Stephanie Scala, MA, CCRP- Clinical Research Specialist Yuval Zabar, MD- Research Director Paul Gross, MD- Chairman Issue 3

September 2012


Effects of subthalamic nucleus stimulation on striatal dopaminergic transmission in patients with Parkinson’s disease

This is an investigator initiated pilot study designed by Diana Apetauerova, MD and funded by a Wise grant. The mechanisms by which deep brain stimulation (DBS) of the subthalamic nucleus (STN) leads to clinical benefit in Parkinson's disease (PD), especially with regard to dopaminergic transmission, remain unclear. DaTscan™ (Ioflupane I 123 Injection) in brain SPECT imaging is an FDA approved screening test which helps differentiate between PD and other similar movement disorders and it permits us to measure and see dopamine’s activity in the brain. By performing DAT scan before and after DBS, we will be able to directly visualize any quantitative changes in dopaminergic uptake. If there is improvement of dopaminergic uptake, this might suggest a neuroprotective benefit in DBS. The study objective is to evaluate alterations of synaptic dopaminergic signaling following bilateral STN-DBS in PD within a 6 month follow-up in 20 patients. Enrollment will begin late fall/early winter. Principal Investigator: Diana Apetaeurova, MD A Prospective, Multinational, Open-Label, Single-Arm, Explorative Study to Evaluate the Tolerability and Efficacy of Lacosamide When Added to Levetiracetam With Withdrawal of the Concomitant Sodium Channel Blocking Antiepileptic Drug in Subjects with Uncontrolled Partial-Onset Seizures

This study, sponsored by UCB Biosciences, Inc., is a Phase 3b, prospective, multinational, open-label, single-arm, explorative study. The primary objective of this study is to assess the overall effectiveness of Lacosamide (200mg/day to 600mg/day) when added to a stable dose of Levetiracetam (1000mg/day to 3000mg/day) with withdrawal of the concomitant sodium channel blocking antiepileptic drug in subjects with partial-onset seizures not adequately controlled on their dual Levetiracetam and sodium channel blocking antiepileptic drug regimen. Enrollment should begin late fall and up to 4 patients will be enrolled. Principal Investigator: Joel Oster, MD 1




Title:

Summary:

A randomised, double-blind, parallel-group placebo-controlled phase lll study to evaluate the efficacy and safety of desmoteplase in subjects with acute ischemic stroke (DIAS 4)

This study, sponsored by International Clinical Research, is a randomized, double-blind, parallel-group placebo-controlled phase III study designed to confirm the efficacy and further evaluate the safety of desmoteplase 90 µg/kg in acute ischemic stroke within 3 to 9 hours after the onset of symptoms. The primary objective of this study is to evaluate the efficacy of desmoteplase 90 µg/kg vs. placebo in terms of favorable outcome at Day 90 in subjects with acute ischemic stroke. The study will investigate one dose of desmoteplase (90 µg /kg) versus placebo given as a single intravenous bolus. Following baseline assessments eligible subjects will receive treatment with the IMP within 3-9 hours after the onset of stroke symptoms. In the subsequent hours and days subjects will undergo regular safety and efficacy assessments until they are discharged. Subjects will have follow-up visits at Day 30 and Day 90. This study is IRB approved, but not yet open to enrollment.

PI: Barbara Voetsch, MD, PhD

Title: Cerebral Perfusion Abnormalities on the Electroencephalogram (EEG)

Contact: (781) 744-3216

Summary:

This is a homegrown project designed by Joel Oster, MD. The primary objective of this study is to determine whether EEG is a useful clinical modality for identifying cerebral perfusion defects. Patients who demonstrate abnormal cerebral perfusion on the basis of a CT study will have an accompanying EEG (up to 5 EEG’s will be performed).

PI: Joel Oster, MD

Title: Dynamic Contrast Enhanced (DCE) MR Permeability Maps: Clinical Application to Acute Ischemic Stroke- A Pilot Study

CRA: Nick Ventura

CRA: Stephanie Scala

Contact: (781) 744-2950

Summary:

This investigator initiated research project, funded by a Wise grant, hopes to answer the question- Who will develop hemorrhagic transformation and it’s location in acute ischemic stroke patients- by using Dynamic Contrast Enhanced (DCE) MRI. DCE MRI technique is still under development and needs standardization, reproducibility and validation of its results to get clinical acceptance. If successfully completed, the results of this project will be able to answer the above key question leading to a greater research project with the ultimate goal of identifying and standardizing DCE MRI for patients with acute ischemic stroke.

PI: Kinan Hreib, MD, PhD; Co-I: Kiron Thomas, MD

CRA: Junius Beebe, BS

Contact: (781) 744-3330 2

Title: A Clock Drawing Test scoring application for dementia, vascular disease and Parkinson’s disease: A pilot study (Pen Study)

Summary:

This is a homegrown project designed by Dana Penney, PhD and funded by a Wise grant. Although widely used, variability exists among administration and scoring of the Clock Drawing Test (CDT). Given this variability, a standardized operationally defined automatic scoring system is needed. The goal of this study is: 1) to evaluate a pen application as an accurate scoring system for the clock drawing test and 2) to potentially develop clinical norms that would improve clinical diagnosis through more accurate scoring of known variables & incorporate in scoring new clinical variables. We are currently only recruiting for patients with Parkinson’s disease undergoing DBS surgery.

PI: Dana Penney, PhD

Title: Clock drawing test & neuropsychological testing: A multicenter repository

CRA: Stephanie Scala

Contact: (781) 744-2950

Summary:

This is a homegrown multicenter prospective data collection study using new software designed by Dana Penney, PhD and Randall Davis, PhD (MIT) to score Clock Drawing Tests of patients referred for routine neuropsychological testing. The purpose of this study is to: 1) determine the degree of diagnostic validity and reliability from using a novel evaluation of the Clock Drawing Test; 2) identify with greater precision clock drawing test results that constitute diagnostic markers (unique test measurements) and profiles (collection of results) and enable their use to determine which measures differentiate best between groups; and 3) improve diagnostic accuracy and potentially offer earlier detection and treatment. Approximately 8 sites are participating in this multicenter study.

PI: Dana Penney, PhD

CRA: Stephanie Scala

Contact: (781) 744-2950

Title:

Summary:

Deep brain stimulation surgery in the subthalamic nucleus for Parkinson’s disease using low frequency stimulation (DBS)

This is an investigator initiated pilot study designed by Diana Apetauerova, MD and funded by a Wise grant. The primary aims are: 1) to determine whether low-frequency stimulation (60 Hz) or combination high/low frequency improves the symptoms of PD in patients who have undergone DBS surgery and standard treatment with high frequency stimulation and medication adjustments and a) continue to have falls, b) have worsening of falls/balance or c) experience falls after DBS surgery; and 2) to determine whether low-frequency stimulation (60Hz) or combination high/low frequency reduces or prevents falls or improves gait/balance post surgery in patients naive to programming. Patients unable to tolerate bilateral low frequency stimulation will have the opportunity to roll over into the combination frequency stimulation arm.

PI: Diana Apetauerova, MD

CRA: Nick Ventura

Contact: (781) 744-3216 3

Title: Effects of Coenzyme Q10 in PSP, A Randomized, Multicenter PlaceboControlled, DoubleBlind Study (PSP)

Summary:

This is a homegrown, multicenter, randomized, placebo-controlled clinical trial designed by Diana Apetauerova, MD and sponsored by grants from the Society for PSP and Wise. The goal of this study is to compare the efficacy, safety and tolerability of Coenzyme Q10 versus placebo in patients with progressive supranuclear palsy (PSP). Efficacy of high doses of Coenzyme Q10 (2400mg/day) will be measured in PSP. We hope to enroll 70 subjects from several sites, including Lahey, Beth Israel, University of Vermont College of Medicine and the University of Alabama. Enrollment will be closing soon.

PI: Diana Apetauerova, MD

Title: Low-frequency repetitive transcranial magnetic stimulation in patients with medication-refractory tardive dyskinesia (rTMS)

CRA: Stephanie Scala

Summary:

This is a pilot, sham controlled, crossover trial designed by Julie LeegwaterKim, MD, PhD in collaboration with Jay Shils, PhD (Neurosurgery) and is funded by a Wise grant. The primary objective of this study is to determine the safety and clinical efficacy of rTMS in Tardive Dyskinesia (TD). This study will look at clinical and adverse event data among subjects with TD, before and after treatment with low-frequency rTMS or sham rTMS. The secondary objective is to assess potential immediate, cumulative and prolonged clinical effects of rTMS in TD.

PI: Julie Leegwater-Kim, MD, PhD

Title: The role of liver transplantation in the treatment of chronic hepatocerebral degeneration and related parkinsonism (Liver PD)

CRA: Nick Ventura

Contact: (781) 744-3216

Summary:

This is a homegrown project designed by Diana Apetauerova, MD in collaboration with hepatobiliary and funded by a Wise grant. The primary aims of the study are: 1) to define the frequency of patients on the transplant list who are affected by parkinsonism secondary to chronic hepatocerebral degeneration, and 2) to determine whether liver transplantation is an effective treatment. Patients are recruited exclusively from the liver transplant list.

PI: Diana Apetauerova, MD

Title:

Contact: (781) 744-2950

CRA: Stephanie Scala

Contact: (781) 744-2950

Summary:

A long term follow up This study, sponsored by St. Jude Medical Center, is a long term follow up study study of the patients designed to evaluate the long-term safety and efficacy of bilateral stimulation of who underwent bilateral the STN when using the Libra/LibraXP DBS system as adjunctive treatment for stimulation of the STN reducing some of the symptoms of advanced, levodopa -responsive PD that are using the LIBRA™/LIBRA™ XP not adequately controlled with medication. Patients who have undergone DBS DBS system as an of the STN may be eligible. adjunctive treatment for reducing some of the symptoms of advanced, levodopa -responsive PD that are not adequately controlled with medication. PI: Diana Apetauerova, MD CRA: Christine Gould (Neurosurgery) Contact: (781) 744-3956 4

Title: A Multicenter, Observational, OpenLabel, Single-Arm Study of Tysabri in Early RelapsingRemitting Multiple Sclerosis in Anti-JCV Antibody Negative Patients (STRIVE MS)

Summary:

This study, sponsored by Biogen Idec, is a phase 4, prospective, open-label, multicenter, single-country, observational study of anti-JCV antibody negative patients with early Relapsing-Remitting Multiple Sclerosis (RRMS) who are initiating treatment with Tysabri. The primary objective of the study is to determine which response factors (clinical and para clinical) predict overall disease-free status at Month 12 and Month 24, and clinical disease-free status in subsequent Months 36 and 48. The response factors include clinical assessments of sustained expanded disability status scale (EDSS) progression, relapse status, MRI measures, and patient reported outcomes (PROs) of cognition, capacity to work, quality of life (QoL), and visual function assessments. Study patients will be patients with RRMS who opt to begin treatment with Tysabri.

PI: Claudia Chaves, MD

Title: A Multicenter, Randomized, DoubleBlind, PlaceboControlled Study of the Efficacy of Natalizumab on Reducing Disability Progression in Subjects With Secondary Progressive Multiple Sclerosis (ASCEND)

CRA: Rik Ganguly

Contact: (781) 372-7196

Summary:

This study, sponsored by Biogen, Idec, is a phase 3b, multicenter, international, randomized, double-blind, placebo-controlled study to assess the efficacy of natalizumab in subjects with Secondary Progressive Multiple Sclerosis (SPMS) who are exhibiting disease progression independent of relapses. The primary objective of the study is to investigate whether treatment with natalizumab slows the accumulation of disability not related to relapses in subjects with SPMS. Subjects will be randomized to receive either natalizumab 300 mg or placebo intravenously (IV) every 4 weeks for 96 weeks. Patients may take part in various optional substudies involving cognition, ambulation and pharmacogenomics.

PI: Ann Camac, MD

CRA: Rik Ganguly

Contact: (781) 372-7196

Title:

Summary:

Natural History of Benign Fasciculations

This is an investigator initiated prospective questionnaire study designed by Doreen Ho, MD. Investigators hope to understand the nature and course of benign fasciculation syndrome (BFS) including the duration of symptoms before resolution, the correlation with anxiety, the percentage of patients who also have cramps, the percentage of patients with abnormal electrodiagnostic testing at time of referral, and the percentage of patients who go on to develop neurological conditions. Eligible patients include adults experiencing fasciculations with or without cramps and an absence of weakness atrophy or other neurologic symptoms. Those with prior neuromuscular history will be excluded.

PI: Doreen Ho, MD

CRA: Lynn Sullivan

Contact: (781) 744-1453 5

Title:

Summary:

Neuromuscular ultrasonography as an adjunctive diagnostic tool (Nerve U/S)

This is a homegrown, prospective, pilot study designed by Doreen Ho, MD in collaboration with the neuromuscular team. Patients will be recruited from the electrodiagnostic testing lab. Patients who undergo an EMG for conditions in which ultrasound has been documented in the literature to serve as a useful adjunctive diagnostic tool will be included. These conditions include but are not limited to focal neuropathies, conditions where fasciculation potentials are part of the diagnostic criteria, conditions with diaphragmatic weakness and other neuromuscular disorders. The study duration consists of a one-time neuromuscular ultrasound and will enroll approximately 100 patients.

PI: Doreen Ho, MD

Title: Prevalence of glossalpterygoid synkinesis in ALS patients (GPS)

CRA: Stephanie Scala

Summary:

This is a homegrown study designed by James Russell, DO and will evaluate the prevalence of glossal-pterygoid synkinesis in patients with ALS. The study will consist of three groups of subjects: 1) patients with ALS, 2) patients with idiopathic Parkinson’s disease, & 3) normal age matched controls. 50 patients in each group will be studied. Identification & validation of a new upper motor neuron sign would be of considerate value in early & accurate diagnosis of ALS. Enrollment is currently open in all 3 arms.

PI: James Russell, DO

Title: A clinical study of 3,4Diaminopyridine (3, 4- DAP) in LambertEaton Myasthenic Syndrome (LEMS) and Congenital Myasthenic Syndromes (CMS)

CRA: Stephanie Scala

PI: James Russell, DO

Contact: (781) 744-2950

Summary:

This is a homegrown study designed by H. Royden Jones, MD and hopes to determine the effectiveness and adverse effects of open label 3, 4diaminopyridine for the treatment of the Lambert-Eaton Myasthenic Syndrome (LEMS) and Congenital Myasthenic Syndromes (CMS). The drug, 3,4diaminopyridine has been demonstrated to be effective in treating weakness associated with LEMS and CMS but is not yet FDA approved for use and only available under an IND. Enrolled patients will be followed indefinitely with long term bi-yearly visits.

PI: Jayashri Srinivasan, MD, PhD, MRCP

Title: Reliability Studies: Outcome Measures in ALS Research (ALS Outcomes)

Contact: (781) 744-2950

CRA: Lynn Sullivan

Contact: (781) 744-1453

Summary:

The purpose of this protocol is to provide for uniform initial and continued reliability assessments for NEALS clinical site evaluators and to ensure their expertise in the performance of outcome measures such as: ALSRFS-R, Vital Capacity, hand-held dynamometer HHD, MUNE and Quality of Life Scales, in NEALS clinical trials. These outcome measures are used to measure multiple aspects of decline in ALS patients. Repeat certification of reliability for each site evaluator will occur every two years. CRA: Nick Ventura

Contact: (781) 744-3216 6

Title:

Summary:

Cost Assessment of Care at Multidisciplinary ALS Clinics Adhering to Practice Standards

This study, sponsored by the ALS Association, is a 3-month prospective, descriptive, multicenter study of costs related to care at 15 ALS Association multidisciplinary certified centers. We hope this data will allow the ALS community and healthcare policy makers to have a better understanding of the breadth of services provided at ALS clinics. This data will also identify opportunities for medical directors and their institutions to develop more cost effective ways to provide multi-disciplinary care, and to identify areas to potentially reduce expenses or capture lost revenue. Data pertaining to all patients who are evaluated in the multidisciplinary clinics at participating centers, and are deemed to have ALS by appropriate diagnostic criteria, will be included. Although exempt from IRB review, this study will be conducted in the department of Neurology.

PI: James Russell, DO

Title: Continuous TransCranial Doppler Ultrasound for Enhanced Seizure Localization in Patients with Intractable Epilepsy Undergoing Continuous EEG Monitoring.

CRA: Janet Zani, NP

Contact: (781) 744-8822

Summary:

This is a homegrown project designed by Matthew Tilem, MD and funded by a Wise grant. The purpose of this study is to determine if Transcranial Doppler Ultrasound (TCD) is helpful for seizure localization. If focal seizures are reliably accompanied by detectable changes in cerebral blood flow, simultaneous monitoring may allow for enhanced seizure localization over continuous EEG alone. The addition of continuous TCD monitoring may decrease monitoring time & increase the number of surgical candidates among patients with medication refractory temporal lobe epilepsy. This technique has the potential to bring a cure to a larger proportion of the epilepsy population. Patients with a confirmed or suspected diagnosis of medication refractory temporal lobe epilepsy may be eligible.

PI: Matthew Tilem, MD Co-I: Joel Oster, MD

CRA: Nick Ventura

Contact: (781) 744-3216

7


Dual Energy CT, Carotid Occlusive Disease & Correlation with Pathological Specimen This is a homegrown study designed by Kinan Hreib, MD, PhD & funded by a Wise grant. The aim of this project is to identify the composition of carotid artery plaques ex vivo using Dual Energy CT scanner and correlate the pathological specimen histologically. This study will determine if a correlation exists between Dual Energy CT scans & surgical pathology specimens from carotid endarterectomy patients. Enrollment has been completed and analysis is currently underway. PI: Kinan Hreib, MD, PhD

CRA: Lynn Sullivan

Contact: (781) 744-1453

Cervical Dystonia - Patient Registry for Observation of BOTOX® Efficacy (CD PROBE) This is a multi-center, prospective, standard-of-care, observational registry study sponsored by Allergen, Inc. The primary purpose of this study is to capture current diagnostic and treatment approaches for cervical dystonia (CD) and their effects on patient’s quality of life. Patients diagnosed with cervical dystonia and new candidates for BOTOX® therapy, may be eligible. This study will capture real world clinical practices of neurologists, movement disorders specialists, and other physicians who regularly treat CD patients and hopes to offer a wealth of new information about CD and botox treatment. PI: Julie Leegwater-Kim, MD, PhD

CRA: Stephanie Scala

Contact: (781) 744-2950

A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Study to Evaluate the Safety and Efficacy of Davunetide for the Treatment of Progressive Supranuclear Palsy This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel group study in subjects with Progressive Supranuclear Palsy (PSP), sponsored by Allon Therapeutics, Inc. The primary objective of the study is to evaluate the efficacy and safety of davunetide 30 mg BID intranasally (IN) compared with placebo administered for 52 weeks to subjects with PSP. The preclinical and clinical findings to date suggest that davunetide delivered IN may provide benefit to patients suffering from PSP with acute symptomatic improvement and long-term disease modification. PI: Julie Leegwater-Kim, MD, PhD

CRA: Lynn Sullivan

Contact: (781) 744-1453

JCV Antibody Program in Patients with Relapsing Multiple Sclerosis Receiving or Considering Treatment with Tysabri®: STRATIFY-2 This is an observational, longitudinal cohort study in patients with MS, sponsored by Biogen Idec. The use of Tysabri® (natalizumab) for the treatment of multiple sclerosis (MS) has been associated with an increased risk of Progressive Multifocal Encephalopathy (PML), a rare brain infection that usually causes death or severe disability. PML is caused by a polyomavirus called the JC virus (JCV). The study aims to define the prevalence of JCV in patients with relapsing MS considering initiation of Tysabri treatment and those receiving Tysabri. All patients with relapsing MS treated with or considering treatment with Tysabri are eligible to participate. PI: Claudia Chaves, MD

CRA: Rik Ganguly

Contact: (781) 372-7196

Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Safety and Efficacy of Two Doses of Oral Dalfampridine Extended Release Tablets (5 mg and 10 mg twice daily) in Patients with Multiple Sclerosis (DER-401) This is a prospective placebo-controlled trial to investigate the safety and efficacy of a lower dose of dalfampridine extended release tablets (5 mg twice daily), and is sponsored by Acorda Therapeutics, Inc. This dose will be compared to the approved commercial dose of 10mg twice daily in improving walking speed in MS patients during a four-week period of treatment. Patients will receive one of three treatments: Dalfampridine 10 mg bid, Dalfampridine 5 mg bid or placebo. PI: Ann Camac, MD

CRA: Rik Ganguly

Contact: (781) 372-7196 8

A Multicenter Study for the Validation of ALS Biomarkers This study, sponsored by MGH and NEALS, seeks to identify factors that contribute to the pathogenesis of ALS and how discovered biomarkers change with disease course. Blood samples will be collected from ALS and suspected ALS volunteers along with patients with Motor Neuron Disease and healthy volunteers. Development of disease biomarkers and diagnostic laboratory tests would facilitate earlier treatment intervention, help monitor treatment efficacy; and, ultimately, lead to the identification of targets that could be used in therapy development. PI: James Russell, DO

CRA: Stephanie Scala

Contact: (781) 744-2950

Double-Blind, Randomized, Historical Control Study of the Safety and Efficacy of Eslicarbazepine Acetate Monotherapy in Subjects with Partial Epilepsy Not Well Controlled by Current Antiepileptic Drugs This is an 18-week, double-blind, randomized, historical control, multicenter study with conversion to monotherapy in subjects with partial onset seizures sponsored by Sunovion Pharmaceuticals, Inc. The primary objective of this study is to evaluate the efficacy of eslicarbazepine acetate (Stadesa™) monotherapy in subjects with partial epilepsy not well controlled by current AEDs. Patients who enroll into this trial will have the option of tapering off study drug at the completion of this study or rolling over into the open label extension study: Long-Term Eslicarbazepine Acetate Extension Study PI: Joel Oster, MD

CRA: Nick Ventura

Contact: (781) 744-3216

An open-label, follow-up trial to evaluate the long-term safety and efficacy of brivaracetam (up to 200mg/day) used as adjunctive treatment at a flexible dose up to a maximum of 200mg/day in subjects in subjects suffering from partial onset seizures This is a phase III, therapeutic confirmatory long-term follow-up, multicenter, non comparative, open-label clinical trial sponsored by UCB. The purpose of this study is to evaluate the long-term safety and efficacy of brivaracetam as an adjunctive treatment (maximum dose 200 mg/day) for partial onset seizures. PI: Joel Oster, MD

CRA: Nick Ventura

Contact: (781) 744-3216

A phase 3, Randomized, Double-Blind, Parallel, Placebo Controlled, Multicenter Study, with Optional Open Label Continuation, of the Efficacy and Safety of Vanquix Auto-Injector (Diazepam Injection) for the Management of Selected, Refractory, Patients with Epilepsy who Require Intermittent Medical Intervention to Control Episodes of Acute Repetitive Seizures This is a phase 3, randomized, double-blind, parallel, placebo controlled, multicenter study, sponsored by King Pharmaceuticals Research and Development, Inc. The primary objectives of this study are: 1) to evaluate the efficacy of Vanquix™ for the management of selected, refractory, patients with epilepsy who require intermittent medical intervention provided by caregivers to control episodes of acute repetitive seizures (ARS), and 2) to evaluate the safety of Vanquix™ when administered by caregivers who are not health care professionals, and who are not under the direct supervision of a healthcare professional at the time of administration. PI: Joel Oster, MD

CRA: Nick Ventura

Contact: (781) 744-3216

An Open-Label, Multinational, Multi-center, Follow-up Study to Evaluate the Long-Term Safety and Efficacy of Brivaracetam, Used at a Flexible Dose up to a Maximum of 150 mg/day, in Subjects Aged 16 Years or Older Suffering From Epilepsy This is a phase III, therapeutic confirmatory long-term follow-up, multinational, multi-center, non-comparative, open-label and single arm trial. The primary objective is to evaluate the long-term safety and tolerability of brivaracetam at individualized doses with a maximum of 150 mg/day in subjects suffering from epilepsy. PI: Joel Oster, MD

CRA: Nick Ventura

Contact: (781) 744-3216 9


The Clinical Trial of Ceftriaxone in Subjects With Amyotrophic Lateral Sclerosis (ALS) has been stopped early after a recent DSMB review. “In July 2012, the DSMB recommended that based on existing data the trial be stopped because the study was unlikely to reach the pre-determined efficacy criteria. Pre-clinical research identified ceftriaxone as a promising treatment for ALS, therefore it was important for people with ALS to find out if the drug could be beneficial in ameliorating the disease. The study used a novel seamless adaptive design. Final analysis and presentation of the results will occur after completion of site monitoring and database lock. The important contributions of patients, their families and the hard work of the investigators and their teams made it possible to implement the trial. While all had hoped for a more positive result, the trial has moved ALS research forward.” (http://www.alsa.org/news/archive/ceftriaxone-statement.html) This study, sponsored by MGH and NINDS, was a double-blind, placebo controlled clinical trial of ceftriaxone in 600 subjects with ALS. The study objective was to determine the safety and efficacy of ceftriaxone in subjects with amyotrophic lateral sclerosis (ALS). The study hypothesis was that intravenous (IV) ceftriaxone will prolong survival, free of tracheostomy or permanent assisted ventilation in patients with ALS. James Russell, DO was the Lahey Clinic principal investigator and a total of 7 Lahey Clinic patients were enrolled into the trial.


IMS III: A phase III, randomized, multicenter, open label, 900 subject clinical trial that will examine whether a combined intravenous (IV) and intra-arterial (IA) approach to recanalization is superior to standard IV rt-PA (Activase®) alone when initiated within 3 hours of acute ischemic stroke onset.

The overall goal of this multi-center, open-label, randomized Phase III Trial with blinded 3 month follow-up evaluation is to determine if subjects with an NIHSS ≥ 10 at baseline, treated with a combined IV/IA approach to recanalization started within 3 hours of onset, are more likely to have a favorable outcome at 3 months (Rankin 0-2) as compared to subjects treated with standard IV rt-PA alone. PI: In Sup Choi, MD; Neurology Sub-investigators: Kinan Hreib, MD, PhD; Matthew Tilem, MD Contact: Kiron Thomas, MD (781) 744-8630

IMPACT Study: The IMPACT of BIOTRONIK Home Monitoring Guided Anticoagulation on Stroke Risk in Patients with Implanted ICD and CRT-D Devices.

The IMPACT Study will investigate the clinical benefit of the combined use of BIOTRONIK Home Monitoring (HM) technology and a predefined anticoagulation plan compared to conventional device evaluation and physician-directed anticoagulation in patients with implanted dual-chamber defibrillators or cardiac resynchronization therapy devices. PI: David Martin, MD; Neurology Sub-investigator: Kinan Hreib, MD, PhD Contact: Jean Byrne (781) 744-1901 10




PREVAIL Study: Prospective Randomized Evaluation of the WARCHMAN LAA Closure Device in patients with Atrial Fibrillation Versus Long Term Warfarin Therapy

The purpose of this research study is to provide additional information on the WATCHMAN device to determine if the WATCHMAN device can be safely implanted and evaluate the effectiveness of the device compared to patients who receive the blood thinning medication called Coumadin (or warfarin). This study will determine if the WATCHMAN device is an alternative to Coumadin for patients with atrial fibrillation. PI: Bruce Hook, MD; Neurology Sub-investigators: Kinan Hreib, MD, PhD Contact: Jean Byrne (781) 744-1901

A prospective multicenter randomized study of the impact of regional cerebral metabolic assessment in patients undergoing evaluation for mild cognitive impairment

The purpose of this study is to examine the effects of information on regional brain metabolism on diagnosis and management decisions for patients with mild cognitive complaint who are otherwise evaluated in clinically routine settings and to measure the effect of information on regional brain metabolism on long term clinical outcome of patients initially presenting with mild cognitive complaints who are managed in clinically routine settings. PI: Edward Pinkus, MD; Neurology Sub-Investigator: Yuval Zabar, MD; Dana Penney, PhD; Caitlin Macaulay, PhD Contact: Nanette Matrullo (781) 744-2906

Evaluating The Impact Of Cerebral Ischemic And Degenerative Changes On Cognition

The purpose of this study is to evaluate whether or not cerebral atrophy scores obtained from brain MRIs can correlate with mini mental status test results. PI: Sami Erbay, MD; Neurology Sub-Investigator: Yuval Zabar, MD

Contact: Karen Hanley (781) 744-8799

11

136th American Neurological Association's (ANA) Annual Meeting, Boston, MA, October 2012

Anxiety in Benign Fasciculation Syndrome

Poster Title

Alexandra LaMela MS¹, Stephanie Scala MA², Ioannis Karakis MD², James Russell DO², and Doreen Ho MD² ¹University of New England College of Osteopathic Medicine, Biddeford, Maine ²Lahey Clinic Medical Center, Burlington, Massachusetts

OBJECTIVE

METHODS

To study the prevalence and intensity of anxiety in patients with benign fasciculation syndrome (BFS) and its correlation with fasciculation duration.

BACKGROUND Despite the favorable natural history of benign fasciculation syndrome (BFS), patients frequently appear distressed about their disorder. Blexrud¹ reported that a large percentage of patients with BFS were medical professionals, implying that awareness of fasciculation significance increases anxiety and the motivation to seek medical care. However, the psychological correlates of BFS have not been systematically studied. We postulate that awareness of fasciculation significance produces anxiety, which may perpetuate symptoms.

A 2-year prospective study of patients with BFS is underway at the Lahey Clinic, Burlington, MA. Patients seen for fasciculations in any location of the body (e.g., arms, legs, bulbar muscles, axial muscles) in the absence of weakness, atrophy, or other neurological symptoms were eligible. Patients were diagnosed with BFS by a neuromuscular physician based on otherwise normal neurologic examinations and had normal electrophysiologic studies except for fasciculation potentials. To date, 15 patients have been enrolled. BFS course, including background, location and fasciculation type; psychiatric history; and medications were reviewed at initial diagnosis, Months 1, 3, and 6 with plans to continue for 2 years. Anxiety was measured using the Zung SelfRating Anxiety Scale (SAS)².

Table 1. Summary of preliminary data.

Gender

77.8% Male (7)

22.2% Female (2)

Yes

No

Medical professionals

44.4% (4)

55.6% (5)

Premorbid anxiety

44.4% (4)

55.6% (5)

Normal SAS score

100% (9)

0% (0)

Persistence of fasciculations

88.9% (8)

11.1% (1)

RESULTS Preliminary data is based on 9 patients who have completed their 6 month follow-up. There were seven men and two women with a mean age of 46.7 ±6.4 years. Four patients were in a medical field. Four patients reported premorbid anxiety and four patients reported anxiety at the time of diagnosis. However, based on SAS scores, all patients fell within the normal range (20-44) with a mean score of 32.4 ±4.72 (Figure 1). In eight patients, fasciculations persisted at the six month follow-up. Fasciculations resolved in one patient. Anxiety levels remained within the normal range.

CONCLUSION Our tentative conclusions are descriptive due to the small sample size at this time. During a six month follow-up period of nine patients, mean SAS scores were lower than published normative data. We plan to enroll further patients and add controls, but our findings suggest that anxiety may not be higher than normal in this population at the time of or after diagnosis, despite the persistence of fasciculations for at least six months.

REFERENCES ¹ Blexrud, M. D., Windebank, A. J. and Daube, J. R. (1993). Long-term follow-up of 121 patients with benign fasciculations. Ann Neurol., 34: 622–625. ² Zung, W.W. (1971). A rating instrument for anxiety disorders. Psychosomatics, Nov-Dec;12(6):371-9.1

Figure 1. Zung SAS scores for all nine patients at baseline.

ACKNOWLEDGEMENT: The authors acknowledge Yoojin Lee, MS, Tufts Clinical and Translational Science Institute (CTSI) for providing statistical analysis for this project.

Subacute Combined Degeneration of the Spinal Cord Due to Functional B12 Deficiency Subhashie Wijemanne, MBBS, MD, MRCP*, Sui Li, MD*, Michal Vytopil, MD** *Department of Neurology, Tufts University School of Medicine, Boston, MA **Department of Neurology, Lahey Clinic, Burlington, MA INTRODUCTION

Vitamin B12 deficiency typically presents with megaloblastic anemia with or without neurological abnormalities. Pernicious anemia is a common cause of vitamin B12 deficiency and is thought to be mediated by antibodies against gastric intrinsic factor (IF). Subacute combined degeneration of the spinal cord (SCDC) is one of the most serious neurological manifestations of vitamin B12 deficiency. Severe cases of SCDC are seen less often than in former years as the availability of the vitamin B12 assay has allowed for early diagnosis in most patients when they present with mild hematological or neurological abnormalities. As physicians, we rely on laboratory tests to guide our workup especially when the clinical presentation is subtle. It is important to know the limitations of common laboratory tests to avoid misdiagnosis or delay in diagnosis. We report a case of severe pancytopenia and SCDC that initially presented as megaloblastic anemia eight months prior. The diagnosis of B12 deficiency was not made at the time due to spuriously elevated B12 levels possibly related to laboratory interference of intrinsic factor antibodies with the vitamin B12 assay.

RESULTS

DISCUSSION

WBC 1.37, Hgb 7.8, Hct 22.8, Plt 52, MCV 104, RDW 30. Peripheral smear: macrocytosis with hypersegmented neutrophils. Vitamin B12 >1200 pg/ml (nl 200-1200).

A diagnosis of B12 deficiency is made when the serum B12 level is low or low-normal with a concomitant elevation in serum methymalonic acid and homocysteine.

MRI scan of the spine revealed increased T2 signal involving the posterior columns from the cervical to lumbar segments without any enlargement, edema, or abnormal contrast enhancement.

The standard practice guidelines indicate testing methylmalonic acid and homocysteine levels only if the B12 level is low or lownormal, and do not recommend routine testing of methylmalonic acid and homocysteine levels along with the serum B12 levels in order to minimize cost.

Subsequently, methylmalonic acid and homocysteine levels were checked which were elevated at 23.53 (nl 0-0.4 µmol/L) and 54.3 (nl 4-12 µmol/L) respectively. Intrinsic factor antibody was positive. Copper 96 µg/dL (70-140). Folate 15.2 ng/ml (>3.0). B6 2.1 nmol/L (20-125), B1 59 nmol/L (70-180) zinc 77 ug/dL (60-120). Treponema pallidum IgG, Lyme antibody, HIV, and parietal cell antibody tests were negative. Upper endoscopy showed atrophy of the antral mucosa.

CASE REPORT

A 65-year-old right-handed male with Idiopathic Parkinson’s disease (PD) for many years presented to the emergency department with a rapidly progressive gait disorder of three weeks’ duration that eventually rendered him bedbound. He complained of paresthesias of both hands and feet which slowly ascended up to the waist and elbows. He had a 50-pound weight loss over 1 year associated with decreased appetite and a burning sensation of the tongue. Eight months prior, he was evaluated for macrocytic anemia. Vitamin B12 levels were >1200 pg/ml (nl 200-1200) on multiple occasions. A subsequent bone marrow biopsy revealed macrocytosis and led to a diagnosis of myelodysplastic syndrome. Examination during the current presentation was remarkable for vitiligo, slow cognitive processing, and severe loss of joint position and vibration sense in both upper and lower extremities. Pain and temperature modalities were spared. Both ankle reflexes as well as the left knee jerk were absent. Toes were down-going bilaterally. He was unable to ambulate due to severe sensory ataxia. He also had masked facies, rigidity, and bradykinesia, consistent with the diagnosis of PD.

Fig. A&B: T2 FAT-SAT shows T2 hyperintensity in the dorsal aspect of the spinal cord. Fig. C: Axial T2 of cervical spine showing T2 hyperintensity confined to the posterior columns.

The diagnosis of functional B12 deficiency was made. He was treated with intramuscular injection of cyanocobalamin 1000 µg daily for a week and then weekly thereafter along with oral B6 and B1 supplementation. His symptoms improved over 6 weeks at which point he was able to ambulate with a cane. Pancytopenia improved promptly and at 1 month, WBC was 5.64, Hgb 12.6, MCV 98 and Plt 202. Methymalonic acid and homocysteine levels also normalized at 1 month. His appetite improved and he gained 25 pounds of over 4 months. Currently he does not require assistance to ambulate.

In our patient the serum B12 was elevated on multiple occasions above the upper limit of the laboratory range which would normally indicate an adequate B12 reserve. Based on this clinical reasoning, methylmalonic acid and homocysteine levels were not checked. It has been observed that falsely normal B12 levels can be generated by automated analyzers when the serum of patients with pernicious anemia is tested. Since most assays are based on competitive binding of serum vitamin B12 with reagent intrinsic factor, the falsely normal B12 results have been attributed to the possibility of intrinsic factor–blocking antibodies interfering with the assay. W e speculate that the falsely elevated B12 level in our patient was caused by this proposed phenomenon. There may be insufficient awareness in the neurological community of the possibility of spuriously high vitamin B12 levels in patients with pernicious anemia and intrinsic factor-blocking antibody. Since pernicious anemia is a common cause of vitamin B12 deficiency, we propose that methylmalonic acid and homocysteine levels should be checked in such patients even if vitamin B12 levels are not low.

REFERENCES 1. 2.

3.

Yang, D. T. and R. J. Cook. Spurious elevations of vitamin B12 with pernicious anemia. N Engl J Med 2012; 366(18): 1742-1743. Vlasveld, L. T., J. W. van't Wout, et al. High measured cobalamin (vitamin B12) concentration attributable to an analytical problem in testing serum from a patient with pernicious anemia. Clin Chem 2006; 52(1): 157-158; discussion 158-159. Savage, D. G., J. Lindenbaum, et al. Sensitivity of serum methylmalonic acid and total homocystein determinations for diagnosing cobalamin and folate deficiencies. Am J Med 1994; 96(3): 239-246.

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136th American Neurological Association's (ANA) Meeting, Boston, MA, October 2012 Low Frequency DBS in PD Patients with Gait and Speech Problems Diana Apetauerova, MD, Stephanie A. Scala, MA and Janet W. Zani, NP Neurology, Lahey Clinic, Burlington, MA, USA OBJECTIVE:

RESULTS:

BACKGROUND: High frequency stimulation (>130 Hz) is the primary frequency effectively used in controlling cardinal features of PD with DBS of the STN. We looked at bilateral low (60Hz) and combination high (>130Hz)/ low (60Hz) frequency stimulation in patients with PD post DBS with gait and speech problems.

METHODS: A prospective clinical trial of 10 Lahey Clinic patients with Parkinsons disease post DBS STN surgery who experience persistent gait freezing and falls after a clinically deemed adequate trial of high frequency programming and medication regimen exhaustion (Table 1). Table 1. Demographics of enrolled patients (n=10)

SUMMARY: A total of 10 patients were enrolled. Three patients tolerated low frequency stimulation throughout study duration and completed the 1 month study. One of these 3 patients (LF4) continued on low frequency after his final visit, one returned to his previous setting, bilateral high frequency (LF3) and one tried combination high/low frequency (LF7). Seven of the 10 patients withdrew due to intolerance. Of these 7 patients, 5 returned to previous settings and 2 tried combination high/low frequency (LF1and LF8) when they withdrew.

LOW FREQUENCY: LF4 was the only patient who remained on bilateral low frequency settings at the end of the study. Throughout the study duration he experienced improvement in speech, gait and postural stability by week 4, remained fairly stable on rigidity and tremor but experienced increased bradykinesia (Figure 1.) Improvements were also noted on GFQ, Berg Balance and UII and UIV.

8 6 4 2

Seven patients were unable to tolerate bilateral low frequency settings. Patients with tremor predominant symptoms developed tremor recurrence within 24 hrs; bradykinesia and rigidity returned within days. Speech improved in 4 patients. Gait improved transiently for several days, but worsened due to severe immobility (Figures 2-6).

0 Speech

Tremor

Rigidity

Bradykinesia

Gait

Postural stability

UPDRS Questions

Figures 2-6: Total scores from Baseline (off meds/on high stim.) to Weeks 2 and 4 (off meds/on low stim.)

Patients were evaluated on low frequency stimulation for a period of 1 month with Baseline, Week 2 & 4 follow up visits consisting of United Parkinsons Disease Rating Scale (UPDRS), Tinetti Gait and Balance, Berg Balance Scale (BBS), and Gait and Falls Questionnaire (GFQ). Scores were collected in all on/off states (ON high stimulation/OFF medication; OFF high stimulation/OFF medication; OFF high stimulation/ON medication; ON high stimulation/ON medication; ON low stimulation/ON medication- for safety) at baseline and collected in 2 states (OFF medication/ON low stimulation; ON medication/ON low stimulation) at weeks 2 and 4. Patients were adjusted to bilateral low frequency settings at the baseline visit after all evaluations were completed. Patients remained on this setting throughout the study duration as tolerated. Patients who were unable to tolerate bilateral low frequency settings were then offered a combination of high (>100Hz) and low (60Hz) frequency stimulation or returned to their previous settings.

6 4 2 0

LF2

LF3

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LF5

LF6

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LF8

LF9

LF10

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Berg Balance

LF1

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GFQ 60

60 50

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40 30 20 10 0 LF1

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40 30

Total Score

8

MOTOR & SPEECH

Total Score

8 6 4 2 0

60

10

GAIT

Total Score

BALANCE

Motor Section III UPDRS 70

12

Total Score

Use of Assistive Device 4 always 5 occasionally 1 never

Tinetti- Gait 14

LF1

Total Score

15.2 4.2 10 10 (score range 1- 4)

Tinetti- Balance 18 16 14 12 10

LF3

LF4

LF5

LF6

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9 8 7 6 5 4 3 2 1 0 LF1

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Pa tient

Speech (U5, U18)

10

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50

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UDPRS Score

Gender 8M 2F Mean Age, y 65 Race 9 Caucasian 1 Asian Mean Disease Duration, y Mean DBS Duration, y Falls/Near Falls past 6 mos. Speech impairment (U5, U18)

Figure 1. LF4 Motor Scores on bilateral low frequency settings throughout study duration 10

Score

To analyze the effect of bilateral low frequency stimulation (60Hz) and combination low (60 Hz) and high frequency (135 Hz) stimulation in patients with Parkinson's disease (PD).

Note: Higher scores on Tinetti Gait & Balance and Berg Balance Scale indicate symptomatic improvement Higher scores on the GFQ, UPDRS scales and Speech U5/U18 indicate symptomatic worsening

Three patients tried combination frequency stimulation after stopping the study with the less affected body side on low frequency and the more affected side on high frequency. Clinical follow up post study showed improvements in gait, balance and speech. Bradykinesia and rigidity did not worsen significantly on the side with low frequency stimulation and mild dyskinesia occurred on the side with low frequency only.

CONCLUSION: Bilateral low frequency stimulation didn't show to be beneficial in our study as many cardinal PD symptoms including tremor, rigidity and bradykinesia worsened or returned shortly after frequency stimulation change. Speech was the only symptom which improved in 3/10 patients. Gait improved temporarily but immobility soon returned. Only one patient continued on low frequency settings at study end due to improvements in speech, gait and postural stability during study duration. In contrary, a combination of high/low frequency stimulation was a reasonable option for patients who experienced gait and speech issues before and after DBS for 3 patients. Combination frequency stimulation might be a reasonable option for PD patients with gait and speech problems and we continue our study to further explore this option. This study is ongoing and enrollment continues until an additional 20 patients with gait problems and medication exhaustion are enrolled. Ten patients pre-DBS will be started on low frequency & 10 patients post DBS with worsening gait will be started on a combination high/low frequency stimulation.

Acknowledgements: 1) Thank you to the Robert E. Wise Foundation for providing grant funding for this project. 2) Thank you to Robin Ruthazer, MPH from the Design & Data Resource Center (DDRC) at Tufts Clinical & Translational Science Institute (CTSI), Boston, MA for statistical analysis.

Previously Presented: Low Frequency Stimulation in Parkinson's Disease Patients with Gait Problems and Falls, MDS, Toronto, 6/6/11 DBS stimulation frequencies in PD patients with gait and speech problems, MDS, Dublin, 6/18/12

Chronic Parkinsonism Associated with Liver Cirrhosis Diana Apetauerova, MD, Peter Hildenbrand, MD, Janet Zani, NP and Stephanie Scala, MA, CCRP Neurology, Lahey Clinic, Burlington, MA, USA

BACKGROUND: Cirrhosis-related parkinsonism represents a unique subset of acquired hepatocerebral degeneration. Disorder prevalence and natural history after transplant remains largely uncertain. METHODS: A prospective study of 120 patients with liver cirrhosis recruited from the liver transplant list at Lahey Clinic, Burlington, MA (Table 1). Each patient underwent Table 1. Parkinsonism No Parkinsonism Unified Parkinson's n=62 n=58 Demographics Disease Rating Scale Gender 37 M 25 F 46 M 12 F (UPDRS) testing, standard Mean Age, y 55.5 54.2 liver transplant evaluation (range 38-68) (range 20-69) and repeat testing preDisease Category 27 Mixed 26 Mixed transplant and at 6 weeks, Mixed= multiple diagnoses 15 Alcohol 12 Other Alcohol= alcoholic cirrhosis 3 and 12 months postViral= Hepatitis 10Viral 11 Viral Other= PCS, etc transplant. Patients with 10 Other 9 Alcohol parkinsonism also Disease Duration, y 8.4 6.0 (range 0.6-30) (range 0.1-20) underwent brain MRI preMean MELD 14.4 14.0 and 1 year post -transplant. Manganese, UG/L 18.55 16.98 Correlation was measured Ammonia, UMOL/L 59.7 Not Done between MELD severity Copper, UG/DL 95.7 Not Done and motor part UPDRS, Iron, UG/DL 118.4 103.2 copper, ammonia, UIII (Motor) Total 15.2 0 manganese, and iron levels UPDRS (U) Total 28.6 10 and signal MRI changes. We also performed a sub-study in which brain MRI of the patients with hepatocerebral degeneration (HCD) were blindly evaluated with a matched cohort of patients with Parkinson's Disease (PD). T1 weighted brain MR ratios were obtained from symmetrically placed standardized (25 mm²) regions of interest (ROIs) within the medial globus pallidus versus thalamus versus forceps minor white matter in an effort to normalize for minor variations in the T1 pulse sequence, equipment/ coil enhancements & head positioning over the 5 year prospective time interval. Ratios of right (R) and left (L) medial globus pallidus/thalamic (thal) and medial globus pallidus/white matter (WH) were calculated and subsequently correlated with clinical metrics. The ROIs for the Figure 1 medial globus pallidus were positioned symmetrically on the right and left, just posterior to the anterior commissure and 10mm off midline (Fig 1).

Signal intensity within the adenohypophysis on sagittal T1 weighted imaging was considered elevated if its signal intensity was equal to or Figure 2 greater than that of the corpus callosum (Figure 2).

Acknowledgements : 1) Thank you to the Robert E. Wis e Foundation for providing grant funding for this project. 2) Thank you to Robin Ruthazer, MPH (Associate Director, Biostatistical Research Center, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA) for statistical analys is.

RESULTS: BIOLOGICAL: Out of 120 patients, 62 (52%) exhibited parkinsonism (Table 2). In the parkinsonian group (HCD), we found no correlation between severity of MELD and motor part UPDRS (p=0.71) and no correlations were found with copper (p=0.36), ammonia (p=0.86), manganese (p=0.90) or iron levels (p=0.30). There was also no correlation with type of cirrhosis and total motor UPDRS (UIII). No differences were seen between the 2 groups (HCD vs. non-parkinsonism) in mean manganese (18.55 vs. 16.98; p=0.39). Mean iron level was found to be higher in the group with parkinsonism, representing a slight trend (118.4 vs. 103.2, p=0.10). PARKINSONISM: Nineteen patients with parkinsonism (HCD) underwent liver transplantation (Figure 3). Statistical analysis was performed using paired t-tests (p 50 % of patients are reflected)

NEURORADIOLOGICAL and SUB-STUDY: Basal ganglia hyperintensity was seen in all pre-transplant images, resolving 1 year post transplant (n=14). Increased pituitary T1 signal was seen in 59% of the HCD group pre-transplant compared to only 7% in the PD group (chi square; p=0.05) with any of the four MRI parameters (R/L Thal or R/L WH) pre- (n=47) or 1 year post-transplant (n=14), all correlations were positive. Larger drops in MRI ratios were associated with larger drops in motor UPDRS (Figure 4). The absence of significance is suspected due to the rather small sample size. There were statistical differences seen between the pre transplant HCD group (n=47) and PD group (n=32) in the following: R/Thal (p