patient. Study supported in part by a
Research Grant (16A-1) for Nervous and Mental Disorders
and Research Grant (H18-pharmaco-002) for the Research
on Advanced Medical Technology from the Ministry of
Health, Labour and Welfare of Japan.
M-112. In Vitro Differentiation of CD45low Microglia
to CD45high Macrophage-Like Cells
Afif Hentati, Mohammed Jameel, Cathleen V. Allen, and
Jilling Thamas; Evanston, IL; and Chicago, IL
Microglia are CNS resident cells of myeloid lineage thought
to be derived from circulating monocytes and are constitutively CD45low while monocytes are CD45high. Current concepts postulate that microglia are terminally differentiated,
unable to proliferate, and remain CD45low after activation.
All CD45high cells, which are consistently co-isolated with
CD45low cells in primary microglia (PM) preparations, are
thought to be derived from monocytes. We found that murine PM and immortalized microglia cell lines EOC2 and
EOC20 cultured with M-CSF are composed of CD45low
and CD45high populations which reflected a smaller nonphagocytic cell (NPC) and a larger phagocytic cell (PC) populations (determined by incubation with latex beads (LB)).
The segregation analysis of engulfed LB in EOC and PM,
determined by the distribution of LB in parent and progeny
cells, supported a 2 cell population model in which NPC
replicated more rapidly than PC. The persistence of PC over
generations, which is unexpected in this model, resulted
from their continuous generation from NPC. These data
suggest that CD45low microglia are not terminally differentiated but rather immature myeloid cells able to proliferate
and spontaneously differentiate to macrophages. Study supported by National Institute of Neurological Disorders and
Stroke. ENH Research Institute.
Annals of Neurology
Vol 62 (suppl 11)
Background: Many survivors of poliomyelitis experience the
reemergence of symptoms decades after recovery. Physical
manifestations are most obvious, but some also complain of
subtle cognitive difficulties. Few studies attempted to characterize cognitive fatigue in this population unsuccessfully.
Methods: Cross-sectional study. After written consent, we interviewed and evaluated polio survivors clinically and by laboratory tests. Eligible subjects underwent cognitive assessments using a validated construct of the Automated
Neuropsychological Assessment Metric (ANAM), which was
administered twice, an hour apart. Results: Thirteen polio
survivors and 13 historic controls, among whom available
ANAM data matched on age, educational level, and sex,
were studied. A significant difference between groups regarding ANAM throughput (speed/accuracy ratio) scores was
found using Fisher’s exact test. Rather than showing the expected practice-effect between the first and second ANAM
administration, a majority of the polio subjects actually
showed a decline in performance. Conclusion: Our study is
the first to examine the applicability of computerized testing
in a population of polio survivors. The test was well tolerated. The present findings suggest the study subjects have
intact capabilities in the well-rested state, but precipitous decline in mental function following even moderate effort expenditure. Study supported by DOD: Health Affairs, Grant
MDA 905-01-007.
M-114. Orbital Aspergillosis Presenting in
Immunocompetent Patients without Apparent Sinus
Desmond P. Kidd, Louise O’Toole, Pauline Wilson,
Bronia Unwin, and James A. Acheson;
London, United Kingdom
We present two patients with painful orbital apex syndromes
with a protracted disease course. Each was initially diagnosed
with giant cell arteritis then Tolosa Hunt syndrome, and
each was treated with high dose corticosteroids. Neither
showed evidence for sinus disease but in time a mass developed in the orbital apex. Biopsy in each case was followed by
meningitis and complicated by cerebral ischaemia. Aspergillus fumigatus was seen and grown in each case.
Aspergillus fumigatus is generally acquired by inhalation,
gaining central access via the ethmoidal and sphenoidal sinuses. Aspergillus infection may be classified into fulminant,
chronic invasive, aspergilloma and allergic aspergillus sinusitis. Fulminant apergillosis is seen in the immunocompromised patient. Orbital apergillosis represents contiguous infection following chronic invasive aspergillus sinusitis in
immunocompetent patients.
Our cases are unusual as they were both immunocompetent
and neither had a history of sinus disease. Both cases were
initially treated with corticosteroids and had a protracted and
complicated clinical course before and after diagnosis.
M-115. Effects of Visual Pathway Lesions on the
Visual Aura of Migraine
Frederick E. Lepore; New Brunswick, NJ
OBJECTIVE: To determine if visual aura of migraine is altered by disease of pre- and postgeniculate visual pathways.
BACKGROUND: Functional neuro-imaging during migraine demonstrates primary visual/extrastriate cortex as anatomic substrate of visual aura.
METHODS: Neuro-ophthalmologic records (including kinetic perimetry) of 25 patients with visual loss and typical
aura with or without migraine headache were reviewed.
RESULTS: 25 patients (16 women, 9 men) (mean age 59.8
years) with typical aura had visual loss from pregeniculate (72%)
or postgeniculate lesions (28%). 8 patients (4 - postgeniculate
CVA or AVM, 2 - lifelong optic neuropathy/retinopathy, 1 childhood ocular trauma, 1- anisometropic amblyopia) reported
absence or alteration of visual aura.Postgeniculate lesions were
significantly associated (p ⫽.02) with visual aura changes.
CONCLUSIONS: The association of postgeniculate lesions
with altered auras points to a postgeniculate effect on aura appearance (consistent with functional neuro-imaging findings).
Although statistically significant, this series’ association of postgeniculate disease and aura changes is even more robust when
structural changes of ocular dominance columns are posited in 3
patients with optic neuropathy, retinopathy, and keratopathy of
congenital or childhood origin.
M-116. Adjusted Cerebrospinal Fluid Pressure
Measurement by Its Density and Biochemical
Helard A. Miranda, and Rosa G. Reymundo;
Cincinnati, OH; and Lima, Peru
Objective: To design a practical way of avoid errors when
pressure of the cerebrospinal fluid (CSF) is been taken.
Methods: We obtained 322 CSF samples, with known cytological and biochemical composition, density and pressure
values. The CSF’s pressure measurements was adjusted and,
for each case, we calculated the exact pressure exerted by the
column of CSF from its density, which was already known.
The working variable was set as the pressure error (PE) that
resulted from:
PE⫽Abs (Calculated pressure of the column of CSF from its
density)-(Pressure taken). “Abs” is the absolute value of the
Results: Cell and glucose levels have little impact in CSF’s
PE. It was found that protein concentration levels in CSF
had an important effect on the PE, especially in values above
150 mg/cm3, and this result is extrapolated from our ad hoc
mathematical model:
Adjusted CSF pressure (mmH2O) ⴝ CSF pressure
(mmH2O) ⴙ [CSF protein (mg/cm3) / 50] – 2.
This model proved to be a suitable predictor of PE in our
sample, with ␣⫽ 0.005.
Conclusions: Under actual usual methods measurements of
the CSF’s pressure could conduct to errors. CSF’s pressure
associated with a CSF protein concentration above 150 mg/
cm3 must be adjusted.
M-117. Frequency and Pattern of Mild Cognitive
Impairment in Nigerian HIV Seropositive Patients
without Overt Neurological Manifestations
Ikenna O. Onwuekwe, Austin C. Nwabueze, and
Myles C. Nwosu; Enugu, Enugu State, Nigeria; and
Nnewi, Anambra State, Nigeria
Background: The abnormalities of cognition in HIV infection have not been fully studied in Nigerians.
Aim: To determine the frequency and pattern of mild cognitive impairment (MCI) in HIV infected patients without
overt neurological disease.
Design: Cross-sectional study.
Setting: Enugu, south east Nigeria.
Participants: 135 patients (77 males and 58 females) with
HIV infection who satisfied the study criteria were assessed
for cognitive function and the findings compared with 135
healthy HIV seronegative controls (79 males and 56 females)
suitably matched.
Intervention: Cognitive function was tested using the
MMSE, suitably adjusted for the locale. BMI, haemoglobin
level and CD4 cell count were also determined. Relevant
bio-data were recorded.
Results: MCI was found in 8 (5.9%) of the 135 study patients and was significantly correlated with CD4 count and
BMI. The relationship between CD4 count and cognitive
impairment was particularly strong at CD4 counts ⱕ 200/ul.
Conclusions: The study found mild cognitive impairment to
be present in 5.9% of Nigerian HIV seropositive patients
who do not have overt neurological disease. This impairment
correlated with low CD4 cell count and low BMI. There is a
need for follow up studies. Study supported by University of
Nigeria Teaching Hospital, Enugu, Nigeria.
M-118. Interaction between Primary Motor Cortices
at Different Force Levels
Monica A. Perez, and Leonardo G. Cohen; Bethesda, MD
A strong unilateral voluntary contraction with an upper limb
muscle facilitates motor evoked potentials (MEPs) in the
contralateral and ipsilateral homologous muscle. The mechanisms by which primary motor cortices interact at different
levels of force generation remain unclear. We investigated the
effect of voluntary isometric right wrist flexion on recruitment curves to transcranial magnetic stimulation (RC), short
intracortical inhibition (SICI), and interhemispheric inhibition (IHI) from the active (left) to the resting (right) hemisphere in 10 healthy volunteers. Electromyographic (EMG)
activity was recorded bilaterally from the flexor carpis radialis
(FCR) muscles. Measurements were taken at rest and during
10, 30, and 70% of right wrist maximum voluntary contraction (MVC). FCR RCs were increased in both hemispheres
at 70% compared to 10% of MVC. In the resting hemisphere, SICI was decreased at 70% compared to 10% of
MVC. IHI was decreased at 70% compared to 10% of
MVC. These results suggest that modulation of interhemispheric inhibition and local changes in intracortical excitability may contribute to motor cortical facilitation in the resting
hemisphere at high levels of force generation. Transcallosal
inhibition appears to be more sensitive to low levels of force
M-119. The Role of the Supplementary Motor Area in
Intermanual Transfer of Procedural Learning
Monica A. Perez, Satoshi Tanaka, Steven P. Wise,
Norihiro Sadato, Hiroki Tanabe, Daniel T. Willingham, and
Leonardo G. Cohen; Bethesda, MD; Okazaki, Aichi, Japan;
and Charlottesville, VA
In healthy humans, the two cerebral hemispheres show a degree of functional specialization unmatched in other animals.
Although we typically learn a new motor skill with our dominant hand, it is advantageous when that learning results in
performance improvements in the opposite hand, as well. Efficient use of the opposite hand requires that some information be transferred intermanually, but the neural mechanism
for such transfer is almost completely unknown. Here we
Program and Abstracts, American Neurological Association
found with functional brain imaging that the supplementary
motor area (SMA) and its principal thalamic nucleus have
more activity when a skill transfers well compared to when it
transfers poorly. Furthermore, using repetitive transcranial
magnetic stimulation during skill learning, we found that
disrupting neural processing in the SMA blocks such transfer. These findings provide direct evidence for an SMA-based
mechanism that supports intermanual transfer of motor skill
M-120. Posterior Reversible Encephalopathy Syndrome
(PRES) May Not Necessitate a Change in
Chemotherapeutic Regimen When Associated with
Tumor Lysis Syndrome
Terri L. Postma, and Gregory A. Jicha; Lexington, KY
PRES is diagnosed by characteristic clinical and radiographic
findings which are often reversible. Specific chemotherapeutic agents have been implicated as causative factors. Treatment typically involves cessation or modification of these
agents. It remains unclear whether changing to a potentially
less effective regimen is warranted. Several reports suggested
the lack of clinical recurrence of PRES following readministration of the offending therapy but failed to document this
radiographically. We followed a young man with Burkitt
lymphoma who developed PRES in association with spontaneous TLS and hyper-CVAD chemotherapy. MRI findings
were consistent with PRES. Medically managed hypertension
and seizures resulted in clinical and radiographic resolution
of PRES. One month later, rechallenge with the same chemotherapeutic regimen in the absence of TLS produced no
clinical or radiographic evidence of PRES. Multiple additional courses of chemotherapy were completed without further incident. The risk of developing PRES after induction
of chemotherapy may be related to TLS or associated features and may not be specific to the chemotherapeutic agent
used. Rechallenge with optimal chemotherapeutic combinations should be considered providing associated risks such as
TLS are well controlled.
M-121. Use of Autologous Mesenchymal Stem Cells
for Neural Repair
Violaine K. Harris, Pamela Good, Nara Chhua, and
Saud A. Sadiq; New York, NY
Aim: We investigated whether bone marrow derived mesenchymal stem cells (MSC) are capable of differentiating into
functioning neural cells and are safe to use in autologous
stem cell therapy in patients with multiple sclerosis (MS).
Methods: Bone marrow aspirates are obtained from 25 patient volunteers through an IRB approved protocol. MSC are
isolated from the mononuclear fraction after gradient centrifugation, specifically enriched, and expanded in media containing 10% autologous patient serum. MSC are differentiated into neural precursors by culturing in serum-free media
containing EGF and bFGF for 10 – 15 days. Neurospheres
are analysed for further differentiation potential into neuronal, astrocytic and oligodendroglial lineage by immunofluorescence and gene expression. In 5 patients autologous neurospheres were injected intrathecally to determine
Results: All MSCs show characteristic growth, morphology,
cell surface marker expression pattern, and adipogenic/osteogenic differentiation capability. Differentation into Nestinpositive neurospheres is achieved in all samples and in vitro,
these neurospheres further differentiate into neuronal and
Annals of Neurology
Vol 62 (suppl 11)
oligodendroglial cells. Intrathecal injection of autologous
neurospheres appears safe and well tolerated.
Conclusion: Adult autologous MSC are an easily accessible
source of neural stem cells and ongoing studies may help
establish their feasibility in neural repair strategies. Study
supported by Damian Foundation. Advisory Board of
M-122. Subsequent Adverse Event Following Syncope:
Who Is at Highest Risk?
Benjamin J. Sandefur, M. Fernanda Bellolio, Latha G. Stead,
and Wyatt W. Decker; Rochester, MN
OBJECTIVE: To determine which patients have a greater
risk of subsequent adverse event (SAE), defined as death,
stroke, myocardial infarction (MI), or cardiac arrhythmia, in
the year following syncope.
METHODS: Study population: 183 consecutive patients
presented to the Emergency Department with syncope. We
reviewed demographics, laboratory and electrocardiographic
data, and SAEs in the following year.
RESULTS: There were 75 men (41%). The mean age⫾SD
was 57.8⫾22.2 years (range, 18 – 93 years).
A total of 17 (9.3%) SAEs occurred: 9 deaths, 6 arrhythmias,
2 strokes. There were no Mis in the year following syncopal
event, although 6% of the cohort had an elevated troponin
at presentation.
In the linear regression model we found (patients without
SEA vs. with SAE):
– higher age (56.5⫾2 vs. 74.5⫾6 years; p⫽0.005),
– longer QTc (430 vs. 468 msec; p⫽0.0002) and QRS (94
vs. 109 msec; p⫽0.010) intervals
– and higher levels of plasma glucose (119.7⫾3 vs.
165.5⫾11 mg/dL; p⬍0.0001) were significantly associated
with an increased risk of subsequent event.
CONCLUSION: This study suggests that older age, hyperglycemia and prolonged electrocardiographic intervals are associated with an increased risk of SAE in patients presenting
with syncope. Study supported by Emergency Department,
Mayo Clinic, Rochester, MN. Mayo Medical School, Mayo
Clinic, Rochester, MN.
M-123. Obstructive Hydrocephalus Is a Common
Etiology of the NPH Syndrome
Robin K. Wilson, and Michael A. Williams; Baltimore, MD
Objective: To evaluate the frequency of obstructive hydrocephalus (OH) in elderly patients with symptoms of normal
pressure hydrocephalus (NPH).
Background: OH in the elderly is thought to be rare.
Methods: From 2001 – 2005, we evaluated 205 patients ⱖ
age 65 for suspected NPH. Patients with communicating hydrocephalus were evaluated by CSF drainage via lumbar
puncture or spinal catheter. 8/12 with OH were evaluated by
ICP monitoring.
Results: 193 (94.1%) had communicating ventricles, of
whom 141 responded to CSF drainage and were referred for
shunt surgery. 12 (5.9%) had partial or complete OH. Etiologies included aqueductal stenosis (n⫽9), acoustic neuroma (n⫽1), colloid cyst (n⫽1), and Chiari malformation
(n⫽1). 10/12 were referred for treatment.
Conclusions: Nearly 8% (12/153) of patients diagnosed with
NPH actually had OH, which is more common in the NPH
population than generally appreciated. Evaluation of Sylvian
aqueduct anatomy by MRI or high resolution CT is warranted in elderly patients with possible NPH. OH requires
different diagnostic strategies, such as ICP monitoring via
intraventricular catheter rather than CSF drainage via LP or
spinal catheter. OH in the elderly can be treated with shunts
or endoscopic third ventriculostomy.
M-124. Mitochondrial DNA A8344G tRNALys
Mutation Associated with Recurrent Migratory Brain
Stem Stroke-Like Episodes
Ioannis Zaganas, Latsoudis Helen, Papadaki Eufrosini,
Vorgia Pelagia, Spilioti Martha, and Plaitakis Andreas;
Herakion, Crete, Greece; and Heraklion, Crete, Greece
The A8344G tRNALys mitochondrial DNA mutation is
typically associated with MERRF syndrome. We studied a
17-year-old female who had a long-standing MERRF-like
disorder characterized by deafness, seizures, peripheral neuropathy, ataxia, endocrinopathy and elevated blood and CSF
lactate and who recently experienced two distinct episodes of
clinical worsening associated with brain stem stroke-like lesions. The first occurred in August 2006 and it was clinically
manifested by oculomotor disturbances and severe gait ataxia
with partial recovery occurring over the ensuing months.
Brain MRI revealed a stroke-like lesion in the tegmentum of
the right midbrain. In January of 2007, the patient experienced the abrupt onset of swallowing difficulties, dysarthria
and increasing gait ataxia. Repeated brain MRI revealed a
new stroke-like lesion in the right medulla while the previous
midbrain lesion showed substantial resolution. Both lesions
showed high signals on DWI with normal apparent diffusion
co-efficient values. DNA analysis revealed the A8344G
tRNALys mitochondrial mutation in almost homoplasmic
state. The A3243G mutation that is typically associated with
MELAS and occasionally with the MERRF/MELAS overlap
syndrome was absent. Hence, the A8344G tRNALys mutation can produce recurrent migratory stroke-like episodes involving the brain-stem.
M-125. A Reliable Beta Rhythm-Based BrainComputer Interface Associated with Human Natural
Motor Behavior
Ou Bai, Peter Lin, Sherry Vorbach, Mary Kay Floeter,
Noriaki Hattori, and Mark Hallett; Bethesda, MD
A brain-computer interface (BCI) provides an alternative
brain communication pathway to restore motor function for
patients with severe neurological disorders. We have been exploring the reliability of a new BCI method using noninvasive EEG signals associated with human natural motor
behavior that does not require extensive training. We used a
natural behavior, where the users perform or imagine either
sustaining or stopping a motor task which is time locked in
a predefined time window. The performance of the proposed
BCI was validated by an online binary control game for
2-dimensional cursor movement. The feature analysis
showed that EEG beta band activity over sensorimotor area
provided the best signal. With simple, model-free classification of beta band EEG activity from a single Laplacian channel, the online classification of the binary motor intentions
were (actual movement/imagery): 90%-100%/80%-95% for
healthy volunteers, and 93%/85% for a stroke patient, and
90%/88% for an ALS patient. This new non-invasive BCI
method may be practical for clinical applications since extensive training is not required. Study supported by the Intra-
mural Research Program of the NIH (National Institute of
Neurological Disorders and Stroke).
M-126. Differential Determinant Factors above and
below the Injury Level Regulate Differentiation Fate of
Transplanted Neural Progenitors in Chronic Spinal
Cord Injury
Daniel Becker, Carlo O. Martinez, and John W. McDonald;
Baltimore, MD
Neural activity is important for endogenous stem cell proliferation in the normal and injured central nervous system.
We examined whether the differentiation fate of transplanted
ES cell-derived neural progenitors is influenced by the spinal
level of transplantation in rats with chronic spinal cord injury (SCI). Six weeks following complete T8/9 suction ablation SCI in adult female rats, we transplanted 100,000 GFP
expressing (4-/4⫹ staged) neural induced ES cells one segment above and below the injury level. Fifteen days posttransplantation, differentiation fate was quantified using
lineage-specific immunomarkers and stereologic epifluorescence microscopy.
Differentiation of ES cell-derived progenitors to neuron phenotypes was reduced three fold when transplanted below
compared to above the level of SCI (27% ⫾ 9% above vs.
9% ⫾ 1% below). In contrast, the total number of surviving
ES cell-derived cells did not differ as a function of the site of
The fate of neural progenitor differentiation is markedly influenced by the level of spinal transplantation, with preferential differentiation to neurons above, and glia below the
injury level. Further work to understand the contributing
mechanisms will be important. Study supported by NINDS
and NIDCR grants NS39577, NS40520, NS45023, and
M-127. Feasibility of Home Telerehabilitation in
Patients with Multiple Sclerosis
Joseph Finkelstein, Heather K. Castro, and Patricia Provance;
Baltimore, MD
Background. Multiple Sclerosis (MS) is a chronic debilitating disease requiring lifelong rehabilitation and medication
Methods. We assessed the feasibility and acceptance of the
Home Automated Telemanagement (HAT) system to support an individualized home rehabilitation program in 12 patients with Multiple Sclerosis (MS). The patients were asked
to complete their prescribed exercises and track the results
with the assistance of the HAT system on a daily basis for 12
weeks. The HAT system generated alerts in cases of patient
non-compliance. The patients were assessed at baseline and
at the exit from the study.
Results. The attitudinal survey indicated that 83% of participants found the system “not complicated at all” to use.
The majority of the patients (83%) indicated that they
would most likely or definitely use the system again, and
100% of the patients claimed that they would most likely or
definitely advise other patients to use the system. The SixMinute Walk Test, 25 Foot Walk Test and Berg Balance
scale showed statistically significant improvement in patient
functional status. Qualitative interviews showed high acceptance of the system by the patients.
Conclusion. Home telerehabilitation has significant potential for improving care in MS patients.
Program and Abstracts, American Neurological Association
M-128. Myostatin, a Key Regulator of Skeletal Muscle
Mass, Is Increased in Skeletal Muscle after Stroke
Charlene E. Hafer-Macko, Shuzhen Yu, Fred M. Ivey,
Brian C. Salter, and Alice S. Ryan; Baltimore, MD
Skeletal muscle undergoes several major changes after stroke,
including hemiparetic leg atrophy. Myostatin is a negative
regulator of skeletal muscle mass and is elevated with disuse,
glucocorticoid use, and[ HIV-associated muscle wasting.
This study investigated whether myostatin expression was elevated in hemiparetic skeletal muscle after stroke. Twentythree participants with hemiparetic stroke and eight age, gender, and BMI matched healthy volunteers consented for
muscle biopsy. Myostatin transcript expression was measured
and normalized to the housekeeping gene 36B4. A natural
logarithm transformation was performed for data analysis.
Mean age of stroke and healthy participants was 65.7 ⫾ 7.8
and 65.5 ⫾ 7.9 years, respectively.
Mid-thigh cross-sectional muscle area was reduced in the
hemiparetic (67⫾5.4 cm2) compared to both nonparetic
(82 ⫾ 6.0; p ⬍0.01) stroke and healthy volunteer (95 ⫾
5.0; p ⬍0.01) thighs by computed tomography. Myostatin
expression was significantly increased on the hemiparetic versus non-paretic side for stroke participants before (69.7 vs.
46.1; p ⫽ 0.043) and after (0.20 vs. 0.13; p ⫽ 0.041) normalizing to 36B4 expression. There was a trend for elevated
myostatin expression in hemiparetic compared to healthy
volunteer skeletal muscle. Myostatin might play an important[ role in the hemiparetic leg skeletal muscle atrophy after
chronic stroke. Study supported by the VA Geriatrics Research, Education, and Clinical Center and NIA Pepper
Center; The VA provides salary support as well as research
M-129. Validation of the “Four Score” Coma Scale in
the Emergency Department
Rahul Kashyap, David L. Nash, Anjali Bhagra,
M. Fernanda Bellolio, Latha G. Stead, and
Eelco F. M. Wijdicks; Rochester, MN
OBJECTIVE: FOUR score has previously been validated
scale in the neurointensive care setting. In this study, we
sought to: 1) validate the use of FOUR score in the busy
emergency department (ED) setting by non-neurologists via
interrater reliability assessment 2) compare its performance
against the Glasgow Coma Scale (GCS) 3) correlate it to
functional outcome at hospital discharge.
METHODS: 162 observations prospectively collected in
ED. Three types of examiners performed FOUR score: ED
physician, ED resident, ED nurse. Each patient rated on
both scales by two raters blinded to their colleague’s score.
Order of evaluations randomized to reduce bias. Patients followed through hospital discharge; functional outcome measured using modified Rankin Score (mRS).
RESULTS: Interrater reliability for FOUR score was excellent, overall k⫽0.88. There was no difference between median FOUR score assigned by nurses, residents or physicians
(p⫽0.265), but there was for GCS (p⫽0.018). FOUR score
significantly correlated with mRS (p⬍0.001) with a robust
strength of association R2⫽0.35.
CONCLUSION: There is excellent interrater reliability for
FOUR score even in a busy ED. In this regard it outperforms the GCS, and will improve communication with the
neurologist. It is also predictive of functional outcome.
Annals of Neurology
Vol 62 (suppl 11)
M-130. Long-Term Outcome of Everyday Functioning
and Neurocognitive Ability Following CNS
Opportunistic Infection in AIDS
Andrew J. Levine, Charles H. Hinkin, Ellen Haupt,
Mariana Martinez, Miguel Valdes-Sueiras,
Ernestina H. Saxton, Glen Mathisen, Deborah L. Commins,
Ardis Moe, Kaz Ando, Charles Farthing, and Elyse J. Singer;
Los Angeles, CA; and Sylmar, CA
Central nervous system opportunistic infections (CNS-OI)
are a significant cause of morbidity in AIDS. While current
interventions are more successful in treating CNS-OI, little
data exists regarding long-term behavioral outcomes. We examined neurocognitive and activities of daily living (ADL)
data among 3 groups of adults with AIDS/CNS-OI: cryptococcal meningitis (CM), toxoplasmosis encephalitis (TE),
and progressive multifocal leukoencephalopathy (PML). A
group of 10 adults with AIDS, but without CNS-OI, was
used as a comparison group. Neurocognitive tests and an
ADL measure were administered upon study entry, allowing
for cross sectional analyses. Demographic, medical, and neurocognitive predictors of change in ADLs were examined via
logistic regression. Results indicate that the CNS-OI groups
did not differ from the comparison group with regards to
baseline neuropsychological or ADL functioning. However,
trends in the data suggest lasting impairments among those
with PML and TE. Also, neuropsychological ability was
found to be the sole predictor of decline of most ADLs from
premorbid levels to study entry. The results likely reflect the
known neuropathological consequences of the various CNSOIs. Future strategies for further exploring longterm outcomes in AIDS/CNS-OI are discussed. Study supported by
NS38841, National Neurological AIDS Bank.
M-131. Intensive Nutritional Supplements Can
Improve Outcomes in Stroke Rehabilitation
Meheroz H. Rabadi, Patricia L. Coar, Meredith Lukin,
Martin Lesser, and John P. Blass; White Plains, NY; and
Long Island, NY
Background. Poor nutrition is a common complication following stroke severe enough to require in-patient rehabilitation. We therefore tested whether intensive nutritional supplements given to undernourished patients on their
admission to a specialized stroke rehabilitation service would
improve patient outcomes.
Method. Randomized, prospective, double-blind, single center study comparing intensive nutritional supplementation to
routine nutritional supplementation in 102 undernourished
patients. Successive admissions were studied, except for patients who did not grant informed consent. The nutritional
supplements are commercially available and FDA approved.
The company manufacturing the supplements was not involved in the design, execution, or analysis of this study.
Results. The patients receiving intensive nutritional supplementation improved more than those on standard nutritional
supplements, on measures of motor function (total FIM,
FIM motor sub-score, 2-minute and 6-minute timed walk
tests, all significant at (p⫽⬍0.002)) but not on measures of
cognition (FIM cognition score). A higher proportion of patients who received the intensive nutritional supplementation
went home compared to those on standard supplementation
Conclusion. Intensive nutritional supplementation, using
readily available commercial preparations improves motor recovery in malnourished patients receiving intensive in-patient
rehabilitation after stroke. Study supported by Burke Foundation.
M-132. Driving and Multiple Sclerosis: What Factors
Make a Difference? Cognitive? Physical? Or Both?
Maria T. Schultheis, Valerie Weisser, Nicole Sestito,
Elie Elovic, Jocelyn Ang, Richard Nead, and Scott R. Millis;
Philadelphia, PA; West Orange, NJ; and Detroit, MI
Recent studies have examined changes in driving capacity
among individuals with multiple sclerosis (MS). This study
examined the relationship between driving, cognitive, and
physical measures in sixty-six individuals with clinically definite MS and 30 normal controls (NC). Cognitive measures
included tests that assessed cognitive domains relevant to
driving. Physical measures included 1) Expanded Disability
Status Scale, 2) lower and upper extremity measures and 3)
visual measures. Driving measures included 1) performance
on behind-the-wheel (BTW) and 2) composite DMV score
reflecting accident and violation history. Among MS participants, a logistic regression showed that information processing was only marginally significant predictor of driving performance on the BTW and a multiple regression revealed
that the visual memory and the visual perception were significant predictors of the DMV score. Correlational analysis
examining physical and driving measures revealed a significant relationship between upper extremity function and peripheral with number of accidents and number of violations.
These findings indicate that specific aspects of cognitive
functioning may influence driving performance in MS. Interestingly, the clinically used BTW, was associated to only
physical measures. The clinical relevance and application of
these findings are discussed. Study supported by National
Multiple Sclerosis Society.
DOI: 10.1002/ana.11640
Program and Abstracts, American Neurological Association
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