Columbia Experts at American Academy of Neurology

Columbia University Medical Center & NewYork-Presbyterian Hospital Experts at American Academy of Neurology

The following research from Columbia University Medical Center and NewYork-Presbyterian Hospital is being presented at the annual meeting of the American Academy of Neurology (AAN), April 28"May 5, in Boston.

EMBARGO NOTE: The embargo for all abstracts to be presented at the 59th Annual Meeting is in effect until the date and time of the presentation unless otherwise noted on the abstract and/or press release. If there are questions, please contact the AAN media and public relations team.

Oral Presentations (Abstracts Copied Below)

Midazolam Challenge Test as a Guide to Oral GABAergic Treatment of Patients with Post-Stroke Dystonic Hemiparesis

Authors: Randolph S. Marshall, Laura Lennihan, Mitchell Berman, J. Mohr, Ronald Lazar

Session Info: Scientific Sessions: Neural Repair (3:45 PM-5:00 PM)

Presentation Time: Wednesday, May 2, 2007, 4:15 pm

Room: 310

Summary/Significance: Use of short-acting intravenous medication, midazolam, to test whether patients will react well to treatment with long-acting clobazam to eliminate increased tone problem that cause dystonia, a huge burden for patients & rehab strategies. Lead author Dr. Randolph Marshall, associate professor of clinical neurology and chief, Division of Stroke & Critical Care, describes this as a novel methodology—using a therapy to determine treatment success with another medication.

Epidemiology of Non-Traumatic Pediatric Subarachnoid Hemorrhage in the United States

Authors: Brian T. Bateman, Belmont, MA, Geoffrey Heyer, Douglas Sproule, Marc Patterson, H. Christian Schumacher, New York, NY

Session Info: Scientific Sessions: Child Neurology (2:00 PM-3:30 PM)

Presentation Time: Wednesday, May 2, 2007, 2:30 pm

Room: 311

Summary/Significance: This research was conducted to determine the frequency of stroke or other sudden neurological events of a vascular nature in children. Strokes, while much less common among children and young adults, may occur at any age. While results found that the incidence of these events are rare—indeed, much less common than in adults—but that they do occur. Parents, especially parents of children with congenital heart disease or sickle cell disease, should be aware of the symptoms of stroke and what to do. Just as in adults, symptoms may include severe headache, sensory changes, seizure and sudden changes in speech. According to Dr. Marc Patterson, senior author on the study and chief, Division of Pediatric Neurology, this study is important as it helps advance knowledge of stroke in children. "Compared to the vast amounts of information we know about stroke in adults—risk factors, etc.—relatively little is known about stroke in children," said Dr. Patterson. "However, we do know that children with stroke generally have better outcomes because their brains generally more plastic; outcomes in adults are always worse."

A Randomized Trial of Unruptured Brain AVMs (ARUBA Trial)

Authors: J. P. Mohr, Alan J. Moskowitz, Michael K. Parides, Annetine C. Gelijns, Deborah V. Ascheim, Ronald G. Levitan, New York, NY, Ellen Moquete, New York, Eric Vicaut, Christian Stapf, Paris, France

Session Info: Scientific Sessions: Hemorrhagic Stroke (1:30 PM-3:30 PM)

Presentation Time: Thursday, May 3, 2007, 2:45 pm

Room: 312

Summary/Significance: Session will outline a planned international trial to look at genetic malformations of AVMs and to determine the optimal treatment for unruptured brain arteriovenous malformations (AVMs) compared to invasive treatment. The trial, which began enrolling patients in 2006, aims to enroll 800 patients that will be randomized between surgery and medical intervention, at 100 participating centers around the world.

Silas Weir Mitchell's Essential Tremor

Authors: Elan D. Louis, Center for Parkinson 's disease & Other Movement Disorders

Session Info: Scientific Sessions: History (2:00 PM-3:30 PM)

Presentation Time: Wednesday, May 2, 2007, 2:30 pm

Room: 310

Summary/Significance: Dr. Louis set out to determine whether Silas Weir Mitchell (1829-1914), recognized as one of the most important neurologists in American Medicine, suffered from an essential tremor. Upon analysis of Mitchell's writing samples and those of several of his family members, Dr. Louis has determined that Mitchell had a familial action tremor that began in his early 40s and worsened considerably with age; later handwriting was nearly illegible. The likely diagnosis was essential tremor.

Stroke Prevention in 2007

Speaker: Mitchell S. V. Elkind, MD, MS, FAAN

Session Info: AM Half-Day Course (9:00 AM-12:45 PM)

Presentation Time: Monday, April 30, 2007, 9:00 am

Summary: The key to reducing the burden of morbidity and mortality from stroke is prevention. The past decade has seen a dramatic increase in evidence-based prevention strategies. The pillars of stroke prevention include medical risk reduction, procedures to reduce stenosis of vessels, and anticoagulant and antiplatelet therapies. Dr. Elkind will lead a review of results from recently completed clinical trials of statins, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs).

Stroke/Critical Care Scientific Topic Highlights

Speakers: Stephan A. Mayer, MD, Brett M. Kissela, MD

Session Info: Scientific Topic Highlights (6:00 PM-8:00 PM)

Presentation Time: Thursday, May 3, 2007, 6:00 pm

Summary: Roundup of stroke critical care issues presented at AAN.

Posters:

* "Mediterranean Diet (MeDi) and Longevity in Alzheimer's Disease (AD) Course" Wednesday, May 2, 2007, 7:00 am, Aging and Dementia: Epidemiology (7:00 AM-10:00 AM), poster # P04.098 * "Dementia in a Series of 109 Persons with Autopsy-Confirmed Amyotrophic Lateral Sclerosis (ALS)" Tuesday, May 1, 2007, 4:00 pm, Aging and Dementia: Clinical II (4:00 PM-7:30 PM), poster #P03.047 * "How Useful Is the ICD-9 CM Code 333.1 as an Identifier of Patients with Essential Tremor?" Wednesday, May 2, 2007, 4:00 pm, Neuroepidemiology / Health Services and Outcomes Research (4:00 PM-7:00 PM), poster # P05.040 * "Function, Early Phase Trial Outcomes, and the Timed Get up and Go Test in Amyotrophic Lateral Sclerosis" Tuesday, May 1, 2007, 7:00 am, Anterior Horn: Clinical Research and Outcome Measures (7:00 AM-10:00 AM), poster #P01.085 * "Pyruvate Carboxylase Deficiency: Mosaicism Correlates with Prolonged Survival" Tuesday, May 1, 2007 - 11:30 AM, Child Neurology / Developmental Neurobiology (11:30 AM-2:30 PM), poster #P02.016 * "Oxidative and Anti-Oxidative Biomarkers in Patients with Sporadic ALS" Thursday, May 3, 2007, 4:00 pm, Anterior Horn: Biomarkers and Imaging (4:00 PM"7:00 PM), poster # P08.035 * "Molecular Genetics of Glut1 Deficiency Syndrome" Thursday, May 3, 2007"4:00 PM, Neurogenetics and Gene Therapy I (4:00 PM-7:00 PM), poster # P08.144

ABSTRACTS FOR ABOVE-LISTED ORAL PRESENTATIONS

[S37.003] Midazolam Challenge Test as a Guide to Oral GABAergic Treatment of Patients with Post-Stroke Dystonic Hemiparesis. Randolph S. Marshall, Laura Lennihan, Mitchell Berman, J. Mohr, Ronald Lazar, New York, NY

OBJECTIVE: To explore a novel method of treating post-stroke dystonic hemiparesis.

BACKGROUND: Post-stroke hypertonia seriously hinders rehabilitation of hemiparesis. We previously showed that administering a short-acting GABA(A) agonist, midazolam, transiently re-induces former stroke deficits in recovered patients,1 suggesting GABA up-regulation differentially inhibits reorganized excitatory pathways responsible for recovery. Because the emergence of post-stroke dystonia may represent a maladaptive reorganization of inhibition-excitation balance, we hypothesized that a GABA challenge might reduce excessive excitatory influence and mediate a more normal corticospinal output. Such a finding could suggest new treatment approaches for this difficult condition.

DESIGN/METHODS: Eight patients with post-stroke dystonic or spastic hemiparesis underwent midazolam challenge as previously published. All had undergone treatment with baclofen, tizanidine, and/or intramuscular Botox, which reduced tone and discomfort, but produced no functional gains in the dystonic limbs. Under neuroanesthesia monitoring, midazolam was administered intravenously in aliquots of 1mg, titrating to mild awake sedation. Motor examination for power, tone and repetitive movements was performed and videotaped for adjudicated review before, during, and 1 hour post-drug.

RESULTS: Under midazolam, all patients tone was reduced and all had mild reduction in power as expected from previous work. In 4, the dystonia (involuntary distal torsion during proximal limb movement) temporarily diminished. In 3, voluntary distal extension movements were seen that were previously impossible. The 4 with positive responses to midazolam were subsequently placed on a long-acting, non-sedating GABA(A) agonist, clobazam, with demonstrable functional improvements, particularly with gait, assessed with an active titration regimen over the course of several months.

CONCLUSIONS/RELEVANCE: For patients with post-stroke dystonic hemiparesis who have failed standard antispasticity approaches, a positive response to a short-acting GABA(A) agonist can suggest the use of a long-acting GABAergic agent to produce meaningful improvements in motor function. 1. Lazar, RM et al. (2002). Reemergence of stroke deficits with midazolam challenge. Stroke;33:283-5. Supported by: NICHD HD43249 (Lazar, PI).

[S27.003] Epidemiology of Non-Traumatic Pediatric Subarachnoid Hemorrhage in the United States. Brian T. Bateman, Belmont, MA, Geoffrey Heyer, Douglas Sproule, Marc Patterson, H. Christian Schumacher, New York, NY

OBJECTIVE: To examine the epidemiology, in-hospital morbidity and mortality of pediatric non-traumatic subarachnoid hemorrhage (SAH).

BACKGROUND: Pediatric non-traumatic SAH is a devastating disorder associated with high rates of morbidity and mortality. Only few population-based studies have examined its epidemiology, risk factors, and outcomes.

DESIGN/METHODS: Patients 20 years of age with a diagnosis of non-traumatic SAH were extracted from the Nationwide Inpatient Sample (NIS) that reflects approximately 20% of admissions to non-Federal hospitals in the United States, for the years 1993-2002. Data from the United States Census Bureau were used to estimate the incidence of hospitalized non-traumatic SAH in pediatric patients. A comparison group of hospitalized young adults 20-39 years of age was also analyzed. Frequencies of risk factors/co-morbidities are described in both patient groups.

RESULTS: We identified 914 children 20 years of age with non-traumatic SAH corresponding to a hospitalization incidence of 0.59 cases per 100,000 at-risk person years. Using the same method we calculated an incidence of 4.2 hospitalized cases per 100,000 person years from our young-adult cohort. The most frequently occurring co-morbidities / risk factors among pediatric cases include cerebral vascular malformations (6.5%), sepsis (6.0%), sickle cell disease (3.5%), congenital heart disease (3.3%), and consumptive coagulopathy (3.1%). Compared to young adults the pediatric cohort had a higher proportion of males (57.7% vs. 42.9%), and a higher proportion of subarachnoid hemorrhage associated with infectious, congenital, hematologic, and oncologic comorbidities. The in-hospital mortality rate for the pediatric cohort was 20.2%.

CONCLUSIONS/RELEVANCE: Non-traumatic SAH is a rare disorder among children, with an incidence that is approximately one-eighth of that seen in young adults. Pediatric subarachnoid hemorrhage has a distinct risk profile and merits further study as a unique disease entity. Supported by: B.T.B. was supported by the Doris Duke Charitable Foundation; H. C. S. was supported by the NIH training grant PHS 5-T32-NS007155-26.

[S44.006] ARUBA A Randomized Trial of Unruptured Brain AVMs. J. P. Mohr, Alan J. Moskowitz, Michael K. Parides, Annetine C. Gelijns, Deborah V. Ascheim, Ronald G. Levitan, New York, NY, Ellen Moquete, New York, Eric Vicaut, Christian Stapf, Paris, France

OBJECTIVE: We propose a randomized treatment trial testing the hypothesis that medical management improves long-term outcomes of patients with unruptured brain arteriovenous malformations (AVMs) compared to invasive treatment.

BACKGROUND: Current invasive treatment for brain arteriovenous malformations (AVMs) is varied and includes endovascular procedures, neurosurgery, and radiotherapy alone and in combination. However, no controlled treatment data on invasive AVM therapy exist and recent prospective data raise serious doubt about the treatment benefit for unruptured brain AVMs.

DESIGN/METHODS: ARUBA is an international, multicenter, multidisciplinary, randomized, controlled, open, prospective clinical trial. Sample Size: 800 patients (1:1 random assignment). Population Studied: Patients aged 18 years, diagnosed with an unruptured brain AVM considered treatable by the local investigators. Primary Aim: To determine whether medical management is superior to invasive therapy for preventing the composite outcome of death from any cause or stroke (symptomatic hemorrhage or infarction confirmed by imaging) in the treatment of unruptured brain AVMs. Secondary Aim: To determine whether treatment of unruptured brain AVMs by medical management decreases the risk of death or clinical impairment (Rankin Score >/= 2) at 5 years post-randomization compared to invasive therapy. Interventions: Patients will be randomly assigned to invasive therapy (endovascular, surgical, and/or radiation therapy) versus medical management alone. Patients will be followed for a minimum of 5 years and a maximum of 7.5 years (mean 6.25 years) from randomization.

RESULTS: The statistical test will have 87.5% power to detect a risk reduction of 40% (hazard ratio of 0.60), and 80% power to detect a risk reduction of 36.5% (hazard ratio of 0.635). These hazard ratios correspond to an absolute decrease in 5-year event rates of 7.5% and 6.7% respectively for medical management.

CONCLUSIONS/RELEVANCE: First-ever clinical trial evaluating brain AVM therapy with over 100 participating centers world-wide (North America, Europe, South America, Australia). Patient enrollment has started in 2006. Contact information: www.arubastudy.org. Supported by: NIH/NINDS (R01 NS 051483-01).

[S28.003] Silas Weir Mitchell's Essential Tremor. Elan D. Louis, New York, NY

OBJECTIVE: To: (1) characterize Silas Weir Mitchell's tremor using handwriting samples, (2) examine available handwriting samples of family members to determine whether this tremor was familial, (3) study Mitchell's allusions to his tremor in his personal writings, and (4) assess the extent to which Mitchell referred to tremor in his scientific writings and fictional works.

BACKGROUND: Weir Mitchell (1829-1914) is recognized as one of the most important neurologists in American Medicine. His biographers refer in passing to a tremor although this tremor has not been the focus of historical research.

DESIGN/METHODS: Primary sources were the Papers of S. Weir Mitchell, College of Physicians of Philadelphia (i.e., Mitchell's correspondence and diaries) including handwriting samples (1850-1914) as well as Mitchell's scientific and 27 fictional writings.

RESULTS: Early handwriting was free of tremor, yet by 1873, characters were wobbly. In his travel journal (Yellowstone Park, 1879), Mitchell sketched several mountains; low-amplitude tremor is clearly identifiable. Handwriting in the 1880s and 1890s shows clear oscillations of moderate-amplitude and, by the first decade of the twentieth century, his handwriting was virtually illegible. In a rare diary entry (1910) he summed up his health, referring to the familial malady called tremor. Letters written by his mother and maternal grandfather reveal mild tremor. Tremor was not a prominent feature of Mitchell's scientific writings. Mitchell referred to tremor in four of 27 fictional writings; in The Adventures of Francois, one of the characters clearly had essential tremor.

CONCLUSIONS/RELEVANCE: Mitchell had a familial action tremor that began in his early 40s and worsened considerably with age; later handwriting was nearly illegible. The likely diagnosis was essential tremor. Curiously, Mitchell alluded only rarely to this tremor in his personal writings and tremor was not prominently featured in his scientific or fictional writings.

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