Department of Neurology University of California, San Francisco School of Medicine presents

50th Annual Recent Advances in Neurology

February 8-10, 2017 Parc55 San Francisco, a Hilton Hotel San Francisco, CA

Course Chairs Stephen L. Hauser, MD S. Andrew Josephson, MD University of California, San Francisco

University of California, San Francisco School of Medicine

Table of Contents

Overview and Accreditation pg. 4

General Information pg. 5

Federal and State Law Regarding Cultural Linguistics pg. 6

Acknowledgements pg. 8

Faculty List pg. 9

Disclosures pg. 11

Program pg. 13

Save the Date pg. 14

Neuro-Ophthalmology Pearls, Pitfalls and Advances pg. 15 Neuroinfectious Diseases: Practical Tips for Common Disorders pg. 47 B Cell Therapy for Multiple Sclerosis: A New Day? pg. 69 Multiple Sclerosis Highlights 2016 pg. 75 Advances in Treatment and Diagnosis of Dementia 2017 pg. 95 Challenges and Controversies in Movement Disorders Management pg. 99 Psychiatry for the Neurologist pg. 119 Difficult Epilepsy Management Decisions pg. 147 Difficult Headache Management Decisions pg. 157 The Changing World of Stroke Management pg. 183 An Interactive Session: Difficult Diagnosis pg. 21 The New Anatomy of Language pg. 223 Clinico-Pathologic Conference pg. 227

University of California, San Francisco School of Medicine Presents

51st Annual Recent Advances in Neurology

Educational Objectives

Upon completion of this program, attendees will be able to:

 Apply new concepts to epilepsy, multiple sclerosis, aging and movement disorders in practice;  Recognize and select diagnosis and management of stroke, multiple sclerosis, headache, dementia, and apply best practices for their management.;

Accreditation

The University of California, San Francisco School of Medicine (UCSF) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

UCSF designates this live activity for a maximum of 15.75 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This CME activity meets the requirements under California Assembly Bill 1195, Continuing Education and Cultural and Linguistic Competency.

NURSES: For the purpose of recertification, the American Nurses Credentialing Center accepts AMA PRA Category 1 Credit™ issued by organizations accredited by the ACCME.

PHYSICIAN ASSISTANTS: AAPA accepts category 1 credit from AOACCME, Prescribed credit from AAFP, and AMA PRA Category 1 Credit™ from organizations accredited by the ACCME.

PHARMACY: The California Board of Pharmacy accepts as continuing professional education those courses that meet the standard of relevance to pharmacy practice and have been approved for AMA PRA Category 1 Credit™.

American Board of Psychiatry and Neurology (ABPN) MOC: This course features a post-test which is valid toward meeting the MOC Part II self- assessment requirements for the American Board of Psychiatry and Neurology. ABPN diplomates will receive 15.75 Self-Assessment Category 1 CME credits after passing the post-test. General Information

Attendance Verification/Sign-In Sheet / CME Certificates Please remember to sign-in on the sign-in sheet when you check in at the UCSF Registration Desk on your first day. You only need to sign-in once for the course, when you first check in.

After the meeting, you will receive an email from [email protected] with a link to complete your online Course Evaluation/ Electronic CME Certificate. Please make sure that you add this email to your safe senders list. The Qualtrics system will send you reminders to complete your CME Certificate Claiming until you complete it.

Upon completing the Electronic CME Certificate, your CME certificate will be automatically generated to print and/or email yourself a copy. For smartphone users, you may want to take a photo of your certificate as some settings prevent you from emailing the certificate.

The link will be available for 30 days after the last day of the course. However, after that date the link will expire and you will no longer be able to claim your credits online. You must then contact the Office of CME at [email protected] to receive your certificate and a $15 administrative fee may be applied.

Speaker Survey Your opinion is important to us – we do listen! The speaker survey is the bright yellow hand-out you received when you checked in. Please complete this during the meeting and turn it in to the registration staff at the end of the course.

Security We urge caution with regard to your personal belongings and syllabus books. We are unable to replace these in the event of loss. Please do not leave any personal belongings unattended in the meeting room during lunch or breaks or overnight.

Exhibits Industry exhibits will be available outside the ballroom during breakfasts and breaks, and lunches.

Final Presentations

PDF presentations will be available on our website, www.cme.ucsf.edu, approximately 3 – 4 weeks post course. Only presentations that have been authorized for inclusion by the presenter will be included

Federal and State Law Regarding Linguistic Access and Services for Limited English Proficient Persons

I. Purpose. This document is intended to satisfy the requirements set forth in California Business and Professions code 2190.1. California law requires physicians to obtain training in cultural and linguistic competency as part of their continuing medical education programs. This document and the attachments are intended to provide physicians with an overview of federal and state laws regarding linguistic access and services for limited English proficient (“LEP”) persons. Other federal and state laws not reviewed below also may govern the manner in which physicians and healthcare providers render services for disabled, hearing impaired or other protected categories

II. Federal Law – Federal Civil Rights Act of 1964, Executive Order 13166, August 11, 2000, and Department of Health and Human Services (“HHS”) Regulations and LEP Guidance. The Federal Civil Rights Act of 1964, as amended, and HHS regulations require recipients of federal financial assistance (“Recipients”) to take reasonable steps to ensure that LEP persons have meaningful access to federally funded programs and services. Failure to provide LEP individuals with access to federally funded programs and services may constitute national origin discrimination, which may be remedied by federal agency enforcement action. Recipients may include physicians, hospitals, universities and academic medical centers who receive grants, training, equipment, surplus property and other assistance from the federal government.

HHS recently issued revised guidance documents for Recipients to ensure that they understand their obligations to provide language assistance services to LEP persons. A copy of HHS’s summary document entitled “Guidance for Federal Financial Assistance Recipients Regarding Title VI and the Prohibition Against National Origin Discrimination Affecting Limited English Proficient Persons – Summary” is available at HHS’s website at: http://www.hhs.gov/ocr/lep/ .

As noted above, Recipients generally must provide meaningful access to their programs and services for LEP persons. The rule, however, is a flexible one and HHS recognizes that “reasonable steps” may differ depending on the Recipient’s size and scope of services. HHS advised that Recipients, in designing an LEP program, should conduct an individualized assessment balancing four factors, including: (i) the number or proportion of LEP persons eligible to be served or likely to be encountered by the Recipient; (ii) the frequency with which LEP individuals come into contact with the Recipient’s program; (iii) the nature and importance of the program, activity or service provided by the Recipient to its beneficiaries; and (iv) the resources available to the Recipient and the costs of interpreting and translation services.

Based on the Recipient’s analysis, the Recipient should then design an LEP plan based on five recommended steps, including: (i) identifying LEP individuals who may need assistance; (ii) identifying language assistance measures; (iii) training staff; (iv) providing notice to LEP persons; and (v) monitoring and updating the LEP plan.

A Recipient’s LEP plan likely will include translating vital documents and providing either on-site interpreters or telephone interpreter services, or using shared interpreting services with other Recipients. Recipients may take other reasonable steps depending on the emergent or non- emergent needs of the LEP individual, such as hiring bilingual staff who are competent in the skills required for medical translation, hiring staff interpreters, or contracting with outside public or private agencies that provide interpreter services. HHS’s guidance provides detailed examples of the mix of services that a Recipient should consider and implement. HHS’s guidance also establishes a “safe harbor” that Recipients may elect to follow when determining whether vital documents must be translated into other languages. Compliance with the safe harbor will be strong evidence that the Recipient has satisfied its written translation obligations.

In addition to reviewing HHS guidance documents, Recipients may contact HHS’s Office for Civil Rights for technical assistance in establishing a reasonable LEP plan.

III. California Law – Dymally-Alatorre Bilingual Services Act. The California legislature enacted the California’s Dymally-Alatorre Bilingual Services Act (Govt. Code 7290 et seq.) in order to ensure that California residents would appropriately receive services from public agencies regardless of the person’s English language skills. California Government Code section 7291 recites this legislative intent as follows:

“The Legislature hereby finds and declares that the effective maintenance and development of a free and democratic society depends on the right and ability of its citizens and residents to communicate with their government and the right and ability of the government to communicate with them.

The Legislature further finds and declares that substantial numbers of persons who live, work and pay taxes in this state are unable, either because they do not speak or write English at all, or because their primary language is other than English, effectively to communicate with their government. The Legislature further finds and declares that state and local agency employees frequently are unable to communicate with persons requiring their services because of this language barrier. As a consequence, substantial numbers of persons presently are being denied rights and benefits to which they would otherwise be entitled.

It is the intention of the Legislature in enacting this chapter to provide for effective communication between all levels of government in this state and the people of this state who are precluded from utilizing public services because of language barriers.”

The Act generally requires state and local public agencies to provide interpreter and written document translation services in a manner that will ensure that LEP individuals have access to important government services. Agencies may employ bilingual staff, and translate documents into additional languages representing the clientele served by the agency. Public agencies also must conduct a needs assessment survey every two years documenting the items listed in Government Code section 7299.4, and develop an implementation plan every year that documents compliance with the Act. You may access a copy of this law at the following url: http://www.spb.ca.gov/bilingual/dymallyact.htm

Acknowledgement of Commercial Support Exhibitors

Acadia Acorda Avanir Axella Bayer Biogen Idec EMD Serono GE Healthcare Genzyme/Sanofi Aventis Jazz Pharmaceuticals Kroger Specialty Infusion (Formerly Biofusion) LivaNova LWW NeuroPace, Inc. Novartis Teva Neuroscience UCB

Faculty List

Course Chairs

Stephen L. Hauser, MD Robert A. Fishman Distinguished Professor and Chair of Neurology

S. Andrew Josephson, MD Carmen Castro Franceschi and Gladyne K. Mitchell Neurohospitalist Distinguished Professor and Senior Executive Vice Chair of Neurology

Special Guest Faculty

Nancy J. Newman, MD LeoDelle Jolley Professor of Ophthalmology Professor of Ophthalmology and Neurology Director, Section of Neuro-Ophthalmology Emory University School of Medicine, Atlanta, GA

Course Faculty (University of California, San Francisco unless indicated)

Liza H. Ashbrook, MD Assistant Professor of Neurology

Carolyn J. Bevan, MD, MS Assistant Professor of Neurology

Edward F. Chang, MD, PhD Associate Professor of Neurosurgery

Felicia C. Chow, MD Assistant Professor of Neurology

Jennifer L. Clarke, MD, MPH Associate Professor of Neurology

Susannah C. Cornes, MD Assistant Professor of Neurology

Bruce A.C. Cree, MD, PhD Associate Professor of Neurology

John W. Engstrom, MD Professor of Neurology

Heather J. Fullerton, MD, MAS Professor of Neurology

Nicholas B. Galifianakis, MD, MPH Assistant Professor of Neurology

Jeffrey Gelfand, MD Assistant Professor of Neurology

Course Faculty (continued) (University of California, San Francisco unless indicated)

Douglas S. Goodin, MD Professor of Neurology

Ari J. Green, MD, MCR Associate Professor of Neurology

Lea T. Grinberg, MD, PhD Associate Professor of Neurology

Nerissa U. Ko, MD, MS Professor of Neurology

Morris Levin, MD Professor of Neurology

Descartes Li, MD Professor of Psychiatry

Daniel H. Lowenstein, MD Professor of Neurology

Bruce L. Miller, MD Professor of Neurology

Nancy Ann Oberheim Bush, MD, PhD Assistant Professor of Neurology

Jill L. Ostrem, MD Professor of Neurology

Gil D. Rabinovici, MD Associate Professor of Neurology

Jeffrey W. Ralph, MD Associate Professor of Neurology

Liliana Ramirez Gomez, MD Assistant Professor of Neurology

Vikram K. Rao, MD, PhD Assistant Professor of Neurology

Wade S. Smith MD, PhD Professor of Neurology

Caroline M. Tanner, MD, PhD Professor of Neurology

Michael Wilson, MD Professor of Neurology

Disclosures

The following faculty speakers, moderators, and planning committee members have disclosed they have no financial interest/arrangement or affiliation with any commercial companies who have provided products or services relating to their presentation(s) or commercial support for this continuing medical education activity:

Liza Ashbrook, MD S. Andrew Josephson Carolyn J Bevan, MD Nerissa Ko, MD Edward F. Chang, MD Descartes Li, M.D. Felicia Chow, MD, MAS Daniel Lowenstein, MD Jennifer L Clarke, MD, MPH Bruce L Miller, MD Susannah Cornes, MD Nancy Ann Oberheim Bush, MD PhD John W Engstrom, MD Jeffrey Ralph, MD Heather J Fullerton, MD, MAS Liliana Andrea Ramirez Gomez, MD Lea T Grinberg, MD, PhD Michael R Wilson, MD, MASKattan, Michael Stephen L Hauser, MD

The following faculty speakers have disclosed a financial interest/arrangement or affiliation with a commercial company who has provided products or services relating to their presentation(s) or commercial support for this continuing medical education activity. All conflicts of interest have been resolved in accordance with the ACCME Standards for Commercial Support:

Bruce A C Cree, MD, PhD, MAS Abbvie Consultant Biogen Consultant EMD Serono Consultant Novartis Consultant Shire Consultant Nicholas B. Galifianakis, MD, MPH Boston Scientific Corporation Grant/Research Support Jeffrey M Gelfand, MD, MAS Genentech Grant/Research Support Consultant MedDay Grant/Research Support Quest Diagnostics Grant/Research Support medical legal consulting Consultant (Spouse) eNeura Grant/Research Support (Spouse) Eli Lilly Consultant (Spouse) Zosano Consultant Douglas S Goodin, MD Genzyme Honorarium Recipient Novartis Grant/Research Support Teva Honorarium Recipient Serono Honorarium Recipient Ari Justin Green, MD Inception Biosciences Grant/Research Support Board Member Stock Shareholder Holder of Intellectual Property Bionure Consultant Stock Shareholder Mediimmune Advisor or Reviewer Mylan/Dr. Panel Member Reddy/Sandoz/Amneal/Synthon Advisor or Reviewer Morris Levin, MD Supernus Consultant Cipla Consultant Depomed Consultant Allergan Consultant Nancy J Newman, MD GenSight Grant/Research Support Consultant Santhera Consultant Quark Advisor or Reviewer Multiple law firms Consultant Jill L Ostrem, MD Medtronic Grant/Research Support Consultant Allergan Grant/Research Support Boston Scientific Grant/Research Support Abbvie Grant/Research Support Google Grant/Research Support Sangamo Grant/Research Support Gil D Rabinovici, M.D. Avid Radiopharmaceutical/Eli Lilly Grant/Research Support GE Healthcare Grant/Research Support Piramal Grant/Research Support Eisai Honorarium Recipient Genentech Consultant Roche Consultant Merck Consultant Lundbeck Consultant Putnam Consultant Vikram R Rao, MD, PhD NeuroPace, Inc Honorarium Recipient Wade Smith, MD Stryker Inc Consultant Caroline M Tanner, M.D., Ph.D. Neurocrine Consultant Adamas Consultant Voyager Advisor or Reviewer Biotie Advisor or Reviewer Intec Pharma Advisor or Reviewer

This UCSF CME educational activity was planned and developed to: uphold academic standards to ensure balance, independence, objectivity, and scientific rigor; adhere to requirements to protect health information under the Health Insurance Portability and Accountability Act of 1996 (HIPAA); and, include a mechanism to inform learners when unapproved or unlabeled uses of therapeutic products or agents are discussed or referenced.

This activity has been reviewed and approved by members of the UCSF CME Governing Board in accordance with UCSF CME accreditation policies. Office of CME staff, planners, reviewers, and all others in control of content have disclosed no relevant financial relationships.

COURSE PROGRAM

Wednesday, February 8, 2017 12:00 noon Registration and Refreshments 1:00 pm Welcome and Introductions S. Andrew Josephson, MD 1:10 Neuro-Ophthalmology Pearls, Pitfalls and Nancy J. Newman, MD Advances: Part 1 2:05 Neuroinfectious Diseases: Practical Tips for Felicia C. Chow, MD Common Disorders 3:00 Coffee Break 3:20 B Cell Therapy for Multiple Sclerosis: A New Day? Stephen L. Hauser, MD 4:05 Multiple Sclerosis Highlights 2016 Stephen L. Hauser, MD Carolyn J. Bevan, MD, MS Bruce A.C. Cree, MD, PhD Douglas S. Goodin, MD Ari J. Green, MD, MCR 5:00 Adjourn 5:00-6:00pm Reception

Thursday, February 9, 2017 8:00 am Continental Breakfast 8:30 Neuro-Ophthalmology Pearls, Pitfalls and Nancy J. Newman, MD Advances: Part 2 9:15 Advances in Treatment and Diagnosis of Bruce L. Miller, MD Dementia 2017 10:00 Coffee Break 10:20 Challenges and Controversies in Movement Jill L. Ostrem, MD Disorders Management: a Case-based Discussion Caroline M. Tanner, MD, PhD 11:15 Psychiatry for the Neurologist Descartes Li, MD 12:00 pm Lunch on your own 2:00 Difficult Epilepsy Management Decisions Daniel H. Lowenstein, MD Susannah C. Cornes, MD Vikram K. Rao, MD, PhD 2:50 Difficult Headache Management Decisions Morris Levin, MD 3:40 The Changing World of Stroke Management Wade S. Smith MD, PhD S. Andrew Josephson, MD Nerissa U. Ko, MD, MS 5:00 pm Adjourn

Friday, February 10, 2017 8:00 am Continental Breakfast 8:30 An Interactive Session: Difficult Diagnosis John W. Engstrom, MD Liza H. Ashbrook, MD Jennifer L. Clarke, MD MPH Heather J. Fullerton, MD, MAS Nicholas B. Galifianakis, MD, MPH Nancy Ann Oberheim Bush, MD PhD Jeffrey W. Ralph, MD Liliana Ramirez Gomez, MD 10:20 Coffee Break 10:40 An Interactive Session: Difficult Diagnosis 12:00 pm Lunch on your own 2:00 The New Anatomy of Language Edward F. Chang, MD, PhD 2:50 pm Clinico-Pathologic Conference Gil D. Rabinovici, MD Lea T. Grinberg, MD, PhD 4:30 pm Adjourn Save the Date

51st Annual Recent Advances in Neurology Wednesday, February 14, 2018 – Friday, February 16, 2018 Thursday, August 1 – Saturday, August 3, 2013 Ritz- Carlton, San Francisco, CA Pearls, Pitfalls and Advances in Neuro-Ophthalmology

Nancy J. Newman, MD Emory University Atlanta, GA

Disclosure

• Consultant for Gensight Biologics, Santhera Data Safety Monitoring Board for Quark AION Study Medical-legal consultant (IIH and peri-op vision loss)

1 Where ? What? Now What?

CRAO BRAO

Vascular TMVL

Acute retinal ischemia Different visual outcomes Same systemic implications

2 Study MRI Results Correlation Boston DWI+ in 31/129 (24%) Neuro sx+ 2012 Same vascular territory as Permanent VL > TMVL visual loss in 28/31 Identified cause Small, multiple infarctions Embolic cause Korea DWI+ in 8/33 (24.2%) Neuro sx+ 2014 Same vascular territory as CRAO > BRAO visual loss in 8/8 Identified cause Small, multiple infarctions Embolic cause Germany DWI+ in 49/213 (23%) Neuro sx+ 2015 Same vascular territory as Identified cause visual loss in 55% Embolic cause Small, multiple infarctions

Am J Ophthalmol 2014

“TIA” + = STROKE

3 (The Neurologist 2012;18:350–355)

Non‐mydriatic fundus cameras • Easy for non‐ophthalmic trained individuals to use • No pupillary dilation • Able to take quality photographs of the posterior pole • Reveals unrecognized findings in ED (Bruce et al. NEJM 2011; 364:387-9)

4 Arch Ophthalmol 2012; 130: 939-940

Optic Neuropathy Classic Features

• Decreased visual acuity • Abnormal visual field • Relative afferent pupillary defect • Can see through to the nerve • Swollen or pale optic nerve

5 Optic Neuropathy Disc Alternatives

Optic Neuropathy Causes • Inflammatory • Vascular • Compressive/Infiltrative •Toxic/Nutritional • Hereditary •Traumatic • Elevated intracranial pressure • Elevated intraocular pressure

Optic Neuropathy Causes • Inflammatory • Vascular • Compressive/Infiltrative •Toxic/Nutritional • Hereditary •Traumatic • Elevated intracranial pressure • Elevated intraocular pressure

6 Optic Neuropathy Papilledema

• Disc swelling from  intracranial pressure •Any age •Painless • Bilateral • Spares visual acuity • Constriction of visual field

Papilledema Causes

• Intracranial mass lesions •Hydrocephalus • Meningeal processes • Cerebral venous thrombosis •Idiopathic (pseudotumor cerebri)

Idiopathic intracranial hypertension • Papilledema • Headaches • No localizing neurologic symptoms/signs except for VIth • No intracranial process, no venous sinus thrombosis • Normal CSF contents

• CSF opening pressure ≥25cm H2O

7 • Elevated ICP measured in the lateral decubitus position: neonates: >76 mm H2O, age 1–18 years: >280 mm H2O • Normal CSF composition except in neonates who may have up to 19 WBC/mm3 if 0–28 days and up to 9 WBC/mm3 if between 29 and 56 days old; the protein may be as high as 150 mg/dl

IIH imaging

 Not just a diagnosis of exclusion  New diagnostic criteria . Papilledema . Measure of intracranial pressure . Neuroimaging findings

8 IIH: Poor visual prognosis

 Patient’s characteristics • Black race. Neurology 2008; 70: 861-7 • Male. Neurology 2009; 72:304-9 • Severe obesity. J Neuro-Ophthalmol 2013; 33: 4-8 • Anemia / sleep apnea syndrome / HTN  Rapid onset (fulminant IIH). Neurology 2007; 68: 229-232

 IIH is everywhere there are obese people

9 10 ScientificWorldJournal. 2015; 2015: 140408.

TS stenosis

After stenting Clinical course of idiopathic intracranial hypertension with transverse sinus stenosis Neurology 2013;80:289-95

Optic Neuropathy Causes • Inflammatory • Vascular • Compressive/Infiltrative •Toxic/Nutritional • Hereditary •Traumatic • Elevated intracranial pressure • Elevated intraocular pressure

11 Optic Neuropathy Typical Optic Neuritis

• Inflammation of the optic nerve •F:M 3:1 • Age: 15-45 • Pain on eye movement • Normal or swollen disc • Spontaneous improvement • Associated with multiple sclerosis

ONTT

• No difference in visual acuity between steroid and placebo groups at 6 months. • I.V. steroids may accelerate recovery by 2 to 3 weeks. • P.O. steroids doubled the risk of recurrence in either eye.

(NEJM 326:581, 1992)

12 ONTT: MRI predicts the risk of MS

70 Total 50%

60 at 15 yrs ≥ 1 lesion 72%

50

40

30

20 No lesion 25% 10

0 Years 1 2 3 4 5 6 7 8 9 10 11 12

Clinical Features of Optic Neuritis with Low Risk of CDMS in Patients with No Brain MRI Lesions

No cases of CDMS have developed when any one of the following clinical features* was present: • Severe Disc Swelling (21 patients) • Hemorrhage, disk or peripapillary (16 patients) • Macular Exudates (8 patients) • Painless (19 patients) • No Light Perception (7 patients)

OCT: Retinal Nerve Fiber Layer (RNFL) Thickness • Correlates with axonal loss • Correlates with visual dysfunction • Correlates with: – Brain atrophy in MS – Disability – Quality of life

13 From: Relationships Between Retinal Axonal and Neuronal Measures and Global Central Nervous System Pathology in Multiple Sclerosis

JAMA Neurol. 2013;70(1):34-43. doi:10.1001/jamaneurol.2013.573

Cellular composition of the retinal layers : ILM: inner limiting membrane RNFL: retinal nerve fiber layer GCL: ganglion cell layer IPL: inner plexiform layer INL: inner nuclear layer OPL: outer plexiform layer ONL: outer nuclear layer ELM: external limiting membrane IPS: inner photoreceptor segments OPS: outer photoreceptor segments PR: photoreceptors RPE: retinal pigment epithelium

-Healthy subject. 3-dimensional macular volume cube generated by Cirrus HD-OCT from the macular region -The individual layers of the retina are readily discernible, except for GCL and IPL, which are difficult to distinguish. -During the segmentation process (performed in 3-dimension), the segmentation software identifies the outer boundaries of the macular RNFL, IPL, and OPL, as well as the inner boundary of the RPE, which is identified by the conventional Cirrus HD-OCT algorithm. The identification of these boundaries facilitates OCT segmentation, enabling determination of the thicknesses of the macular RNFL, GCL + IPL, the INL + OPL, and the ONL including the inner and outer photoreceptor segments

Fingolimod and Macular Edema

1. Incidence of macular edema is low (~1%); (uveitis, DM increase risk). Ophthalmology 2013; 120: 1432-1439 2. Screening evaluation for uveitis, macular or retinal vascular disease prior to starting, or within the first few weeks of starting fingolimod 3. Re-evaluation (complete eye exam +/- macular OCT) at 3-4 months of therapy (most reported cases of macular edema occurred within 3-4 months)

14 Optic Neuropathy Causes • Inflammatory • Vascular • Compressive/Infiltrative •Toxic/Nutritional • Hereditary •Traumatic • Elevated intracranial pressure • Elevated intraocular pressure

15 Optic Neuritis and NMO Abs • Severe • Bilateral • Bilateral • Poor recovery • Severe • Recurrent • Poor recoveryOptic Neuritis and NMO Abs • Recurrent

16 Optic Neuropathy Causes • Inflammatory • Vascular • Compressive/Infiltrative •Toxic/Nutritional • Hereditary •Traumatic • Elevated intracranial pressure • Elevated intraocular pressure

Optic Neuropathy

Anterior Ischemic Optic Neuropathy • Ischemia to the optic nerve head •M:F 1:1 • Age: older than 50 • Diabetes, hypertension •Painless • Swollen disc • Permanent visual loss • Associated with giant cell arteritis

 Small cup‐to‐disc ratio

c/d:0.8 c/d:0.5 c/d:0.1

17 AION vs ON

Age Older (>50) Younger Gender M = F F > M Visual loss Acute Rapidly progressive Pain Infrequent Frequent with EOM Color Vision May be normal Commonly abnormal Visual Field Altitudinal defect Central defects Optic Disc Acute: edema Normal or edema Small c/d Late: seg pallor Temporal pallor MRI Nl optic nerve Abnl optic nerve Visual prognosis Poor Good Systemic disease HTN, DM, r/o GCA Subsequent MS

23% of NAION patients are less than 50 years‐old

AION vs. ON

• Prognosis for visual recovery • Recognition of giant cell arteritis • Prognosis for multiple sclerosis • Treatment of demyelination

18 JAMA Ophthalmol 2015; 133: 797‐804

J Sex Med. 2015 Jan;12(1):139-51.

Risk of AION increased by 3.86 when taken within the week preceding the AION vs. when taken 7 weeks prior

Risk of 2.36 when taken the day before vs. within the 29 days before

19 • Intravitreal injection of QPI‐1007 (small interfering ribonucleic acid that blocks Caspase 2 apoptosis) • NAION 50‐80 years old • Within 14 days of visual loss • USA • India, Israel, Italy, Germany, Australia, and China.

Giant Cell Arteritis

• Rule-out giant cell arteritis (ESR, CRP, platelets) in all > 50 yo patients with ischemic optic neuropathy

• Arteritic ION: – AION or PION – Systemic symptoms of GCA absent in 25% – Often with transient visual loss or diplopia – Bilateral if no treatment – Steroids emergently, then temporal artery biopsy – Poor visual prognosis

JAMA Neurol 2015; 11: 1281

20 Perioperative Visual Loss Ischemic Optic Neuropathy

• Anterior optic nerve – Acute: swelling of disc – > 6 wks: pallor of disc

• Posterior optic nerve – Acute: normal fundus – > 6 wks: pallor of disc

• Mechanism: ischemia

ASA Registry- n=131 Other Head and neck

Cardio pulmonary bypass Spine

21 Perioperative Visual Loss ASA Registry – Spine (n=93)

CRAO Unspecified ION

AION

PION

Anesthesiology 2012; 116: 15-24

Optic Neuropathy Causes • Inflammatory • Vascular • Compressive •Toxic/Nutritional • Hereditary •Traumatic • Elevated intracranial pressure • Elevated intraocular pressure

22 Toxic Optic Neuropathies

• Ethambutol –Dose-related – Early dyschromatopsia • Linezolide –Dose-related – Mild disc edema – Peripheral neuropathy • Amiodarone – Disc edema (mimics AION) • Cobalt-chromium metallosis – Hip implants • Methanol and ethylene glycol

Optic Neuropathy Causes • Inflammatory • Vascular • Compressive •Toxic/Nutritional • Hereditary •Traumatic • Elevated intracranial pressure • Elevated intraocular pressure

23 Optic Neuropathy Hereditary

• Maternal/Mitochondrial (Leber’s) • Autosomal dominant (Kjer’s)

Optic Neuropathy Hereditary

Hereditary Optic Neuropathies Treatment

• Genetic counseling • Symptomatic • Disease-modifying • Mitochondrial diseases • Hereditary optic neuropathies • Idebenone (900mg/d) • Gene therapy (ongoing clinical trials)

24 Leber Hereditary Optic Neuropathy Treatment – Idebenone?

-Carelli V, La Morgia C, Valentino ML, et al. Idebenone treatment in Leber’s hereditary optic neuropathy. Brain 2011;134:1-5/e188

Leber Hereditary Optic Neuropathy Gene Therapy

Proc Natl Acad Sci U S A. 2012 May 15;109(20):E1238‐47

Allotopic Rescue

Am J Hum Genet. 2008 Sep;83(3):373‐87.

Safety and Tolerability Study

• Intravitreal injection of rAAV2/2‐ND4 in one eye of 9 patients (3 groups escalating doses) with LHON (11778) and chronic visual loss

• Excellent systemic safety and tolerance • No vector shedding • Good local tolerance with mild AE’s • Mild ↑IOP (23‐34) and ocular inflammation: • Treatment responsive and reversible • No unexpected adverse events

NANOS, ARVO and AAO meetings, 2015

25 Rescue & Reverse Studies

• Two, simultaneous, parallel Phase III clinical trials of intravitreal gene therapy for the treatment of LHON, occurring at 7 study sites worldwide (Atlanta, Los Angeles, Philadelphia, Paris, London, Munich, Bologna)

• Goal is to randomize 36 patients for each study over 1 year with 2‐year followup

From a Patient’s Perspective

• Social media growth makes it easier for LHON patients and families to connect – Global LHON Facebook (2,500+ members) – Clinical database (3,400+ entries) • Website and social media facilitate study trial recruitment with just a “click”

26 27 (2015)

28 86

2004

29 JAMA Neurol 2015; 72: 1170

30 31 What’s New Next Year??

– Nonmydriatic fundus photography – Idiopathic intracranial hypertension clinical trial – OCT and MS Trials – Treatment of NMO – Treatment of GCA – Ocular myasthenia gravis – LHON (Gene therapy clinical trials) – Diagnosis of concussion

http://novel.utah.edu/

32 1/27/2017

NEUROINFECTIOUS DISEASES: PRACTICAL TIPS FOR COMMON DISORDERS Felicia Chow, MD, MAS Assistant Professor of Neurology and Medicine (ID) February 8, 2017

Disclosures

• I have no disclosures.

Learning objectives

• Recognize the clinical presentation of common neuroinfectious diseases

• Identify pitfalls of diagnostic testing frequently obtained in the evaluation and management of common neuroinfectious diseases

• Be familiar with the approach to the treatment of common neuroinfectious diseases

1 1/27/2017

Question: My patient has neurosyphilis. Does that automatically mean they have late, or like later, or latent syphilis?

Stages of syphilis

Lafond et al. Clin Microbiol Rev 2006

Reply: Neurosyphilis can occur at any stage of infection.

2 1/27/2017

Question: I have a patient whose MRI demonstrated a small acute infarct in the internal capsule. He has hypertension and uncontrolled diabetes, and urine tox screen was positive for cocaine. His RPR was 1:64 and was negative 6 months ago. Since strokes in syphilis usually occur as a late presentation and he has many other vascular risk factors, I don’t have to LP him, do I?

Think meninges, CSF and blood vessels in early syphilis and parenchymal disease in late syphilis

Ghanem CNS Neurosci Ther 2010

Reply: I would recommend an LP for any patient with a newly positive RPR (or positive RPR of unknown duration) and clinical/radiologic evidence of strokes.

3 1/27/2017

Question: My clinic patient has uveitis and an RPR of 1:128. Ophtho sent him to clinic for neurological evaluation, but he has no neurological symptoms. I don’t have to LP him, do I?

Which syphilis patients need an LP?

• Any stage of syphilis + neurological symptoms

• Any stage of syphilis + ocular or otologic disease

• HIV-infected patients PLUS: • Late latent syphilis • Syphilis of unknown duration • Inappropriate serologic response after treatment • Consider for any HIV-infected patient with RPR ≥ 1:32 and/or CD4 < 350 cells/mm3

Ghanem Clin Infect Dis 2009

Reply: I would recommend an LP for all patients with ocular syphilis.

4 1/27/2017

Beware the ongoing ocular syphilis epidemic

• Can occur at any stage of syphilis  most cases now present in early syphilis

• Can involve ANY ocular structure • Anterior uveitis (iris, ciliary body) • Posterior uveitis (chorioretinitis) • Retinitis, retinal detachment • Optic neuritis

• ~50% of patients with ocular syphilis will have evidence of meningitis in the CSF

• Treatment is the same as neurosyphilis even if CSF is non-inflammatory

• May have residual vision loss despite treatment

Woolston et al. MMWR 2015

Question: My HIV+ patient, intermittently non-adherent to his ARVs, presented to clinic with headaches that are more severe than his usual migraines.

Serum RPR was 1:64. CSF had 20 WBC and a mildly elevated protein, but CSF VDRL was negative. Could this still be neurosyphilis?

Syphilis diagnostic testing

Test characteristics Notes SERUM Sensitivity: *Titers correspond to disease 1°: 78-86% activity RPR and 2°: Near 100% VDRL (non- 3°/Latent: Varies, ~85% *Used to assess treatment treponemal tests) False positives 1-2%, usually titer < 1:8 response  4-fold decline (autoimmune disease, IVDU, TB, considered to be clinically pregnancy, endocarditis) significant

False negatives in HIV, prozone effect SERUM False positives with other spirochetal *Titers do not correspond to infections, malaria, leprosy disease activity Treponemal *Most positive for life despite tests False negative in HIV treatment (TPPA, *15-25% treated in primary stage FTA-Abs) revert to seronegativity CSF VDRL CSF VDRL Sensitivity: 30-80%, *+CSF VDRL at any titer = NS and FTA- Specificity 99% *Syphilis of any stage + clinical Abs s/sx c/w NS + elevated CSF WBC FTA-abs high sensitivity but low specificity + protein with no other cause

5 1/27/2017

Reply: Yes, CSF VDRL can be insensitive for neurosyphilis. This absolutely could still be neurosyphilis, and based on the clinical data, I would recommend treating him for neurosyphilis with 2 weeks of Penicillin G (4 million units IV q4 hours).

Question: We have an inpatient who presented with 2 days of fever, headache and confusion. CSF s 11 WBC (85%L), protein 75 and glucose 53.

CSF HSV 1 PCR negative. Could this still be HSV encephalitis?

HSV encephalitis

• HSV is the most frequently identified viral etiology of sporadic encephalitis in the US

• Occurs any time of year

• Bimodal distribution: 1/3 cases <20 y, 2/3 >40 y

• Case fatality rate >70% if untreated; 1/3 of patients may be significantly disabled despite treatment

• CSF: 5-500 WBC/mm3, normal to moderately elevated protein, glucose typically normal

• DWI may be most sensitive sequence early in the course of infection

6 1/27/2017

What is the utility of HSV-1 PCR in the CSF?

• 54 patients with biopsy- proven HSE underwent HSV-1 PCR from CSF • Sensitivity 98% • Specificity 94%

Lakeman J Infect Dis 1995

Sensitivity of CSF HSV-1 PCR is lower early in the course of HSV encephalitis

Weil Clin Infect Dis 2002

Reply: Yes, this could definitely still be HSV-1 encephalitis. I recommend you repeat the lumbar puncture, resend an HSV-1 PCR from the CSF and start IV acyclovir 10-15 mg/kg every 8 hours as you await the results.

7 1/27/2017

Question: The repeat CSF HSV-1 PCR was positive. She received 3 weeks of IV acyclovir but is still quite impaired, far from her baseline. Should we discharge her on oral antiviral therapy?

No significant cognitive benefit of oral therapy after IV acyclovir

• 87 HSE patients randomized to valacyclovir 2 g TID versus placebo x 90 days

• Excluded individuals with life expectancy <90 d and those who couldn’t take PO

• Primary outcome was survival with no/mild impairment at 12 months

Gnann Clin Infect Dis 2015

Reply: No, unfortunately there is no evidence that a longer course of oral antiviral therapy after completing IV acyclovir is beneficial, and I do not recommend she be discharged on oral therapy.

8 1/27/2017

Question: Our HSV-1 encephalitis patient was readmitted from rehab 4 weeks after she was discharged with worsening confusion. Could this be recurrent HSV infection?

• ~15-25% of patients have early relapsing symptoms after completing acyclovir

• More common in children  chorea, dystonia, fever, AMS, behavioral changes, seizures

• Adults  movement symptoms less common

• CSF pleocytosis and elevated protein; contrast enhancement on MRI

• Immune-mediated hypothesis supported by recent discovery of NMDAR and other antibodies patients with relapsing symptoms

Armangue Neurology 2015

Diagnostic approach to relapsing symptoms in HSV

RELAPSING NEUROLOGICAL SYMPTOMS (e.g., CHOREOATHETOSIS, CONFUSION, AGGRESSION, AGITATION, SEIZURES )

CSF HSV-1 PCR PCR + CSF/SERUM FOR ANTIBODIES TO ACYCLOVIR NMDAR, OTHERS

PCR -

NEGATIVE CONSIDER ANTIBODY RESULTS IMMUNOTHERAPY

POSITIVE

IMMUNOTHERAPY

Titulaer Mov Disorder 2014

9 1/27/2017

Reply: I would repeat a lumbar puncture and resend the CSF HSV-1 PCR. If the HSV-1 PCR is negative, I would NOT restart IV acyclovir and would consider serum/CSF evaluation for NMDAR antibodies if there is no identified cause for a persistent decline.

Question: Our patient with newly diagnosed HIV infection (CD4 count 90 cells/mm3, viral load 75K) presented with progressive right sided weakness and confusion.

I know the serum toxoplasma antibody status of an HIV+ patient with focal brain lesions is key. The patient’s serum toxo IgM ELISA is negative, so does this rule out toxplasmosis?

10 1/27/2017

CNS toxoplasmosis

• Most common focal brain lesion in HIV+ w/ CD4 < 200 in US

• Presentation usually evolves over weeks to months

• TMP/SMX prophylaxis reduces risk of toxoplasmosis

• Ddx: CNS lymphoma, pyogenic abscess, tuberculoma, cryptococcoma

• May end up treating empirically and monitor for clinical and radiographic improvement

Tan et al. Lancet Neurology 2012, Laing et al. Int J STD AIDS 1996

Utility of toxoplasma serology • Toxoplasmosis seropositivity in general population in the US is estimated to be 10-40%

• Toxoplasmosis in HIV is typically reactivation of prior infection (i.e., IgM antibodies unhelpful)

• Serum IgG is positive in most HIV patients with CNS toxoplasmosis

• CSF toxo IgG (>1:64) and PCR are very specific but sensitivity varies

Laing Int J STD AIDS 1996, Correira Trans R Soc Trop Med Hyg 2010, Vidal J Clin Microbiol 2004, Sakamoto Parasitol Int 2014

Reply: The serum toxoplasma IgG is typically more informative in an HIV patient in whom you are worried about toxoplasmosis. Send the IgG and, if safe, do a lumbar puncture and send the CSF for toxoplasma IgG and/or toxo PCR.

11 1/27/2017

Question: Serum toxo IgG was positive. CSF demonstrated 23 WBC (80%L), 27 RBC, glucose 47 and protein 58. CSF toxoplasma and EBV PCR are pending. What else can help us distinguish between toxo and CNS lymphoma?

Toxoplasmosis versus CNS lymphoma in HIV

Toxoplasmosis Primary CNS Lymphoma Clinical Focal s/sx (~75%), HA (~50%), fever Focal s/sx including hemiparesis, presentation (~50%); sx evolve faster than CNSL aphasia, visual field deficit

At risk with CD4 count <200 At risk with CD4 count <50 Radiologic Basal ganglia, thalamus, grey-white Periventricular, deep white matter findings junction Can be solitary/few lesions with Usually multiple lesions (75%) with solid/homogeneous enhancement; in ring or nodular enhancement patients with HIV, can ring-enhance

+Mass effect and edema +Mass effect and edema Diagnosis Serum IgG (reactivation), CSF IgG CSF EBV PCR (Se 90-100%), brain and PCR; response to empiric Rx biopsy; cytology has poor sensitivity (<20%) Treatment Pyrimethamine (w/ leucovorin) and Corticosteroids, XRT, methotrexate sulfadiazine or clindamycin; and other chemotherapy

AVOID steroids if possible!

Raffi et al. AIDS 1997

Toxoplasmosis or CNS lymphoma ?

12 1/27/2017

Question: CSF toxoplasma PCR was positive. The patient was started on pyrimethamine, sulfadiazine and leucovorin 10 days ago and has been clinically improving. When is it safe to start ARVs?

• Over a 9-year period, 65 cases of CNS toxo diagnosed

• 0 cases of paradoxical CNS toxo IRIS

• 3 cases fulfilled criteria for unmasking CNS toxo IRIS

Reply: It is reasonable to start ARVs in a patient who is on appropriate toxoplasmosis treatment and stable x ~7- 14 days

Martin-Blondel et al. J Neurol Neurosurg Psychiatry 2011

Question: My patient, originally from Mexico, was referred for evaluation of a single ring-enhancing right frontal lesion. While in the ED with her husband who was being seen for chest pain, she had a witnessed convulsive spell and was confused for hours afterward.

13 1/27/2017

Blood cultures, HIV test, PPD and chest/abdomen/pelvis CT were negative. Serum cysticercal ELISA was also negative. Could this still be cysticercosis?

Neurocysticercosis (NCC)

• Infection of the nervous system with larval stage of the helminth, Taenia solium

• 50+ million people affected worldwide

• One of the most common causes of acquired epilepsy in developing world

Stages of neurocysticercosis

Viable cyst Degenerating cyst Dead cyst

Garcia et al. Curr Opin Infect Dis 2003;16:411-419.

Courtesy of HH Garcia

14 1/27/2017

Location, location, location

• Intraparenchymal (70%) • Cortical (>90%) • Deep gray matter (5%) • Brainstem/infratentorial (Uncommon)

• Extraparenchymal (30%) • Sylvian fissure • Basal cisterns • Spine • Intraventricular

Serological diagnosis of NCC

• ELISA • Serum sensitivity 75-80+%, specificity 75% • CSF sensitivity higher than serum (>85%) and nearly 100% for subarachnoid disease • Sensitivity MUCH lower for single or calcified lesions (<50%)

• Western blot (available through CDC) • Sensitivity 80-100%, specificity 100% • Performs as well in serum as CSF • Sensitivity much lower in patients w/ single or calcified lesions (<50%) and higher (100%) for subarachnoid disease

• Neither can be used to distinguish prior from active infection

Tsang VC et al. J Infect Dis 1989

Reply: The epidemiology, clinical presentation and radiology findings are all highly suggestive of NCC, and this is exactly the type of patient in whom the ELISA might be less sensitive. I would send a CSF ELISA and western blot.

15 1/27/2017

Question: But I checked with the patient, and he rarely eats meat and never eats pork, so I don’t think this could still be cysticercosis.

Life cycle

Garcia et al. Curr Opin Infect Dis 2010

Reply: You don’t have to eat pork to be at risk for NCC because it results from fecal- oral contamination, so even vegetarians can develop NCC!

16 1/27/2017

Question: I saw a patient in clinic, originally from Mexico, currently working as a construction foreman, who complained of 1 month of worsening headaches and several episodes of left arm/leg shaking followed confusion.

Serum cysticercal ELISA was positive. I wanted to treat with albendazole + steroids, but ID is also recommending praziquantel. Is that a good idea?

Extraparenchymal NCC

• Less common form of infection w/ proliferating, invasive membranous structures

• Associated with more protracted course and worse prognosis

• Complications, particularly of basal subarachnoid disease, include: • Hydrocephalus and elevated ICP • Vasculitis +/- infarcts and hemorrhages

17 1/27/2017

Should I treat with dual therapy?

• Double-blind, placebo-controlled RCT

• Inclusion: 1-20 viable cysts

• Exclusion: Subarachnoid NCC at base of brain, most IV cysts, cysts in brainstem, larger cysts (>30 mm), ocular cysts

• Albendazole 15 mg/kg + praziquantel 50 mg/kg vs albendazole 15 mg/kg vs albendazole 22.5 mg/kg x 10 days

• Primary outcome: Cyst resolution at 6 months

Reply: A recent RCT showing benefit of dual anti-helminthic therapy for NCC patients excluded most patients with subarachnoid disease. Dual anti- helminthic therapy is still reasonable in this patient, but steroids should be initiated before starting treatment, and he should be observed carefully for complications (e.g. ICP, seizures).

18 1/27/2017

Treatment summary

CALCIFIED VIABLE DEGENERATING SUBARACHNOID OCULAR CYSTS CYSTS CYSTS CYSTS CYSTS Single lesion: No Single/few ABZ +/- PZQ + Surgical ABZ +/- antiparasitic lesions: ABZ steroids +/- resection steroids vs no therapy +/- steroids resection  therapy often requires Antihelminthic therapy may Multiple prolonged and Multiple result in loss lesions: ABZ + multiple lesions: ABZ + of vision PZQ + steroids courses of PZQ + secondary to therapy inflammation steroids

Singh et al Neurology 2010 Natarajan et al Arch Clin Exp Ophthalmol 1999

Question: I am seeing a middle-aged African American man from Modesto with a 6 week history of progressive headache, confusion and lethargy. CSF demonstrates 290 cells/mm3, protein is 100 and glucose 40 (serum 100). CSF gram stain and fungal stains are negative.

Question: I’m worried about Cocci meningitis. What testing on the CSF is most sensitive to make the diagnosis?

19 1/27/2017

https://www.cdc.gov/fungal/diseases/coccidioidomycosis/statistics.html

Coccidioidomycosis meningitis

• Most primary infections are asymptomatic (~2/3)

• CNS dissemination (1%) occurs weeks to months after 1o infection

• Risk factors for extrapulmonary/disseminated disease: • African or Filipino ancestry • Immune compromise (HIV, malignancy, DM, SOT, steroids) • Pregnancy

Imaging: ~66% 50-60% 33% (focal) • Meningeal enhancement • Hydrocephalus • Focal lesion (e.g, infarct, abscess) • Spinal arachnoiditis also common

Drake Neurology 2009, Galgiani Clin Infect Dis 2005, Johnson Clin Infect Dis 2006

20 1/27/2017

Performance of Cocci testing in CSF

Mixed prospective + retrospective study of 36 patients with cocci meningitis + 88 controls

Test Sens (%) Specificity (%) Fungal culture 7 100 Immunodiff IgM/IgG 67 99 Complement fixation 70 100 Antigen 93 100 Antigen, ID, CF 98 99

Kassis Clin Infect Dis 2015

Reply: If you suspect Cocci meningitis, in addition to checking an opening pressure, cell count, glucose, protein and fungal culture, I recommend you send a CSF Cocci immunodiffusion, complement fixation and antigen.

Galgiani Clin Infect Dis 2016

Treatment for Cocci meningitis

• 1st line: Fluconazole 400-1200 mg/day FOR LIFE

• If failing 1st line therapy: 1. Increase dose of fluconazole as tolerated 2. Consider another azole (e.g., voriconazole, posaconazole, isavuconazole) 3. Consider IT amphotericin B

• Hydrocephalus is a common complication  neurosurgery evaluation for shunt

• Infarcts  adjunctive steroids?

Galgiani Clin Infect Dis 2005, Johnson Clin Infect Dis 2006

21 1/27/2017

Useful references

• Marra CM. Update on neurosyphilis. Curr Infect Dis Rep 2009;11:127-134.

• Weil AA, Glaser CA, Amad Z, Forghani B. Patients with herpes simple encephalitis: rethinking an initial negative polymerase chain reaction result. Clin Infect Dis 2002;34:1154-57.

• Gnann JW, Skoldenberg B, Hart J et al. Herpes simplex encephalitis: lack of clinical benefit of long-term valacyclovir therapy. Clin Infect Dis 2015;61;683-91.

• Armangue T, Moris G, Cantarin-Extremera V et al. Autoimmune post-herpes simplex encephalitis of adults and teenagers. Neurology 2015;85:1736-43.

• Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescent: https://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-oi-prevention • -and-treatment-guidelines/0.

• Garcia HH, Gonzales I, Lescano AG et al. Efficacy of combined antiparasitic therapy with praziquantel and albendazole for neurocystiercosis: a double-blind randomized controlled trial. Lancet Infect Dis 2014;14:687-95.

• Garcia HH, Nash TE, del Brutto OH. Clinical symptoms, diagnosis and treatment of neurocysticercosis. Lancet Neurol. 2014;13:1202-15.

• Galgiani JN, Ampel NM, Blair JE et al. Clinical practice guideline for the treatment of coccidioidomycosis. Clin Infect Dis 2016;63:e112-46.

• Kassis C, Zaidi S, Kuberski T et al. Role of Coccidioides antigen testing in the CSF for the diagnosis of Coccidioidal meningitis. Clin Infect Dis 2015;61:1521-26.

THANK YOU

[email protected]

22 1/27/2017

50TH ANNUAL RECENT ADVANCES IN NEUROLOGY

B CELL THERAPY FOR MULTIPLE SCLEROSIS: A NEW DAY?

Stephen L. Hauser, MD Department of Neurology University of California, San Francisco

February 8, 2017

COI: Symbiotix, Annexon, Bionure, Neurona, Molecular Stethoscope

B cell Surface Markers

B CELLS PLASMA CELLS

CD19 CD20 CD22 CD138 CD27 HLA‐Class II

Image adapted from Krumbholz M, et al. Nat Rev Neurol 8(11):613–23, 2012

Targeting CD20+ B cells May Preserve B cell Reconstitution and Long‐Term Immune Memory

B CELLS PLASMA CELLS

B cell Reconstitution Long‐term Immune Memory Preserved1‐3 Preserved1,2,4 CD20

Rituximab (chimeric), ocrelizumab (humanised), and ofatumumab (human) are monoclonal antibodies that selectively deplete CD20+ B cells

Image adapted from Krumbholz M, et al. Nat Rev Neurol 8(11):613–23, 2012 1. Hauser SL. Mult Scler 21(1):8–21, 2015; 2. Pescovitz MD. Am J Transplant 6(5pt1):859–66, 2006; 3. Leandro MJ, et al. Arthritis Rheum 54(2):613–20, 2006; 4. DiLillo DJ, et al. J Immunol 180(1):361–71, 2008

1 1/27/2017

OPERA I and II: Two Identical Studies of Ocrelizumab in Relapsing MS

• RMS diagnosis • 18–55 yrs • EDSS of 0.0–5.5

• ≥2 clinical OLE relapses within last 2 yrs or 1 relapse in last yr OLE screening period 1:1 Randomization

Safety follow-up ≈48 weeks from date of last infusion

B-cell monitoring‡

‡Continued monitoring occurs if B cells are not repleted. EDSS, Expanded Disability Status Scale; IFN, interferon; i.v., intravenous; OLE, open‐label extension; RMS, relapsing multiple sclerosis; s.c., subcutaneous.

Ocrelizumab in Relapsing MS Reduction in Annualized Relapse Rate Compared With IFN β‐1a

OPERA IOPERA II 0.5 0.5

0.4 0.4 46% 47%

Weeks* ARR reduction vs ARR reduction

Weeks* IFN β‐1a vs IFN β‐1a 96

0.292 96 0.3 p<0.0001 0.3 0.290 p<0.0001 at

at

ARR

ARR

0.2 0.2 0.156 0.155 Adjusted Adjusted 0.1 0.1

0.0 0.0 IFN β‐1a Ocrelizumab IFN β‐1a Ocrelizumab 44 μg 600 mg 44 μg 600 mg (n=411) (n=410) (n=418) (n=417)

ITT *Adjusted ARR calculated by negative binomial regression and adjusted for baseline EDSS score (<4.0 vs ≥4.0), and geographic region (US vs ROW). ARR, annualised relapse rate; EDSS, Expanded Disability Status Scale; IFN, interferon; ROW, rest of the world.

Ocrelizumab in Relapsing MS Reduction in Mean Gadolinium‐Enhancing Lesions Compared With IFNβ‐1a

OPERA I OPERA II

0.6 IFN β‐1a 44 μg 0.6 IFN β‐1a 44 μg Ocrelizumab 600 mg Ocrelizumab 600 mg Scan* Scan*

97% 0.5 0.5 p<0.0001 MRI MRI

Per Per 0.4 95% 0.4 p<0.0001 96%

Patient 0.3 Patient 0.3 92% p<0.0001 p<0.0001 Per Per

0.2 0.2 98% 91% p<0.0001 Number Number 0.1 p<0.0001 0.1

Mean 0.0 Mean 0.0 Week 24 Week 48 Week 96 Week 24 Week 48 Week 96 n n IFN β‐1a 372 357 335 IFN β‐1a 372 334 311 Ocrelizumab 382 377 359 Ocrelizumab 385 373 359

ITT *Adjusted by means calculated by negative binomial regression and adjusted for baseline T1 Gd lesion (present or not), baseline EDSS (<4.0 vs ≥4.0) and geographical region (US vs ROW). EDSS, Expanded Disability Status Scale; Gd+, gadolinium enhancing; IFN, interferon; MRI, magnetic resonance imaging; ROW, rest of the world.

2 1/27/2017

Ocrelizumab in Relapsing MS Reduction in Total New and/or Enlarging T2 Hyperintense Lesions Compared With IFNβ‐1a

OPERA I OPERA II

2.5 IFN β‐1a 44 μg 2.5 IFN β‐1a 44 μg Ocrelizumab 600 mg Ocrelizumab 600 mg

Scan* 97% Scan*

p<0.0001 2.0

MRI 2.0 MRI

98% 61% p<0.0001 Per Per

p<0.0001 1.5 1.5 Patient 41% Patient

p=0.0002 Per Per

1.0 1.0 96% p<0.0001 94% p<0.0001 Number Number

0.5 0.5 Mean Mean 0.0 0.0 Week 24 Week 48 Week 96 Week 24 Week 48 Week 96 n n IFN β‐1a 373 357 336 IFN β‐1a 374 337 314 Ocrelizumab 385 378 360 Ocrelizumab 387 376 360

ITT *Adjusted by baseline T2 lesion count, baseline EDSS (<4.0 vs ≥4.0) and geographical region (US vs ROW). EDSS, Expanded Disability Status Scale; IFN, interferon; MRI, magnetic resonance imaging; ROW, rest of the world.

Reduction in Pre‐specified Pooled Analysis of Confirmed Disability Progression (CDP)

Time to CDP for ≥12 weeks Time to CDP for ≥24 weeks

15.2 12.0 9.8 7.6

Risk reduction: 40% Risk reduction: 40% HR (95% CI): 0.60 (0.45, 0.81); p=0.0006 HR (95% CI): 0.60 (0.43, 0.84); p=0.0025

n n IFN β‐1a 828 784 741 696 665 632 608 583 449 IFN β‐1a 828 785 747 705 677 644 622 600 466

OCR 827 795 765 737 716 702 688 672 526 OCR 827 797 772 748 731 717 704 688 540

ITT CI, confidence interval; HR, hazard ratio; IFN, interferon; OCR, ocrelizumab.

Total Serious Adverse Events Were Low and Similar

IFNβ‐1a Ocrelizumab 44 μg 600 mg n(%) (n=826) (n=825)

Overall patients with ≥1 SAE 72 (8.7) 57 (6.9)

Infections and infestations 24 (2.9) 11 (1.3)

Nervous system disorders 11 (1.3) 8 (1.0)

Injury, poisoning, and procedural complications 10 (1.2) 6 (0.7)

During OPERA I and OPERA II, three deaths occurred • IFN β‐1a 44 μgarm: completed suicide, mechanical ileus • Ocrelizumab 600 mg arm: completed suicide

Six malignancies were reported: • IFN β‐1a 44 μg arm: mantle cell lymphoma and squamous cell carcinoma • Ocrelizumab 600 mg arm: renal cancer, melanoma and two breast cancers

IFN, interferon; SAE, serious adverse event.

3 1/27/2017

ORATORIO: Phase 3 Study of Ocrelizumab in Primary Progressive MS

• Diagnosis of PPMS (2005 revised # McDonald criteria)1 • Age 18–55 years • EDSS 3.0–6.5 • CSF: elevated IgG index or >1 oligoclonal bands • No history of RRMS, SPMS, or PRMS • No treatment with other MS DMTs at 2:1 Randomization screening

*Patients received methylprednisolone prior to each ocrelizumab infusion or placebo infusion. †The blinded treatment period may be extended until database lock. #2:1 randomisation stratified by age (≤45 vs >45) and region (US vs ROW). ‡Continued monitoring occurs if B cells are not repleted. BL, baseline; CSF, cerebrospinal fluid; DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; i.v., intravenous; MRI, magnetic resonance imaging. 1. Polman CH, et al. Ann Neurol 2005;58:840–6.

Ocrelizumab in Primary Progressive MS Reduction in 12‐week Confirmed Disability Progression

Time to 12‐week Confirmed Disability Progression

24% reduction in risk of CDP HR (95% CI): 0.76 (0.59, 0.98); p=0.0321

n Placebo 244 232 212 199 189 180 172 162 153 145 136 120 85 66 46 30 20 7 2 Ocrelizumab 487 462 450 431 414 391 376 355 338 319 304 281 207 166 136 80 47 20 7

Analysis based on ITT population; p-value based on log-rank test stratified by geographic region and age. Patients with initial disability progression who discontinued treatment early with no confirmatory EDSS assessment were considered as having confirmed disability progression. CDP, confirmed disability progression; EDSS, Expanded Disability Status Scale; HR, hazard ratio; ITT, intent to treat.

Time to Onset of 12‐Week Confirmed Disability Progression

Overall Study Population (Primary Endpoint) (n=488)

24% reduction in risk of CDP HR (95% CI): 0.76 (0.59, 0.98); p=0.0321

Placebo Ocrelizumab Total Hazard (n=244) (n=488) 95% CI Ratio n nEventsn Events Overall 731 244 96 487 160 0.76 (0.59, 0.98) population T1 Gd+ 193 60 27 133 43 0.65 (0.40, 1.06) lesions No T1 Gd+ 533 183 68 350 115 0.84 (0.62, 1.13) lesions

Analysis based on ITT population; p-value based on log-rank test stratified by geographic region and age. Patients with initial disability progression who discontinued treatment early with no confirmatory EDSS assessment were considered as having confirmed disability progression. CDP, confirmed disability progression; Gd+, gadolinium-enhancing; EDSS, Expanded Disability Status Scale; HR, hazard ratio; ITT, intent to treat.

4 1/27/2017

Time to Onset of 24‐Week Confirmed Disability Progression

Overall Study Population (n=488)

25% reduction in risk of CDP HR (95% CI): 0.75 (0.58, 0.98); p=0.0365

Placebo Ocrelizumab Total Hazard (n=244) (n=488) 95% CI Ratio n nEventsn Events Overall 731 244 87 487 144 0.75 (0.58, 0.98) population T1 Gd+ 193 60 23 133 39 0.67 (0.40, 1.14) lesions No T1 Gd+ 533 183 63 350 103 0.81 (0.59, 1.10) lesions

Analysis based on ITT population; p-value based on log-rank test stratified by geographic region and age. Patients with initial disability progression who discontinued treatment early with no confirmatory EDSS assessment were considered as having confirmed disability progression. CDP, confirmed disability progression; Gd+, gadolinium-enhancing; EDSS, Expanded Disability Status Scale; HR, hazard ratio; ITT, intent to treat.

Secondary Endpoint: Significant Reduction In the Progression Rate of Walking Time

Percent Change in Timed 25‐Foot Walk From Baseline to Week 120 29% reduction vs placebo p=0.0404* Time

Walking

CI)

95%

Baseline

(Mean, from

Change

%

n Placebo 239 233 228 230 218 211 207 196 190 180 174 Ocrelizumab 473 460 454 454 450 435 432 425 419 412 397

*Analysis based on ITT population; p-value based on ranked ANCOVA at 120-week visit adjusted for baseline timed 25-foot walk, geographic region and age with missing values imputed by LOCF. Point estimates and 95% CIs based on MMRM analysis on log-transformed data adjusted for baseline timed 25-foot walk, geographic region and age. CI, confidence interval; HR, hazard ratio; ITT, intent to treat; LOCF, last observation carried forward.

Change in Brain T2 Hyperintense Lesion Volume From Baseline to Week 120

Overall Study Population 20

15 +7.4% with placebo

CI) vs

Baseline 10 −3.4% with ocrelizumab Volume

95% 5 p<0.0001* From

0 Lesion

(Mean, T2 -5 Change

% -10 Placebo n=183 Ocrelizumab n=400

Patients With T1 Gd+ Lesions Patients Without T1 Gd+ Lesions 20 20 at Baseline at Baseline 15 15 CI) CI)

Baseline Baseline

10 10 Volume Volume

95% 95% 5 5 From From

0 0 Lesion Lesion

(Mean, (Mean, T2 -5 T2 -5 Change Change

% -10 Placebo n=39 Ocrelizumab n=107 % -10 Placebo n=144 Ocrelizumab n=291

*Analysis based on ITT population; p-value based on ranked ANCOVA at 120-week visit adjusted for baseline T2 lesion volume, geographic region and age with missing values imputed by LOCF. Point estimates and 95% CIs based on MMRM analysis on log-transformed data adjusted for baseline T2 lesion volume, geographic region and age. CI, confidence interval; Gd+, gadolinium-enhancing; ITT, intent to treat; LOCF, last observation carried forward; MMRM; mixed-effect model repeated measure.

5 1/27/2017

Change of Whole Brain Volume From Week 24 to Week 120

Overall Study Population 0.0

Volume -0.2

-0.4 CI) 24

-0.6 Brain -0.8 95% -1.0 Week -1.2 17.5% Whole -1.4 relative reduction in

From (Mean, -1.6 p=0.0206* -1.8 -2.0 Placebo n=150 Ocrelizumab n=325 Change

%

Patients With T1 Gd+ Lesions Patients Without T1 Gd+ Lesions at Baseline at Baseline 0.0 0.0 Volume -0.2 Volume -0.2

-0.4 -0.4 CI) CI) 24 24

-0.6 -0.6 Brain Brain

-0.8 -0.8 95% 95%

-1.0 -1.0 Week Week

-1.2 -1.2 Whole Whole

-1.4 -1.4 in in

From From (Mean, -1.6 (Mean, -1.6 -1.8 -1.8 -2.0 Placebo n=31 Ocrelizumab n=83-2.0 Placebo n=119 Ocrelizumab n=241 Change Change

% %

*Analysis based on ITT population with Week 24 and at least one post-Week 24 assessment; p-value based on MMRM at 120-week visit adjusted for Week 24 brain volume, geographic region and age. CI, confidence interval; Gd+, gadolinium-enhancing; ITT, intent to treat; MMRM; mixed-effect model repeated measure.

MS Therapies Have Consistent Effects on B cells Beta

OFA

CD20 ‐ Effect on B cells* RTX, OCR, Interferon Glatiramer acetate Fingolimod Dimethyl fumarate Teriflunomide Mitoxantrone Natalizumab Alemtuzumab Anti Therapy Modulation •••••• ••

Differentiation •••••• ••

Activation ••• •• •

Migration ••

Depletion ••••

*In humans and experimental models

Many MS Drugs in Development Target B cell Mechanisms

Trial Status Mode of Action Drug Target MS NMO (SD) Rituximab 1 Off Lable Off Lable Ocrelizumab Phase 3 – CD20 Lytic Ofatumumab Phase 3 Ublituzumab 2 –Phase 2 MEDI‐551 2 CD19 Phase 2 Atacicept (Taci‐Fc) 3 BAFF & APRIL Phase 2 Solouble Tabalumab BAFF Phase 2– Aquaporumab 4 AQP‐4–Phase 2 Alemtuzumab CD52 Approved

Signaling Cell Surface VAY736 BAFF‐RPhase 2– Tocilizumab Off Lable Off Lable IL‐6R SA237 Phase 2 Eculizumab C5a – Phase 3 Effector NPB‐01 (IVIg) Diverse – Phase 2

1 Two studies with intrathecal application; 2 Glyco‐engineeered: binding to FcgammaR indepentdent of haplotype 3 Studies halted: disease exacerbation; 4 Blocks antigen access

6 Efficacy and safety of siponimod in secondary progressive multiple sclerosis - Results of the placebo controlled, double-blind, Phase III EXPAND study

Bruce Cree on behalf of the EXPAND Study Steering Committee and Investigators

Disclosures

 In the past 12 months, Bruce Cree has received personal compensation for consulting from Abbvie, Biogen, EMD Serono, Novartis, and Shire.

Siponimod A selective S1P receptor modulator

 Novel, selective S1P1 and S1P5 receptor modulator

 inhibits the egress of lymphocytes from lymph nodes1

 Readily crosses BBB and may have effects within the CNS2,3

 Half-life ~30 hours; washout period of 6 days1 allows for fast immune reconstitution

 Phase 2 BOLD study (RRMS): a dose of 2 mg/day achieved near-maximal efficacy and dose titration mitigated first dose bradycardia4

BBB: blood-brain barrier; BOLD: BAF312 (siponimod) on MRI Lesion given once-Daily; CNS: central nervous system; RRMS: relapsing-remitting multiple sclerosis; S1P: sphingosine 1-phosphate 1. Gergely P, et al. Br J Pharmacol. 2012;167:1035-1047. 2. Seabrook TJ, et al. Mult Scler. 2010;16:S301. Abstract P858. 3. Brinkmann V. Br J Pharmacol. 2009;158:1173. 4. Selmaj K, et al. Lancet Neurol. 2013; 12(8): 756-767. Kappos L et al. ECTRIMS 2016 3

1 EXPAND: A randomised, double-blind, placebo controlled, event- and exposure- driven study

 Randomization 2:1 siponimod: placebo

 Event driven study design: 374 confirmed disability progression events were needed

 Duration of exposure to study drug was variable

 Patients with 6-month CDP had option to switch to open- label siponimod or other DMTs

Key inclusion and exclusion criteria Key inclusion criteria

• Age: 18–60 years old • Prior history of relapsing-remitting MS • Secondary progressive course of MS (SPMS), defined by a progressive increase in disability (of at least 6 months duration) in the absence of relapses or independent of relapses • EDSS score of 3.0–6.5 • Evidence for EDSS progression in the 2 years prior to study of 1 point or more in patients with a screening EDSS score of less than 6.0 ─ ≥0.5 points for patients with EDSS ≥6.0 at screening

Key exclusion criteria

• Standard exclusion criteria • Defined washout periods or exclusion criteria for other MS medications

Kappos L et al. ECTRIMS 2016 5

Primary and secondary

Primary endpoint endpoints • Time to 3-month Confirmed Disease Progression (CDP), assessed by EDSS*1 Efficacy is reported as a hazard ratio, which quantifies risk reduction under siponimod treatment relative to placebo

Secondary endpoints

• Key secondary endpoints ─ Time to 3-month confirmed worsening of at least 20% from baseline in the Timed 25-foot walk test (T25FW) ─ Change from baseline in T2 lesion volume • Other secondary endpoints ─ 6-month CDP, assessed by EDSS*1 ─ Annualised relapse rate ─ Change from baseline in brain volume ─ others (analysis ongoing) • Safety and tolerability

Kappos L et al. ECTRIMS 2016 6

2 Patient Disposition

 1651 subjects randomized

 1100 siponimod

 82% completed double blind period

 546 placebo

 78% completed double blind period

 Actual median time in double blind period was 18 months

 Actual total double blind study duration was 37 months

Demographics and baseline characteristics Siponimod Placebo N=1105 N=546 Age, years 48.0 (7.8) 48.1 (7.9) Age, n (%) 18-40 188 (17.0) 103 (18.9) >41 917 (83.0) 443 (81.1) Duration of MS since first symptom, years 17.12 (8.39) 16.23 (8.23) Time since conversion to SPMS, years 3.85 (3.61) 3.56 (3.28) EDSS Mean (SD) 5.43 (1.08) 5.41 (1.03) Median (Min-Max) 6.0 (2.0-7.0) 6.0 (2.5-7.0) Number of relapses in last 2 years prior to screening, n (%)* 0 712 (64.4) 343 (62.8) ≥1 390 (35.3) 202 (37.0) Number of Gd+ T1 lesions, n (%)* 0 833 (75.4) 415 (76.0) ≥1 237 (21.4) 114 (20.9) All randomised set. Data represented as mean (SD), unless otherwise specified *Number and percentage of patients with missing screening or baseline observations not displayed

Kappos L et al. ECTRIMS 2016 8

Primary Efficacy

 21% relative reduction in 3 month confirmed disability progression, p=0.129

 26% relative reduction in 6 month confirmed disability progression, p=0.007

 Consistent effect across subgroups: prior relapses in last 2 years, gad enhancement at baseline scan, age, baseline EDSS, disease duration

3 Secondary endpoints and AE  No significant impact on worsening of T25FW  79% relative reduction in T2 lesion volume compared to placebo (p<0.0001)  55% relative reduction in relapse rate compared to placebo (p<0.0001)  23% relative reduction in brain volume loss compared to placebo (p=0.0002)

 Favorable safety profile without new safety signals distinct from those associated with fingolimod

10 Kappos L et al. ECTRIMS 2016

Conclusions

 Siponimod reduces the risk of disability progression in patients with secondary progressive MS in a large international clinical trial

 Siponimod’s was well tolerated with a risk profile similar to that of the established treatment, fingolimod, and without new, distinct safety signals

Acknowledgements (1/2)

Data Monitoring Macdonell Richard China Germany Stangel Martin Ireland Committee Schwartz Raymond Cui Liying Becker Veit U. Strassburger-Krogias Hardiman Orla Easton Donald (Chair) Austria Huang Dehui Bergh Florian Then Katrin Tubridy Niall Calandra Thierry Leutmezer Fritz Huang Yining Bergmann Arnfin Strauss Erik DiMarco John Maida Eva-Maria Li Hongzeng Berthele Achim Then Bergh Florian Israel Kesselring Juerg Weber Joerg R. Lu Jiahong Boehringer Matthias Tiel-Wilck Klaus Achiron Anat Laupacis Andreas Xu Xianhao Boerner Thomas Tumani Hayrettin Karussis Dimitrios Temkin Nancy Belgium Yang Yi N. Bracknies Vera Walter Silke Weissert Robert Weinshenker Brian Decoo Danny Zhang Meini Braune Stefan Italy Wiendl Heinz Zarbin Marco Dubois Benedicte Zhou Hongyu Buttmann Mathias Brescia Morra Vincenzo Guillaume Daniel Emrich Peter J. Wildemann Brigitte Comi Giancarlo Laureys Guy Czech Republic Faiss Juergen Zettl Uwe Francia Ada Study Steering Pandolfo Massimo Liskova Petra Gehring Klaus Ziemssen Tjalf Galgani Simonetta Committee Vanopdenbosch Ludo Skoda Ondrej Haas Judith Grimaldi Luigi Maria Kappos Ludwig (Chair) Willekens Barbara Stourac Pavel Harmjanz Arndt Greece Edoardo Bar-Or Amit Wijmeersch Bart Van Ticha Veronika Heidenreich Fedor R. Grigoriadis Nikolaos Marfia Girolama Cree Bruce Vachova Marta Hoffmann Olaf M. Mastorodimos Alessandra Fox Robert Bulgaria Hofmann Werner E. Vasileios Mirabella Massimiliano Giovannoni Gavin Grigorova Olga Estonia Koehler Juergen Tavernarakis Antonios Nocentini Ugo Gold Ralf Kaprelyan Ara Gross-Paju Katrin Kornhuber Anselm Scarpini Elio Angelo Vermersch Patrick Milanov Ivan Toomsoo Toomas Lassek Christoph Hungary Uccelli Antonio Shotekov Penko Lensch Eckart Dioszeghy Peter Argentina Tarnev Ivaylo France Linker Ralf A. Imre Piroska Japan Correale Jorge Brochet Bruno Maeurer Mathias Jakab Gabor Baba Masayuki Deri Norma H. Canada Camu William Oschmann Patrick Kovacs Krisztina Kaida Kenichi Patrucco Liliana Antel Jack P. Castelnovo Giovani Polzer Udo Koves Agnes Kimura Takashi Piedrabuena Raul Bhan Virender de Seze Jérôme Rauer Sebastian Matyas Klotild Mizuno Masanori Rey Roberto Blevins Gregg Debouverie Marc Reifschneider Gerd Pozsegovits Krisztian Mori Masahiro Sinay Vladimiro Brunet Donald Defer Gilles Schlegel Eugen Rozsa Csilla Nakahara Jin Duquette Pierre Edan Gilles Schmidt Stephan Satori Maria Nakatsuji Yuji Australia Freedman Mark Papeix Caroline Scholz Erich Simo Magdolna Nohara Chiyoko Barnett Michael Grandmaison Francois Pelletier Jean Schwab Matthias Valikovics Attila Nomura Kyoichi Butzkueven Helmut Lee Liesly Vermersch Patrick Siever Arno Saida Takahiko Hodgkinson Suzanne Vorobeychik Galina Wiertlewski Sandrine Sigel Karl-Otto Yamamura Takashi Yeung Michael 12 We thank all participating patients and investigators for their dedication and contribution to this study

4 Acknowledgements (2/2)

Shimizu Yuko Cunha Luis Kurca Egon Derfuss Tobias Bowen James D. Pachner Andrew Latvia de Sa Joao Turcani Peter Lutterotti Andreas Bowling Allen Robertson Derrick Kalnina Jolanta Martins da Silva Ana Gobbi Claudio Burnett Margaret Rowe Vernon Karelis Guntis Salgado Antonio Vasco Spain Mueller Stefanie Cahill Jonathan Rubin Susan Millers Andrejs Casanova Estruch Pless Misha Calkwood Jonathan Sanders Kalina Romania Bonaventura Schluep Myriam C. Scott James Lithuania Bajenaru Ovidiu Coret Ferrer Francisco Cascione Mark Shafer Stuart Kizlaitiene Rasa Balasa Rodica Escartin Siquier Turkey Cohan Stanley Solomon Andrew Malciene Lina Bejinariu Mihaela Antonio Agan Kadriye Conway Jill Stefoski Dusan Rastenyte Daiva Buraga Ioan Fernandez Sanchez Akman-Demir Gulsen Cooper Joanna A. Steingo Brian Hancu Anca Victoria Eugenia Balci Belgin Petek Corboy John Stuve Olaf Netherlands Simu Mihaela Garcia Merino Juan Boz Cavit Costell Brian Tullman Mark J. Fermont Jiske Ticmeanu Marina Antonio Efendi Husnu Coyle Patricia K. Weiss Sara Hengstman G.J.D. Izquierdo Ayuso Siva Aksel Dihenia Bhupesh Zacharias Alan Hupperts Raymond Russia Guillermo Terzi Murat Elias Stanton Zelkowitz Marvin Schrijver H.M. Boyko Alexey N. Martinez Rodriguez Ford Corey van Oosten B.W. Evdoshenko Evgeny P. Jose United Kingdom Frishberg Benjamin Adjudication Martinez Yelamos Visser L.H. Fedyanin Alexander S. Cottrell David A. Gitt Jeffrey Committee Sergio Khabirov Farit A. Craner Matthew Goldstick Lawrence P. Meca Lallana Jose Polman Chris Poland Magzhanov Rim V. Duddy Martin Gross Jeffrey Montalban Xavier Uitdehaag Bernard Bonek Robert Odinak Miroslav M. Ford Helen Gudesblatt Mark Olascoaga Urtaza Brola Waldemar Sazonov Denis V. Nicholas Richard Herring Mark Francisco Javier Czlonkowska Anna Shchukin Ivan A. Nikfekr Esmaeil Honeycutt William D. Oreja-Guevara Celia Jasinska Elzbieta Stolyarov Igor D. Overell James Hua Le H. Ramo Tello Cristina Kozubski Wojciech Rog David Huang DeRen Rodriguez Antiguedad Maciejowski Maciej Slovakia (Slovak Sharrack Basil Katz Amos Alfredo Rusek Stanislaw Republic) Turner Ben Khatri Bhupendra Selmaj Krzysztof Brozman Miroslav Kister Ilya Sweden Cimprichova Andrea United States Komatineni Aparna Fink Katharina Portugal Donath Vladimir Allen Alison B. Mao-Draayer Yang Lycke Jan Cerqueira Joao Hancinova Viera Apperson Michelle Markowitz Clyde Olsson Tomas Klimova Eleonora Bass Ann Miller Aaron E. Krastev Georgi Bernitsas Evanthia Montoya Liliana Switzerland Newsome Scott Achtnichts Lutz We thank all participating patients and investigators for their dedication and contribution to this study

13

5 1/27/2017

Case Discussion

Jeffrey M. Gelfand, MD, MAS, FAAN UCSF MS and Neuroinflammation Center

Recent Advances in Neurology ‐ 2017

Case History 70 yo right‐handed man

‐ Trouble reading & distinguishing letters (i.e. b/p or m/w), word finding difficulties, cognitively slower, over days

‐ Right superior homonymous quadrantanopsia, progressed over days

‐ Fatigue

FLAIR T1 Post‐Gadolinium Ill‐defined, peripherally enhancing solitary lesion in the left occipital lobe with subtle mass effect and surrounding vasogenic edema. No abnormal diffusion or susceptibility or intrinsic T1.

No other brain or spine lesions.

1 1/27/2017

Case History ‐ 2 Past Medical History

‐ PE and mild anemia ‐> dx 1 year prior with Smoldering Multiple Myeloma ‐ SPEP with monoclonal gammopathy ‐ 20‐30% plasma cells on bone marrow ‐ High risk cytogenetic profile ‐ Heme‐onc monitoring, not routinely treated

‐ Hypertension

Key Diagnostics LABS ‐ SPEP with monoclonal gammopathy, IgG 1900 (normal <1760) ‐ Elevated free lamda light chains (222, normal <26), LDH normal ‐ HIV negative, RPR NR, HTLV neg ‐ NMO (AQP4) IgG neg; ANA neg

BODY IMAGING ‐ CT Chest/Abd/Pelvis: No malignancy ‐ FDG‐PET: Brain lesion is hypermetabolic, no other FDG‐avid disease

CSF EXAM Opening Pressure: 14 cm 2 WBC (53%L, 47% Monos, no eos, no polys) 0 RBC Protein 54 (mildly elevated) Glucose 72 (serum 120) IgG index 0.5 1 unique oligoclonal band Cytology/Flow cytometry: Benign JCV PCR negative

Stereotactic Brain Biopsy

“Macrophage‐rich demyelinating lesion”

Foamy macrophages and scattered reactive astrocytes, some of which have mildly enlarged and hyperchromatic nuclei.

Complete loss of myelin, with relative preservation of axons

Many macrophages, no B lymphocytes, small mature perivascular T lymphocytes, no malignancy

Negative for polyoma virus (i.e. negative for PML)

2 1/27/2017

Case Discussion Michael Wilson, MD, MAS UCSF MS and Neuroinflammation Center

Case

• 56 year old right‐handed woman • History of non‐insulin dependent diabetes mellitus • Lifelong smoker • Late summer: Right leg started to occasionally give out • After 2 months: started to fall and had difficulty keeping up with the kids as a playground monitor • After 6 months: right leg became numb and developed lower abdominal pain • Husband insisted they go to the hospital when she had to crawl to the bathroom

Case

• Bladder ultrasound showed severe urinary retention • CSF • WBC 130 (96% lymphocytes, 4% monocytes) • RBC 5 • Total protein 83 • Glucose 45 • One unique oligoclonal band • IgG index 0.57

1 1/27/2017

Case

• Received high dose solumedrol • Improved from not moving her right leg to some movement • Left leg remained numb • Went to inpatient rehab for a month with suspected diagnoses of ADEM or multiple sclerosis • Persistent enhancement on MRI at 10 months after onset • 14 months after onset • New inability to move her left leg • Persistent enhancement on MRI • 15 months after onset: Evaluated at UCSF

Case

Differential Diagnosis? Additional Work‐Up? • ?Autoimmune demyelination • ?Malignancy • ?Vasculitis • ?Infection

2 1/27/2017

Inpatient Evaluation

• CSF • WBC 8 (87% lymphocytes, 13% monocytes) • RBC 1 • Total protein 99 • Glucose 92 • ACE < 5 • HSV, EBV, VZV PCRs neg • NMO, HTLV‐I/II, Lyme, RPR, VDRL, FTA‐ABS neg • Cytology and flow cytometry negative • Whole body PET/CT: unremarkable • Spinal angiogram: unremarkable • Mayo autoimmune panel sent on blood and CSF

Case

• No clinical response to high dose solumedrol • Completed 5 cycles of plasma exchange with mild improvement in lower extremity strength and sensation • Discharged on a high dose prednisone taper • Mycophenolate mofetil initiated with goal dose of 1000mg BID after a 6 week ramp up • Despite maximal mycophenolate mofetil dosing, neuroinflammation persisted on subsequent MRIs

21 months

3 1/27/2017

What is the Differential Diagnosis?

• ?Autoimmune demyelination • ?Malignancy • ?Vasculitis • ?Infection

Brain Biopsy

Epilogue

• 22 months • PLEX repeated • High dose prednisone taper • Oral cyclophosphamide with maximal dose of 100mg daily • 24 months • Slightly improved lower extremity motor exam • Decreased swelling and enhancement in the brain and spinal cord

4 1/27/2017

28 months

What is the next treatment?

• ?PLEX • ?High does steroids • ?Rituximab • ?Other immunosuppressive therapy

5 1/27/2017

Case Discussion ‐ II

Jeffrey M. Gelfand, MD, MAS, FAAN UCSF MS and Neuroinflammation Center

Recent Advances in Neurology ‐ 2017

51 yo right‐handed woman with

‐ 2 years of insidiously worsening right leg heaviness/weakness, limping, cane within 1 year, painless

‐ Word finding difficulties x 2 years

‐ Urinary urgency x 2 years

‐ Subtle cognitive changes, esp slowness of thinking, x 8 years

History ‐ 2 • Carried diagnosis of “discoid lupus” (had patchy hair loss).

• Received pulse glucocorticoids, Rituximab, oral steroids and hydroxychloroquine 1 year prior for suspected “CNS Lupus”

• Insidiously worsened

1 1/27/2017

Past Medical History Hypertension Patchy hair loss several years prior, ?discoid lupus

Family History Arthritis, SLE, migraine

Social History Former smoker, no drug use, no relevant travel or exposure

PHYSICAL EXAM BP 144/100; HR 60 regular. Thin, no scalp lesions, no facial rash, no active synovitis. Digits forward 6. Delayed recall 2/3. Noticeably cognitively slow overall. Saccadic intrusions to smooth pursuit. Mild R ptosis. Slowed FFM. Mild right hemiparesis (pyramidal). Hyperreflexic. Ataxic gait. Slow. 25 foot timed walk 18.5 seconds with a cane.

‐ Bilateral supratentorial FLAIR hyperintensities.

‐ Numerous foci of reduced diffusion in the bifrontal periventricular and deep white matter

‐ No abnormal enhancement

‐ MRA brain normal ‐ MRI Spine with mild DJD, no cord lesions

MRI 1 year after the above

DWI ADC

2 1/27/2017

Diagnostics LABS + ANA, + RNP, +Smith antibodies. PLT 138. SPEP with polyclonal gammopathy. Negative or normal: DS‐DNA, Smith. SSA/SSB, RF, SCL‐70, Jo‐1, Histone, ESR, complements, CK, ACE, HIV, Lyme, TSH, TPO, UA.

CSF Opening Pressure: 16 cm 0WBC, 1 RBC, protein 33, glucose 59 (serum 81) IgG index 0.48; Matched bands in CSF and serum VDRL NR

EMG‐NCS: Mild right axonal peroneal neuropathy that does not explain her right leg weakness

A Diagnostic Test was Performed…

3 1/27/2017

Case Discussion Michael Wilson, MD, MAS UCSF MS and Neuroinflammation Center

Uveitis

• 38 per 100,000 persons in the U.S. • Mean age of onset is 30 years old • 50% of cases are idiopathic

Uveitis and Neurologic Disease

• Inflammatory • Infectious • Multiple sclerosis • Viral: Herpes viruses, HIV‐1, HTLV‐1, • Vogt‐Koyanagi‐Harada disease West Nile virus, measles • Rheumatoid arthritis • Bacterial: cat‐scratch disease, • Polyareteritis nodosa, ANCA vasculitis Whipple’s • Systemic lupus erythematosus • Mycobacterial: TB, leprosy • Spirochetes: syphilis, Lyme, • Sarcoidosis Leptospira • Behcet’s disease • Protozoa: toxoplasmosis, • Acute posterior multifocal placoid Pneumocystis carinii pigment epitheliopathy • Nematode: gnathostomiasis, cysticercosis • Neoplastic • Lymphoma • Paraneoplastic syndromes

1 1/27/2017

Case History: Bilateral Idiopathic Uveitis

• Doan T, Wilson MR, Genome Med 2016

Bilateral Idiopathic Uveitis

• Doan T, Wilson MR, Genome Med 2016

What is the Differential Diagnosis?

• ?Infection • ?Autoimmune • ?Neoplastic

2 1/27/2017

Metagenomic Deep Sequencing • Analyzing all the genetic material in an environmental sample • Massively parallel sequencing approach

Sequencing Library Prep

Abbreviations: NT, nucleotide; NR, non‐redundant protein.

Rubella virus

• Abernathy E, et al. Virology Journal 2009

3 1/27/2017

Substitution rates indicate active RV replication for 20 years

• E1/E2 substitution rate of the patient’s RV is comparable to the documented RV substitution rate detected from person-to-person transmission • Non-synonymous mutation rate in the E1 and E2 proteins was 3.4-fold higher than in the non-structural proteins

• Abernathy E, et al. Virology Journal 2009

Phylogenetic Analysis Correctly Corroborates the Time & Geographic Location of the Initial Infection

Conclusions

• Even RNA viruses can cause chronic infections after long‐term quiescence • Immunosuppressed patients • Immune privileged body compartments • Public health implications for disease surveillance

• https://www.nytimes.com/2015/05/08/health/ebola‐eye‐color‐change‐mystery.html

4

Advances in Treatment and Diagnosis of Dementia 2017

Bruce Miller, MD

Notes

Notes

Notes

2/1/2017

Challenges and Controversies in Movement Disorders Management: A Case-Based Approach

February 9, 2017

Jill L. Ostrem, MD Professor of Neurology

Caroline M. Tanner, MD, PhD Professor of Neurology UCSF Weill Institute of 1 Neurosciences

Disclosures

Caroline Tanner, MD, PHD • Consultant: Neurocrine, Adamas, Apple, Biogen • DMC Member: Biotie, Voyager, Intec

Jill Ostrem, MD • Consultant and speaker: Allergan Inc., Medtronic Inc. • Educational grant support: Medtronic Inc, Allergan Inc, AbbVie Inc, Boston Scientific Inc. • Clinical trial support: Ceregene Inc., St. Jude Medical, Inc, Boston Scientific Inc, Cala Health Inc, Google Inc

Case 1: PD Motor fluctuations • 65 yo female with 8 year history of PD • Developed motor fluctuations 3 years ago with having increasing “off time” and peak dose dyskinesia • Current medications: Carbidopa/Levodopa 25/100 1 ½ tabs 5 times a day Rasagiline 1mg QD Pramipexole 0.25mg TID Donepezil 10mg QD Off Medications On Medications

1 2/1/2017

Challenge: Medical Management of Motor Fluctuations

• Many drug class options: Levodopa, dopamine agonist, MAO B inhibitors, COMT inhibitors, others… • Levodopa – Most effective and widely used treatment in PD – Improves function and QOL, reduces morbidity, and mortality – Dopa decarboxylase (carbidopa) inhibits peripheral LD metabolism‐ more levodopa CNS availability (improves tolerability reducing nausea) – Early PD‐ simple regimen dosing schedules, becomes more complex in advanced PD – Short half‐life (1.5 hours) – As PD progresses, conversion of levodopa to dopamine and storage/release, becomes unpredictable. – Intermittent/pulsatile release of dopamine in the striatum, produces changes in the postsynaptic receptors leading to motor complications and dyskinesia (70% after 5 years).

Motor Fluctuations

“Wearing off” period Symptoms Symptoms adequately controlled (“on time”)

Time

PD Medication PD Medication PD Medication Symptoms not controlledadequately (“off time”)

Typical Clinical Pattern of Wearing Off

Adapted from Hauser RA. Geriatrics. 2006;61:14-20.

Other Levodopa Formulations

• Controlled release or sustained release – Slower release of LD in the gut (degradable polymer matrix) – No difference motor fluctuations and dyskinesia in a 5 year study (moderate to severe PD) – Patient transferred to CR CD‐LD from IR CD‐LD do not experience significant “off time” reduction – Absorption is delayed and symptom relief is less predictable • CD‐LD + Entacapone (CLE) – Entacapone inhibits peripheral conversion of LD and allows more LD to enter CNS – Increases total exposure of IR by 35‐40%, prolongs LD half‐life to 2.4 hrs – CLE has similar LD plasma profiles to CR formulation with higher LD fluctuations

2 2/1/2017

Controversy: Is Rytary‐ IPX066 (Impax) an advance for the field?

•New oral formulation of CD‐LD (contains both IR and CR levodopa) •Each Rytary capsule contains CD‐ LD (1:4) microbeads designed to dissolve at various rates allowing for release and absorption of LD over a longer timeframe. •FDA Approved‐ Jan 2015

Mean LD and CD Plasma Concentration Profiles (Phase 1)

• Healthy volunteers (n=24) assessed the PK of Rytary vs IR, CR, and CLE formulations • Greater mean and sustained plasma concentrations with Rytary • Initial LD plasma peak occurred at 1 hour/tmax of 4.5 hrs • Rytary plasma concentrations remained above 10 until 10.1 hours.

Hsu A, et al. J Clin Pharmacol 2015;55:995–1003.

Rytary vs Placebo in Early PD (Phase 3) Mean UPDRS II +III over 30 weeks

• APEX‐PD – N=381 early LD‐naive PD, fixed titration schedule • No SAE attributed to study treatment • Best balance between efficacy and safety in LD naïve pts achieved at 145mg TID of Rytary.

Pahwa R, et al. Parkinsonism Relat Disord 2014;20:142–148.

3 2/1/2017

Rytary vs IR CD‐LD in Advanced PD

• Advance PD (N=450), randomized, DB, parallel‐ group trial. • Adjustment period to maximize treatment response to IR CD‐LD followed by 6 week Rytary dose‐ conversion period. • Rytary TID but could be adjusted to reduce off time. • Randomly assigned to double blind treatment (Rytary or CD‐LD) for 13 wks. • Four strengths of Rytary. • Primary efficacy endpoint‐ % “off time” reduced with Rytary (1.2 hours) • Mean daily IR CD‐LD dose was 825mg (5.2 doses)/ Rytary 1,621mg (3.6 doses) • 60% required hirer doses of Rytary compared to start conversion • SAE‐ 3 patients on Rytary and 1 on IR CD‐LD developed ICD.

Hauser RA, et al. Lancet Neurol 2013;12:346–356.

Rytary vs CD‐LD‐Entacapone in Advanced PD

• ASCEND‐PD (n=84) • Pts previously treated on stable dose of CLE >4 times /day having >2.5 hours of off time a day. • Open label dose conversion phase followed by two week randomized crossover period of each treatments. • Rytary showed improved “off time” (34%) and increase in “on time” by 1.4 hours without increasing troublesome dyskinesia with reduced dosing frequency.

Stocchi F, et al. Parkinsonism Relat Disord 2014; 20:1335–1340.

Conversion to Rytary

750 mg

4 2/1/2017

Dose Conversion Clinical Pearls

• Insurance approval more difficult unless already “failed” IR and CR CD‐LD formulations • Package guidelines likely will underdose your patient • May need to go to 4X a day or even 5X a day • Can still be used with other forms of LD

Case 2: Unpredictable L‐dopa Benefit Motor Fluctuations in Advanced PD

14

Case 2: Unpredictable L‐dopa Benefit; Motor Fluctuations in Advanced PD

88 year old man –Parkinson’s disease 20 years

Unpredictable benefit from oral carbidopa\levodopa preparations; dyskinesias with disabling blepharospasm alternating with inability to stand and walk even with assistance; dopamine agonists caused paranoid delusions, resolved with discontinuation; frequent nocturnal awakening to move/urinate, excessive day time sleepiness

Current medication regimen: Carbidopa\levodopa 25\100 IR q 1.5 ‐ 2 hrs while awake, 1‐2 doses at night

5 2/1/2017

Challenge: Medical Management of Motor Fluctuations This patient: • Drug class options: – Intolerable adverse effects: dopamine agonists – Inadequate benefit/dose limiting side effects: • MAO B inhibitors, COMT inhibitors, oral levodopa preparations including Rytary • Did not want to consider surgery

Considerations in Selecting Therapies

Oral L‐dopa DA agonists Jejunal infusion DBS preparations L‐dopa gel Motor fluctuations, mild +++ +++ ‐ ++ Motor fluctuations, + + +++ +++ severe Dementia, mild ++ + ++ + Dementia, severe ++ ‐ ++ Psychosis, ICD ++ ‐ ++ Poor social support ++ + ‐‐ Wary of invasive ++ ++ ‐‐ intervention Reduced finances +++ ++ ‐ +

Levodopa‐Carbidopa Intestinal Gel • Continuous intrajejunal infusion of C/L gel • Programmable pump to adjust dose • FDA approval 2015 – AbbVie

6 2/1/2017

Efficacy of Carbidopa\Levodopa Enteral Infusion

Improved on time without dyskinesias compared to oral C\Ll

Moderate to Large CID in most studies reported

Olanow Lancet Neurology 2014; Palhagen 2012; Fernandez 2013

Safety Considerations –4 Clinical Trials

Lang et al, Mov Disord 2016

Practical Considerations

Dose titration: • Outpatient, but at least ½ day in office to initiate • Calculate based on current c\l dose • Infusion usually 16 hours • Morning dose a bolus • Continuous dose thereafter with option for extra doses Return in one week for re‐adjustment of dose Monitor B12, B6 (peripheral neuropathy)

Costs: Est.~ $6000/month • Patient and caregiver understanding key to success • Care of site • Handling of cassette • Pump program can be fixed or adjustable • Adjustable often better efficacy (Medical Letter 2015)

21

7 2/1/2017

Case 3 – Challenge: How to Manage Dystonia in PD?

• Often occurs in LE, with foot inversion • Usually in the “off medication” state and toe curling • Can also have eye opening apraxia • Often painful • Usually in the “off medication” state

22

Botulinum Toxin Injections

• Toxin temporarily weakens dystonic muscles, allowing for a more normal posture, function, reduction of pain • Benefits depend on location and degree of dystonia of muscles being injected. • Bleph: Moderate to marked improvement in 90% of patients – Complications: eyelid ptosis, dry mouth, visual impairment, diarrhea, headache. – Complications usually improve < two weeks, decreases with repeat injections • Limb: Less well studied in PD – Traditionally EMG or E‐Stim used to help guide injections – Temporary muscle weakness can occur

Mechanism of Action

8 2/1/2017

Available Botulinum Toxins

Serotype Generic Name Trade Name Manufacturer A onabotulinumtoxinA Botox® Allergan A abobotulinumtoxinA Dysport™ Ipsen A incobotulinumtoxinA XEOMIN® Merz B rimabotulinumtoxinB Myobloc® Solstice

• Neurotoxin Products contains highly purified botulinum toxin protein refined from the bacterium Clostridium botulinum •All toxins has a heavy chain and a light chain bound by a di‐sulfide bound

Controversy: Are botulinum toxin injections with ultrasound more effective?

Lower Extremity Muscle Anatomy

9 2/1/2017

Also Useful for Sialorrhea in PD

Jost WH J Neural Transm 123:51‐55, 2016

Caution of Use • BTX‐should be used with extreme caution in patients: • myasthenia gravis • amyotrophic lateral sclerosis (ALS) • Taking anticoagulants • Taking certain antibiotics –aminoglycosides • Immunogenicity – Increased risk with larger doses and injections administered < 3 months intervals – Controversial if newer Incobotulinum toxin may have less immunogenicity – Clinicians often use in vivo tests: such as the frontalis test – If resistance occurs, replacing one serotype of BTX with another may be effective.

Case 4: Drug‐Induced Hallucinations

Thanks to: Joseph Freedman for Video 73 year old man, Parkinson’s disease for 8 years Treatment regimen: Carbidopa\L‐dopa 25\100 6 doses, Ropinirole discontinued 6 weeks ago

10 2/1/2017

Psychosis in Parkinson’s Disease

NINDS/NIMH Working Group Criteria: • Primary diagnosis of PD using UK brain bank criteria • Presence of at least one of: illusions, false sense of presence, hallucinations, delusions • Symptoms begin after PD onset • Symptoms are recurrent or continuous for 1 month • No other cause

Epidemiology: 16% ‐ 75% prevalence • Illusions, minor visual hallucinations most common form • Minor visual hallucinations may precede motor signs, esp. in RBD • Most common in advanced disease, cognitive impairment

Ravina 2007; Chang 2016

Psychosis in Parkinson’s Disease Characteristic features Illusions / “minor” hallucinations: • Typically visual • Misperceptions of real stimuli • Sense of presence • Fleeting images in peripheral vision

Hallucinations: • Visual most common • Vivid, people & animals most common, may be known • Low light, certain locations • Often nonthreatening

• Auditory less common • May be solitary or combined with visual • Solitary may be indistinct voices, music; Rarely threatening voices; commands not described

Psychosis in Parkinson’s Disease Characteristic features ‐ 2

Delusions: • False fixed beliefs • Commonly paranoid • Typical themes: • Spousal infidelity • Relatives plotting to steal finances • Sometimes Capgras – like delusions: spouse, home are imposters • Can be very complex, & hallucinations involved in content of the delusion • Can be nonthreatening • Insight often retained but typically incompletely

33

11 2/1/2017

Thanks to: Joseph Freedman for Video

Challenge: Treating Psychosis in Parkinson’s Disease • Exclude delirium (concurrent medical problems) • Exclude psychotic depression • Determine severity and impact of symptoms • Evaluate PD medications: stop anticholinergics; stop amantadine; reduce or stop agonists; reduce or stop hypnosedatives, anxiolytics, opiates; reduce non‐ essential PD therapies • Consider anti‐dementia therapy if cognitive impairment: rivastigmine > donepezil in modest reduction VH, not delusions; CAUTION: memantine may aggravate VH • Consider specific antipsychotic therapy:

Treating Psychosis in Parkinson’s Disease ‐2 Consider specific antipsychotic therapy:

• CAUTION: BLACK BOX WARNING : all cause mortality, CVD • Baseline EKG for QTc prolongation • Atypical antipsychotics: Very low doses often effective – Clozapine : • Efficacy without increased parkinsonism; • Rare agranulocytosis, not dose‐related, requires regular monitoring – Quetiapine: • Efficacy less consistent; may worsen parkinsonism • No monitoring required

36

12 2/1/2017

Pimavanserin (ACP‐103) (Nuplazid) • Treatment for Parkinson’s disease psychosis • An inverse agonist targeting serotonin receptor subtype 5‐HT2A • Phase III pivotal trial was positive • Significant reductions in SAPS‐PD (scale for assessment for positive symptom scores) • FDA approved for hallucinations & delusions in PD psychosis w/o dementia, 2016 • Acadia Pharmaceuticals

Pimavanserin: Efficacy

Reduced caregiver burden; Improved nighttime sleep, daytime wakefulness

Improvement in psychosis vs. placebo

Cummings et al, Lancet, 2014

Pimavanserin: Safety & Tolerability

• QTc prolongation • “Black Box” anti‐psychotic effects • Concomittant use of another antipsychotic may increase serious AEs (open label study)

Cummings et al, Lancet 2014

13 2/1/2017

Pimavanserin – Practical Aspects

Dose: 34 mg p.o. daily (2 x 17 mg) Cost: ~ $24,000/year • Only drug approved for hallucinations & delusions in PD • Most third parties require approval

Initiating treatment: • EKG for QTc at baseline, monitor for prolongation • Therapeutic efficacy may not be immediate; up to 2 weeks for full effect • Abrupt discontinuation of other anti‐psychotic treatments may precipitate worsening of symptoms • May be used chronically with other antipsychotics, but possible safety concerns

Case 5: Challenge –How to manage low threshold for stimulation side effects with DBS?

61 yo male with advanced PD with STN DBS

R STN DBS produced activation of internal capsule resulting in left facial pulling and tonic arm contractions

R STN DBS settings: C+0‐, 1.8V, 60us, 130 hz

Key Structures Surrounding STN

dorsal

medial lateral

Thalamus ventral Paresthesias/ sensory phenomena (medial Muscular contractions, lemniscus) (medial GPi dysarthria or posterior) (corticobulbar/spinal tract) (or anterior)

Contralateral gaze deviation too Diplopia, other lateral (frontal eye fields in IC) oculomotor disturbances, mydriasis (CNIII) STN (medial) Reduction of rigidity, tremor, akinesia/bradykinesia, induction of dyskinesia Affective/ impulsive (dorsolateral) changes Substantia (limbic STN or SNr) Nigra (medial and ventral) Coronal view No side effects at high stimulation (> 10 V) lead too dorsal

14 2/1/2017

Spread of current to internal capsule

• Lower thresholds right after surgery • Can occur with STN, GPi, VIM Targets – STN ‐ lead too lateral and/or anterior D – GPi ‐ lead too posterior or too medial – VIM‐ lead too lateral

• Programming strategies M L – Bipolar stimulation – Try other contacts

V • Image brain to assess lead location, migration – May need lead revision

43

Controversy: Will DBS directional leads be better?

Reker P, et al in press

15 2/1/2017

Directional DBS leads allow for “current steering”

Will likely: • Allow for reduction in stimulation induced side effects • Lower number of lead revision surgeries • Lower energy requirements and extend battery longevity

St Jude Medical/Abbott DBS Infinity System

• Pivotal US PD clinical trial completed • FDA approved 2016 for PD and ET • Approved in Australia and Europe 2015 • Constant current device • BluetoothTM wireless communication • Upgradeable software option • Bilateral frequency control of in single device • Communicates with Apple digital devices (iPad mini/iPod touch) • Directional lead to allow for current “steering” • Not MRI compatible • Non‐rechargable

Boston Scientific Vercise™ DBS System likely coming to market soon

Currently available in Europe Rechargeable and non‐rechargeable neurostimulators Tablet based programmer Current steering and 8 electrode DBS leads Fractional current delivery Not MRI Compatible

16 2/1/2017

New software to localization and visualize shape of electrical stimulation field • Computational modeling / volume of tissue activation (VTA) and individualized direct programming

49

Case 6

• 78 year old woman with Parkinson’s disease for 25 years • The first woman in her law school class • Divorced with two sons • Significant benefit from DBS, but postural instability progressed; she was wheelchair bound for about 5 years • Highly intelligent, MoCA 27/30 • Many non‐motor symptoms (depression, severe neuropathic pain, dysphagia) • Fairly good quality of life • End of life discussions with her & 2 sons: She was consistent in her request for DNR status, no life‐sustaining measures if there was no reasonable hope of recovery to a similar quality of life; did not want to be intubated, did not want any artificial means of nutrition. • Progressive clinical worsening: dysphagia, sepsis, encephalopathy

Case 6

• Despite her verbalizing and documenting clear goals of care, her sons were conflicted regarding the decision not to intubate and not to start a feeding tube. • Extensive discussions were held with the help of the palliative team, and her sons felt at peace carrying out the wishes she had clearly verbally stated and documented. • At her funeral, her youngest son said, “I know it’s a strange thing to say, but my mom’s death was beautiful”. She was placed on a morphine drip and IV fluids, and her sons stayed with her for the week in a quiet large room with a beautiful view on the palliative care service. She was intermittently conscious and able to share in memories, videos and photos; both the patient and her youngest son are singers, and they were able to enjoy singing their favorite songs together that week. A few moments before her death, she opened her eyes, said ‘I love you’ to her son and then passed away quietly and peacefully. • Her PD neurologist continues to have contact with her sons and daughter‐in‐law to share in her memory.

17 2/1/2017

We’ve been wrong about what our job is in medicine. We think our job is to ensure health and survival. But really it is larger than that. It is to enable well‐being. And well‐ being is about the reasons one wishes to be alive.

Being Mortal: Medicine and What Matters in the End Atul Gawande

Parkinson’s Disease Palliative Care Model:

Palliative care principles address “Total Pain” The suffering that encompasses all of a person’s physical, psychological, social, spiritual and practical struggles in the setting of serious illness Saunders, 1996, BMJ

Neurologists as primary palliative providers

Palliative care principles address “Total Pain” • Optimize communication regarding serious news • Manage intractable symptoms • Alleviate suffering • Align treatment with patient preferences • Address end‐of‐life care

18 2/1/2017

Tackling the Myths of “Palliative Care”

. Palliative care is “giving up”

. Palliative care means there is “nothing left to do”

. Palliative care means foregoing lifesaving therapies

. Palliative care shortens life expectancy

. Palliative care = hospice

Palliative Care for Parkinson’s Disease: How to bring it up…

. Multiple studies have shown greater receptiveness to the term, “supportive” rather than, “palliative” • “I would like to give you an extra layer of support to help with your symptoms and the stress of being sick” Fadul et al. 2009, Cancer Rondali et al., 2013, Palliative and Supportive Care

Study Coordinator 415 ‐ 353 – 9453

UCSF Parkinson’s Disease Supportive Care Clinic

UCSF Movement Disorders and Neuromodulation Center Movement Disorder and Neuromodulation Center Jill L. Ostrem, MD, Medical Director Philip Starr, MD, PhD, Surgical Director Research /Support Staff Neurology Sarah Wang, PhD Jill Ostrem, MD Kristen Dodenhoff, BA Nicholas Galifianakis, MD Michael Dodge, BA Caroline Tanner, MD, PhD Janet Allen, BA Marta San Luciano, MD Shatara Blackmon Maya Katz, MD Yasmeen Gonzalez Ian Bledsoe, MD,MS Jeverly Calaunan Robert White, MD, PhD Kathleen Comyns, MPH James Maas, MD, PHD Samantha Betheil, BA Chadwick Christine, MD Cheryl Meng, MPH Michael Aminoff, MD Farah Kauser Robert Edwards, MD Rhonda Lee Ken Nakamura, MD, PhD Alexandra Nelson, MD, PhD Michael Geschwind, MD Psychiatry Amy Viehoever, MD, PhD Andrea Seritan, MD Neurosurgery Philip Starr, MD, PhD Neuropsychology Social Work Paul S. Larson, MD Fellows Monica Eisenhardt, LCSW Edward F. Chang, MD Caroline Racine Belkoura, PhD Cameron Dietiker, MD Daniel Lim, MD, PhD Kyle Mitchell, MD Nursing Chaplin Krzysztof Bankiewicz, MD, PhD Nijee Luthra, MD, PhD Judith Long Coralie De Hemptinne, PhD Monica Volz, FNP, MS Ethan Brown, MD Karen Merchant, MSN Nicki Swann, PhD Mitra Afshari, MD Physical Therapy Andrew Miller, BA Susan Heath, MS, RN Rory Murphy, MD Gina Bringas‐Cinco, RN Nancy Byl, PT, PhD Whitney Chen, PhD Idit Tamir, MD, PhD Heather Bhide, PT Doris Wang, MD, PhD Annie Li Wong, NP 57

19 2/1/2017

1St Annual UCSF Movement Disorders Research Retreat

20 Psychiatry for the Practicing Neurologist

Focus on mood disorders

Descartes Li, M.D. Clinical Professor University of California, San Francisco [email protected]

By Max Halberstadt - http://politiken.dk/kultur/boger/faglitteratur_boger/ECE1851485/psykoanalysen-har-stadig-noget- at-sige-i-noejagtigt-betitlet-bog/, Public Domain, https://commons.wikimedia.org/w/index.php?curid=5234443

Financial Disclosures

none

objectives

• Critique the criteria for “normal sadness” (per Horwitz+Wakefield) • Define Trap of Meaning, and note its impact on treatment adherence • Apply antidepressant treatment algorithm as described in STAR*D study • List risk factors for conversion to bipolar disorder

1 Outline

• Introduction and Epidemiology • “Normal sadness” • Trap of Meaning • Stepped pharmacotherapy of depression (STAR*D) • Using side effect profile to choose an Antidepressant •Four Tips • Diagnosis of Bipolar Disorder

Outline

• Introduction and Epidemiology • “Normal sadness” • Trap of Meaning • Stepped pharmacotherapy of depression (STAR*D) • Using side effect profile to choose an Antidepressant •Four Tips • Diagnosis of Bipolar Disorder

Depression Prevalence

1 year = 6.6% (14 million) lifetime = 16.2% (35 million)

50% rated as severe or very severe 75% with co-morbid psychiatric dx

The Epidemiology of Major Depressive Disorder: Results From the National Comorbidity Survey Replication (NCS-R). Kessler, RC et al. JAMA. 2003;289:3095-3105.

2 http://well.blogs.nytimes.com/2013/08/12/a -glut-of-antidepressants/?_r=0

Is there a glut of coffee, alcohol? http://psychcentral.com/blog/archives/2013/08/19/is-a- How about insulin, Lipitor? glut-of-antidepressants-really-so-bad/

Increased antidepressant usage may decrease overall suicide rates

Olfson M, Shaffer D, Marcus SC et al. (2003), Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry 60(10):978- 982.

Gunnell D, Middleton N, Whitley E et al. (2003), Why are suicide rates rising in young men but falling in the elderly?--A time-series analysis of trends in England and Wales 1950-1998. Soc Sci Med 57(4):595-611

3 Outline

• Introduction and Epidemiology • “Normal sadness” • Trap of Meaning • Stepped pharmacotherapy of depression (STAR*D) • Using side effect profile to choose an Antidepressant •Four Tips • Diagnosis of Bipolar Disorder

Case Vignette A 72yo man is depressed in the context of the death of his wife. How long would you wait before diagnosing MDD? Assume he meets DSM-5 criteria for MDE. a) Two weeks b) One month c) Two months d) Six months e) One year or more

Mourning and Melancholia

Outwardly can look the same Melancholia: • No conscious object loss • Loss of self-regard, but not ashamed • Difficulty with nourishment, digesting • Difficulty with sleeping

4 “Normal Sadness”

Per Horvitz and Wakefield, 3 criteria: 1. Has an environmental trigger 2. Roughly proportionate in intensity to loss 3. Ends when loss situation ends

Horwitz AV, Wakefield JC. The Loss of Sadness: How Psychiatry Transformed Normal Sorrow into Depressive Disorder. New York, NY:Oxford University Press; 2007. (p.16)

Problems with “normal sadness” 1. What constitutes a trigger?

2. When is the response proportionate to the loss?

3. Does the presence of a recent major loss somehow make it more likely that depression will spontaneously resolve?

Resilience to Spousal Loss

New York Times online Accessed October 8, 2016 http://nyti.ms/2cPiePQ

“…resilience in the face of spousal bereavement is less common than previously thought”

-Only 8% showed resilience across all five indicators of life satisfaction and general health functioning Infurna FJ and Luthar SS. Resilience to Major Life Stressors Is Not as Common as Thought. Persp Psychol Sci. 2016 Mar;11(2):175-94. doi: 10.1177/1745691615621271.

5 Depression vs. Grief

Individuals who fulfill MDD criteria after loss of significant other have NOT been shown to recover at a greater rate than MDD alone

What the DSM-5 says about bereavement

Grief is still exists, but depressive episodes must be diagnosed independently of loss Grief and MDD are different and therefore they should be distinguished separately http://www.dsm5.org/Documents/Bereavement%20Exclusion %20Fact%20Sheet.pdf

Depression vs. Grief

6 Case Vignette A 72yo man is depressed in the context of the death of his wife. How long would you wait before diagnosing MDD? Assume he meets DSM-5 criteria for MDE. a) Two weeks b) One month c) Two months d) Six months e) One year or more

Outline

• Introduction and Epidemiology • “Normal sadness” • Trap of Meaning • Stepped pharmacotherapy of depression (STAR*D) • Using side effect profile to choose an Antidepressant •Four Tips • Diagnosis of Bipolar Disorder

Case vignette B

28yo man, recently married 6m ago, appears well, but quickly breaks down: He says he’s made a terrible mistake for imposing himself on his wife. “I’m a terrible person who cheated on my wife and on my taxes.” He reports two months of depressed mood, crying spells, as well as oversleeping and not being able to get out of bed. In addition, his energy has been low, he has no appetite, and he can’t focus at work. Would you diagnose him with http://commons.wikimedia.org/wiki/File:Portrait-as-an-artist-as-a-young-man.jpg Major Depressive Disorder? Would you prescribe an antidepressant?

7 Case vignette

“I cheated on my wife and on my taxes.”

Do we accept his reasons as the causes of his depression?

Even when confronted with an intuitively plausible set of reasons, we must look for objective causes.

http://commons.wikimedia.org/wiki/File:Portrait-as-an-artist-as-a-young-man.jpg

Reason vs. Cause

What the difference?

Reason : (noun) Cause : (noun)

( 1 ) Motive or justification for ( 1 ) That which produces an something effect, thing, event, person, etc…make something happen “Give me the reason for your going.” What was the cause of the fire?

“He has adequate reason for Smoking is one of the causes of doing so.” heart disease.

The Trap of Meaning

“Finding an explanation that appears meaningful and adopting it as causal.”

Lyketsos CG, Chisolm MS. The trap of meaning: a public health tragedy. JAMA. 2009 Jul 22;302(4):432-3. doi: 10.1001/jama.2009.1059.

8 "...humans are incredibly good at linking cause and effect—sometimes too good..."

"... it means that when you see something occur in a complex adaptive system, your mind is going to create a narrative to explain what happened—even though cause and effect are not comprehensible in that kind of system." Embracing Complexity, An interview with Michael https://hbr.org/2011/09/embracing-complexity/ Mauboussin by Tim Sullivan Harvard Business Review 2011

Life Events have NOT been associated with MDD

"in general, MD can be diagnosed independently of the psychosocial context in which it arises."

Kendler KS, Gardner CO. Dependent Stressful Life Events and Prior Depressive Episodes in the Prediction of Major Depression: The Problem of Causal Inference in Psychiatric Epidemiology. Arch Gen Psychiatry. 2010;67(11):1120-1127.

Kendler KS, Myers J, and Halberstadt LJ. Do reasons for major depression act as causes? Molecular Psychiatry (2011) 16, 626– 633; doi:10.1038/mp.2011.22; published online 8 March 2011.

Kendler KS, Myers J, and Halberstadt LJ. Should the Diagnosis of Major Depression made Independent of or Dependent upon the Psychosocial Context? Psychol Med. 2010 May ; 40(5): 771–780. doi:10.1017/S0033291709990845.

Lyketsos CG, Chisolm MS. The trap of meaning: a public health tragedy. JAMA. 2009 Jul 22;302(4):432-3. doi: 10.1001/jama.2009.1059.

What are the Validated Risk Factors for Depression?

9 Take Home Messages

Be aware of "explaining away" mood episodes.

Anticipate patient’s explanatory model and adherence implications

Lyketsos CG, Chisolm MS. The trap of meaning: a public health tragedy. JAMA. 2009 Jul http://jama.jamanetwork.com/article.aspx?articleid=184281 22;302(4):432-3. doi: 10.1001/jama.2009.1059.

Outline

• Introduction and Epidemiology • “Normal sadness” • Trap of Meaning • Stepped pharmacotherapy of depression (STAR*D) • Using side effect profile to choose an Antidepressant •Four Tips • Diagnosis of Bipolar Disorder

Disclosures

still none

10 STAR*D Sequenced treatment alternatives to relieve depression

2,876 outpatients started on citalopram • exclusions: schizophrenia, bipolar disorder, eating disorders, OCD • Not placebo-controlled, therefore unblinded

Evaluation of Outcomes with Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice. Trivedi et al. Am J Psychiatry 2006; 163:28-40.

STAR*D Sequenced treatment alternatives to relieve depression Step 1 - citalopram

Step One: citalopram up to 60mg/d

Reminder: Black box warning for QTc prolongation

Evaluation of Outcomes with Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice. Trivedi et al. Am J Psychiatry 2006; 163:28-40.

11 Level 1 Obtain Consent

Satisfactory Follow-up CIT Response

Unsatisfactory Response*

Level 2

*Defined as nonremission

STAR*D Results

Medication Remit Response Average dose rate rate N, number of subjects QIDS‐SR <5 50% reduction of baseline QIDS‐SR Level Citalopram 33% 47% 1 41.8mg/d 2,876

STAR*D Sequenced treatment alternatives to relieve depression Step 2 Step Two: switch to venlafaxine (Effexor) XR, bupropion (Wellbutrin) SR, sertraline (Zoloft) or cognitive therapy OR augment with buspirone (Buspar), bupropion SR or cognitive therapy

Evaluation of Outcomes with Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice. Trivedi et al. Am J Psychiatry 2006; 163:28-40.

12 Level 2

Randomize

CIT + SER BUP-SR VEN-XR CT CIT + CIT + BUP-SR BUS CT Switch Augmentation Options Options

Medication Remit Response Average dose rate rate N, number of subjects QIDS‐SR <5 50% reduction of baseline QIDS‐SR Level Switch Buproprion‐SR 25.5% 26.1% 283mg/d 2 239 Sertraline 26.6% 26.7% 136mg/d 238 Venlafaxine XR 25.0% 28.2% 194mg/d 250 Augme Bupropion SR 39.0% 31.8% 268mg/d nt 279 Buspirone 32.9% 26.9% 40.9mg/d 286

13 Sequenced treatment alternatives to relieve depression (STAR*D) Step 3

Step Three: One of the following options: switch to mirtazapine (Remeron) or nortriptyline OR Augment with lithium or Cytomel (T3)

Evaluation of Outcomes with Citalopram for Depression Using Measurement- Based Care in STAR*D: Implications for Clinical Practice. Trivedi et al. Am J Psychiatry 2006; 163:28-40.

Level 3

Randomize

MRT NTP L-2 Tx + L-2 Tx + Li THY Switch Augmentation

Medication Remit Response Average dose rate rate N, number of subjects QIDS‐SR <5 50% reduction of baseline QIDS‐SR Level Switch Mirtazapine 12.3% 13.4% 3 42.1mg/d 114 Nortriptyline 19.8% 16.5% 96.8mg/d 121 Augme Lithium carbonate 13.2% 16.2% nt 900mg/d 69 Triiodothyronine T3 24.7% 23.3% 50mcg/d 73

14 Sequenced treatment alternatives to relieve depression (STAR*D) Step 4

Step Four: Switch to tranylcypromine (Parnate) or venlafaxine (Effexor) XR + mirtazapine (Remeron)

Evaluation of Outcomes with Citalopram for Depression Using Measurement- Based Care in STAR*D: Implications for Clinical Practice. Trivedi et al. Am J Psychiatry 2006; 163:28-40.

Level 4

Randomize

TCP VEN-XR + MRT Switch

Medication Remit rate Response Average dose QIDS‐SR <5 rate N, number of subjects 50% reduction of baseline QIDS‐SR Level 4Tranylcypromine 13.8% 12.1% 36.9mg/d 58 Venlafaxine+mirtazapine 15.7% 23.5% 210.3mg/d+35.7mg/d 51

15 Medication Average dose Remit rate Response rate N, number of subjects QIDS‐SR <5 50% reduction of baseline QIDS‐SR Level 1Citalopram 41.8mg/d 33% 47% 2,876 Level 2 Switch Buproprion‐SR 283mg/d 25.5% 26.1% 239 Sertraline 136mg/d 26.6% 26.7% 238 Venlafaxine XR 194mg/d 25.0% 28.2% 250 Augment Bupropion SR 268mg/d 39.0% 321.8% 279 Buspirone 40.9mg/d 32.9% 26.9% 286 Level 3Switch Mirtazapine 42.1mg/d 12.3% 13.4% 114 Nortriptyline 96.8mg/d 19.8% 16.5% 121 Augment Lithium carbonate 900mg/d 13.2% 16.2% 69 T3 50mcg/d 24.7% 23.3% 73 Level 4 Tranylcypromine 36.9mg/d 13.8% 12.1% 58 Venlafaxine+mirtazapine 15.7% 23.5% 210.3mg/d+35.7mg/d 51

Conclusions from STAR*D

• Switching to Bupropion-SR, Sertraline, or Venlafaxine XR equally efficacious (remit rate for all: about 25%); • No difference between different classes of antidepressants • Augmentation with Bupropion (39% remission rate) slightly better than buspirone (33%) • Third and fourth level remission rates less than 20%, except T3 augmentation.

Outline

• Introduction and Epidemiology • “Normal sadness” • Trap of Meaning • Stepped pharmacotherapy of depression (STAR*D) • Using side effect profile to choose an Antidepressant •Four Tips • Diagnosis of Bipolar Disorder

16 “The person who takes medicine must recover twice, once from the disease and once from the medicine.”

Attributed to William Osler

By Unknown - [1], CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=33071914

Cipriani et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 2009; All antidepressants 373: 746–58.

Gartlehner et al. Comparative Benefits and Harms are equally of Second-Generation Antidepressants. Ann Intern Med. 2008;149:734-750. efficacious.

How do you choose? • Food –Fast •Meds – Good –Sedation –Cheap – Weight gain – Sexual dysfunction –(Cheap)

Choosing an Antidepressant Side Effects

• Sedation/activation

• Weight gain For further review, plus tips on how to • Sexual dysfunction manage these side effects, check out: • (cost)

Kelly, K, Posternak, M, & Alpert, J E. (2008). Toward achieving optimal response: understanding and managing antidepressant side effects. Dialogues in https://prezi.com/wbdwrr1txias/how clinical neuroscience, 10(4), 409-18. -to-choose-an-antidepressant/

17 Relative activation vs. Sedation modern antidepressants* Activating [psychostimulants] Bupropion Fluoxetine, Sertraline Neutral or mixed Venlafaxine Sedating Escitalopram Citalopram Sedating Paroxetine Fluvoxamine Nefazodone Tricyclics Strongly sedating Trazadone Mirtazapine**

*based on personal experience, not clinically derived head-to-head data **higher dosage may be less sedating?

Impact on weight*

Weight loss (?) [psychostimulants] Bupropion Neutral or mixed Nefazadone mild to moderate Ssri’s (fluoxetine < paroxetine) Maoi’s Tricyclics Significant mirtazapine

*based on personal experience, not clinically derived head-to-head data

SEXUAL DYSFUNCTION

DECREASED DEPRESSIONLIBIDO ANTIDEPRESSANT

AROUSAL ORGASM DISORDER DYSFUNCTION

Segraves. J Clin Psychiatry Monogr. 1993.

18 Effect on sexual functioning*

Increased? [Psychostimulants] Bupropion Neutral or mixed Nefazadone Mirtazapine Duloxetine Common Ssri’s Venlafaxine Maoi’s Tricyclics

*based on personal experience, not clinically derived head-to-head data

cost • Use generics • Split pills • Check out GoodRx. com

Cost

19 cost

Summary Choosing an Antidepressant

• Sedation/activation

• Weight gain For further review, plus tips on how to • Sexual dysfunction manage these side effects, check out: • (cost)

https://prezi.com/wbdwrr1txias/how -to-choose-an-antidepressant/

Outline

• Introduction and Epidemiology • “Normal sadness” • Trap of Meaning • Stepped pharmacotherapy of depression (STAR*D) • Using side effect profile to choose an Antidepressant • Four Tips • Diagnosis of Bipolar Disorder

20 Tip#1 of 4 Remember Tricyclics

amitriptyline imipramine (Elavil) (Tofranil)

nortriptyline desipramine (Pamelor) (Norpramin)

Tip#2 of 4 Thyroid augmentation T-3, (Cytomel) Dosing schedule: 12.5mcg/day x2days 25mcg/day x2days 37.5mcg/day x2days 50mcg/day x2days

In STAR*D, T3 was started at 25 μg/day for 1 week and then increased to the recommended dose of 50 μg/day.

Li v T3 in STAR*D

STAR*D Level-3 intervention

Results: Remission rates were 15.9% with lithium augmentation and 24.7% with T3 augmentation

21 Tip#3 of 4 Light Therapy

Check out the Center for Environmental Therapeutics: www.cet.org

Lam RW et al. Efficacy of Bright Light Treatment, Fluoxetine, and the Combination in Patients With Nonseasonal Major Depressive Disorder A Randomized Clinical Trial. JAMA Psychiatry. 2016;73(1):56-63. doi:10.1001/jamapsychiatr y.2015.2235

Tip#4 of 4 Bibliotherapy: •Feeling Good, by David Burns •Mind Over Mood, by Greenberger and Padefsky

66

22 Outline

• Introduction and Epidemiology • “Normal sadness” • Trap of Meaning • Stepped pharmacotherapy of depression (STAR*D) • Using side effect profile to choose an Antidepressant •Four Tips • Diagnosis of Bipolar Disorder

Cyclothymic Disorder Major Depressive Disorder

Bipolar I Disorder Dysthymic Disorder

Bipolar II Disorder

National Comorbidity Study (NCS) 2007 Lifetime (and 12-month) prevalence estimates: [9282 Respondents]

•for BP-I 1.0% (0.6%), •for BP-II, 1.1% (0.8%)

Merikangas, K. R. et al. Arch Gen Psychiatry 2007;64:543-552.

69

23 Bipolar Disorder Symptoms Are Chronic and Predominantly Depressive 146 Bipolar I Patients 86 Bipolar II Patients followed 12.8 yrs followed 13.4 yrs 1%2% 6% 9%

53% 46% 32% % of Weeks 50% Asymptomatic Depressed Hypo/manic Cycling/mixed Study 1 Study 2 1. Judd LL, et al. Arch Gen Psychiatry 2002.59:530-537. 2. Judd LL, et al. Arch Gen Psychiatry 2003;60:261-269.

Does the Trap of Meaning occur with mania or hypomania?

Yes!

Different from St Paul’s Conversion! Conversion refers to when individuals previously diagnosed with unipolar depression develop a mania or hypomania.

The individual “converts” to bipolar disorder.

24 Case Vignette C A 22yo woman is admitted to the hospital for severe depression with suicidal ideation. What is the likelihood that she will have a hypomanic or manic episode in the next 15 years? 1) 5% 2) 10% 3) 20% 4) 40% 5) 65%

https://www.pexels.com/photo/blonde-haired-woman-in-blue-shirt-y-27411/

Case Vignette C A 22yo woman is admitted to the hospital for severe depression with suicidal ideation. What is the likelihood that she will have a hypomanic or manic episode in the next 15 years? 1) 5% 2) 10% 3) 20% 4) 40% 5) 65%

https://www.pexels.com/photo/blonde-haired-woman-in-blue-shirt-y-27411/

Risk of Bipolar Illness (Goldberg)

Goldberg JF had a small group (n=74) of subjects who were more severely ill (hospitalized) and who were younger (all were less than 25) The conversion rate in the next 15 years was pretty high: 41%

Goldberg JF et al. Risk for Bipolar Illness in Patients Initially Hospitalized for Unipolar Depression. Am J Psychiatry 2001; 158:1265-1270.

25 Risk of Bipolar Illness (Goldberg)

Goldberg JF et al. Risk for Bipolar Illness in Patients Initially Hospitalized for Unipolar Depression. Am J Psychiatry 2001; 158:1265-1270.

Summary

study n Conversion Years comment rate: of f/u (per year)

Akiskal HS; 559 12.5% 11 Mood lability et al 1995 (1.1%) predictive Coryell et 381 10.2% 10 Avg. age >35 al. 1995 (1.0%)

Goldberg 74 41% 15 Younger pts JF et al. (2.7%) (<25yo) and 2001 hospitalized Angst J et 309 39.2% 13 Linear rate of al. 2005 (3.0%) conversion, severely ill

Rate of Conversion from Depression to Bipolar disorder is about 1-2% per year indefinitely

Angst J et al. Diagnostic Conversion from depression to bipolar disorders: results of a long term prospective study of hospital admissions. J Affect Disord 2005; 84:149-157.

26 DSM-5 Episode Specifiers (that are risk factors for bipolar disorder)

•Atypical • Catatonia • Melancholic (not a risk factor) • Mixed features • Postpartum onset • Psychotic features

Summary

Patients initially diagnosed with unipolar depression are at high risk for converting to bipolar disorder. Several risk factors are associated with conversion: • Age of onset (ie, <25yo) • Family history of bipolar disorder • Number of depressive episodes (ie, > six) • Post-partum onset • Psychotic features • Severity (eg, hospital admission)

The conversion rate is about 1-2% per year, perhaps slightly higher in the first 4 years, but really no obvious plateau’ing of risk (see Angst)

Take home message

Suspect bipolar disorder in the following situations: • Unclear history – How to interview for bipolar disorder, see http://thecarlatreport.com/free_articles/current-issues- bipolar-disorder-diagnosis-life-course-method-free-article • Patient is not improving, or worsening, with standard antidepressant treatment • Patient has multiple risk factors for conversion

27 What to do about Bipolar depression? • Controversial area in psychiatry • Avoid antidepressants, unless clear evidence of benefit • Prevent mania: start mood stabilizers: lithium or divalproex • Depression and Bipolar Support Alliance (800-826-3632; www.dbsalliance.org)

Phelps, J. (2006) Why am I Still Depressed? Recognizing and Managing the Ups and Downs of Bipolar II and Soft Bipolar Disorder. McGraw-Hill Education. 83

Outline

• Introduction and Epidemiology • “Normal sadness” • Trap of Meaning • Stepped pharmacotherapy of depression (STAR*D) • Choosing an Antidepressant • Diagnosis of Bipolar Disorder • Dementia, Agitation, Catatonia and ECT

28 1/27/2017

Neurostimulation for Drug‐Resistant Epilepsy

Vikram R. Rao, MD, PhD Assistant Professor of Clinical Neurology University of California, San Francisco

Disclosures

• NeuroPace, Inc. –I have received fees for consulting and speaking engagements

• Upsher Smith Laboratories –I have served on the Scientific Advisory Board

Antiepileptic drugs: The more things change…

Brodie (2012): 26 drugs, 32% refractory

Gowers (1881): 1 drug, 36% refractory Kwan & Brodie (2000): 15 drugs, 37% refractory Coatsworth (1971): 6 drugs, 38% refractory Löscher et al Nat Rev Drug Disc (2013) 3 Löscher and Schmidt Epilepsia (2011) Kwan and Brodie NEJM (2000), Brodie et al Neurology (2012)

1 1/27/2017

Pre‐surgical evaluation for drug‐resistant epilepsy

Scalp EEG 3T MRI PET MEG SPECT Wada

Stereo‐EEG Stimulation mapping

Grid electrodes

4

Epilepsy surgery can be highly effective

Wiebe et al. N Engl J Med 2001; 345:311‐318 5 Englot and Chang Neurosurg Rev (2014) 37:389

Epilepsy surgery has limits

Henry Molaison (H.M.)

Bitemporal surgery, Traumatic brain injury devastating amnesia

Bilateral temporal lobe seizures

Annese J et al. Nat Comm (2014) 5:3122 6

2 1/27/2017

CASE: Bitemporal Seizures 66F with 30‐year history of epilepsy and cognitive decline Frequent focal dyscognitive seizures Multiple hospitalizations for status epilepticus Failed 10 antiepileptic drugs

UCSF EMU: bitemporal independent seizures

Severe bilateral hippocampal sclerosis 7

CASE: Eloquent Cortex 18F with epilepsy onset at age 5, focal seizures 3‐4x/week Semiology: aphasia, choking, RUE clonus +/‐ generalization Scalp EEG: LEFT frontotemporal onset, MRI: normal Failed VNS

Seizure onset

8

CASE: Prior Surgery 34M h/o severe TBI (R temporal ICH), epilepsy onset age 12 s/p RIGHT ATL, seizures improved but persisted Semiology: L head turn, RUE tonic extension with clonus Scalp EEG: Bitemporal spikes, poorly lateralized ictal onset

9

3 1/27/2017

Neurostimulation for epilepsy

• Electrical modulation of neural activity without removal of brain tissue • Possible therapeutic mechanisms: • Raise threshold for seizure initiation • Limit seizure propagation • Facilitate early seizure termination • Plasticity, network‐level effects

10

? Resection VNS RNS (DBS) ?

11

Patient Selection for Neurostimulation

1. Failure of ≥ 2 AEDs

2. Presurgical evaluation ?

3. Surgical option?

12

4 1/27/2017

Patient Selection for Neurostimulation

I. Multiple foci A. Bilateral (e.g. Bitemporal) i. Lesional ii. Non‐lesional B. Unilateral i. Dual pathology II. Unresectable focus A. Eloquent i. Language ii. Sensorimotor iii. Vision B. Prior Surgery i. ATL C. Extensive / Deep Lesion i. PVNH D. Other i. Cognitive risks ii. Patient preference

13

Vagus Nerve Stimulator

• Open‐loop stimulation of the left vagus nerve; model 106 responsive to ictal tachycardia approved in 2015 (AspireSR)

• No need to localize seizure onset zone

• Magnet swipe triggers additional stimulation

• 44% median seizure frequency reduction at 3 y

• Effective for focal and generalized epilepsy

• Side effects: cough, hoarseness, sleep disruption

• Battery life: 3–8 y

Nune G et al. Curr Treat Options Neurol (2015) 14

VNS Mechanism of Action

EEG desynchronization?

Cai, P.Y. et al. Front Neurol, June 2014 15 Bodin, Epilepsy Res. 2015 Jul;113:98‐103 Fraschini, Neurosci Lett. 2013 Mar 1;536:14‐8

5 1/27/2017

Responsive Neurostimulation

Records brain activity

Detects abnormal activity

Stimulates to stop activity

16

Electrodes (depths/strips): • Record neural activity (ECoG) • Stimulate to reduce seizures

Lead wires

Neurostimulator: • Cranially implanted • Electronics and battery

The RNS® System

PROVIDERS

PATIENTS

6 1/27/2017

RNS System implantation

• Leads (strips and/or depths) placed at the seizure focus/foci • Neurostimulator implanted in the skull

19

Chronic ambulatory electrocorticography

Remote Wand Telemetry Online Data Review

Patient collects data from the Provider logs in to secure neurostimulator and uploads website to view patient's it to a secure website. ECoG data.

20

Hyperacute seizure reduction by the RNS System

Responsive Stim OFF

Responsive Stim ON

21

7 1/27/2017

Subacute seizure reduction by the RNS System

(p= 0.012, GEE)

Morrell M et al., Neurology (2011) 22

Chronic seizure reduction by the RNS System

Seizure‐free Intervals: Reduction

≥ 6 mo: 29% Seizure ≥ 1 yr: 16%

23 Morrell, M. et al., American Epilepsy Society meeting, Dec 2016

UCSF RNS System Patients (N=21)

UNRESECTABLE FOCUS RESECTIVE SURGERY • Bilateral hippocampal (5) • Prior ATL (3) • PVNH (1) • Eloquent cortex (4) • Concurrent resection (2)  Broca’s area (1)  Wernicke’s area (1)  Sensorimotor (1) • Future surgery (2)  Primary Visual (1)

REGIONAL ONSET • Frontal (1)

• Parietal (2)

• Insular (1)

24

8 1/27/2017

UCSF Outcome Data (N=18)

surgery Stim not yet enabled

25

Deep Brain (Anterior Thalamus) Stimulation • Approved in Europe and Canada, soon to be approved in U.S.

• Open‐loop bilateral DBS of anterior thalamic nuclei

• 69% median seizure frequency reduction at 5 y (SANTE trial)

• Temporal lobe epilepsy may respond best

• May have adverse effects on mood, memory, and sleep

Fisher and Velasco, Nat Rev Neurol 2015 26 Salanova et al. Neurology 2015 Mar 10;84(10):1017‐25. Fisher et al. Epilepsia 2010 May;51(5):899‐908

Potential treatment algorithm

Drug‐Resistant Epilepsy Seizures localized? NO YES 1 How many foci? 3+ Safe to resect? YES 2 NO Low cognitive risks? NO YES RNS System VNS Therapy Will it be curative? NO YES Patient willing? NO YES Combination therapies Resective Surgery or Laser Ablation RNS System data may identify surgical candidates

9 1/27/2017

Acknowledgements

UCSF Epilepsy Center

Dan Lowenstein, MD Paul Garcia, MD Robert Knowlton, MD Heidi Kirsch, MD Tina Shih, MD Susannah Cornes, MD Manu Hegde, MD, PhD Maritza Lopez, RN

Edward Chang, MD Mariann Ward, NP

10 Recent Advances in Neurology 2017

Difficult Headache Management Decisions

Morris Levin, MD Professor of Neurology, UCSF Director, UCSF Headache Center

DIFFICULT HEADACHE MANAGEMENT DECISIONS

• Challenging Issues in Headache Diagnosis • Some common Management Impasses • New treatment options

Disclosures for Dr. Morris Levin

Consultant: Supernus, Amgen, Allergan, Pernix

Royalties: Oxford University Press, Anadem Publishing, Wiley Blackwell, Castle Connolly, UCSF Office of Innovation

Grants: American Headache Society

1 INTERNATIONAL CLASSIFICATION OF HEADACHE DISORDERS 2013

Primary HA 1. Migraine 2. Tension-type HA 3. Cluster headaches relatives (TAC) 4. Exertional and other headaches Secondary HA 5. Posttraumatic 6. Vascular disease 7. Abnormal ICP, Neoplasm 9. CNS infection 10. Metabolic disturbances 11. Cervicogenic, Eyes, Sinuses, Jaw 12. Psychiatric 13. Neuralgias

1. Migraine without aura Headache attacks lasting 4-72 h (untreated or unsuccessfully treated) Headache has 2 of the following 1. unilateral location 2. pulsating quality 3. moderate or severe pain intensity 4. aggravation by or causing avoidance of routine physical activity (eg, walking, climbing stairs) During headache 1 of the following: 1. nausea and/or vomiting 2. photophobia and phonophobia

1.2 Migraine with aura

1 of the following fully reversible aura symptoms: 1. visual; 2. sensory; 3. speech and/or language; 4. motor ; 5. brainstem; 6. retinal 2 of the following 4 characteristics: 1. 1 aura symptom spreads gradually over ≥5 min, and/or 2 symptoms occur in succession 2. each aura symptom 5-60 min 3. 1 aura symptom is unilateral 4. aura accompanied or followed in <60 min by headache

2 Migraine with Aura ICHD III

With headache Migraine with typical aura Migraine with Without aura Migraine with headaches brainstem aura

Migraine with hemiplegia

Retinal migraine

1.3 Chronic migraine

A. Headache (TTH-like and/or migraine-like) on ≥15 d/mo for >3 mo and fulfilling criteria B and C B. In a patient who has had ≥5 attacks fulfilling criteria B-D for 1.1 Migraine without aura and/or criteria B and C for 1.2 Migraine with aura C. On ≥8 d/mo for >3 mo fulfilling any of the following: 1. criteria C and D for 1.1 Migraine without aura 2. criteria B and C for 1.2 Migraine with aura 3. believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative D. Not better accounted for by another ICHD-3 diagnosis

Transformation: 2.5% per year Risk increased by High HA frequency, high use of acute meds, poor success with acute tx, obesity, depression, (asthma)

Episodic Chronic Migraine Migraine

Bigal, ME., et al. "Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population‐based study."Headache 48.8 (2008): 1157-1168. Lipton, Richard B., et al. "Ineffective acute treatment of episodic migraine is associated with new-onset chronic migraine." Neurology 84.7 (2015): 688-695. Martin, Vincent T., et al. "Asthma is a risk factor for new onset chronic migraine: Results from the American migraine prevalence and prevention study." Headache (2016).

3 3. Trigeminal autonomic cephalalgias (TACs)

3.1 Cluster headache 3.2 Paroxysmal hemicrania 3.3 Short-lasting unilateral neuralgiform headache. 3.4 Hemicrania continua

All are unilateral and accompanied by cranial autonomic sx

TAC’S

• All involve unilateral pain • Usually periorbital & brief • Duration decreases with name length Cluster 15-180 min Paroxysmal Hemicrania 2-30 min Short lasting unilateral neuralgiform headaches 1-600 sec

3.4 Hemicrania continua A. Unilateral headache fulfilling criteria B-D B. Present >3 mo, with exacerbations of moderate or greater intensity C. Either or both of the following: 1. cranial autonomic activity e.g. ipsilateral symptoms or signs: a) conjunctival injection and/or lacrimation; b) nasal congestion and/or rhinorrhoea; c) eyelid oedema; d) fore- head and facial sweating; e) forehead and facial flushing; f) sensation of fullness in the ear; g) miosis and/or ptosis 2. a sense of restlessness or agitation, or aggravation of pain by movement D. Responds absolutely to therapeutic doses of indomethacin

4 TAC’s: • Duration decreases with name length

HC Years Cluster 15-180 min Paroxysmal Short-lasting Hemicrania unilateral 2-30 min neuralgiform headaches 1-600 sec

4. Other primary headaches

Exertional headaches Cough headache Exercise headache Orgasmic headache Pre-orgasmic headache Thunderclap headache HA related to stimulation HA attributed to cold stimulus External compression headache Epicranias Nummular HA Epicrania fugax Stabbing Headache Other HAs Hypnic HA NDPH

New daily persistent headache (NDPH)

A. Persistent headache fulfilling criteria B and C B. Distinct and clearly‐remembered onset, with pain becoming continuous and unremitting within 24 h C. Present for >3 mo

5 The secondary headaches

5. Headache attributed to trauma or injury to the head and/or neck 6. Headache attributed to cranial or cervical vascular disorder 7. Headache attributed to non‐vascular intracranial disorder 8. Headache attributed to a substance or its withdrawal 9. Headache attributed to infection 10. Headache attributed to disorder of homoeostasis 11. Headache or facial pain attributed to disorder of cranium, neck, eyes, ears, nose, sinuses, teeth, mouth 12. Headache attributed to psychiatric disorder

Headache attributed to traumatic injury to the head

•If persistent, a key component of the post‐concussive syndrome •Can resemble other headache types including migraine • Resistant to treatment • Divided by causative mild or severe head injury

Headaches due to vascular disorders • Stroke • Hemorrhage • Arteritis • Cerebral venous thrombosis • Reversible cerebral vasoconstriction synd • AVM • Aneurysm • Post endarterectomy • CADASIL • MELAS

6 Intracranial Hypertension

Incidence of IIH 1/100,000

In obese young women as high as 20/100,000

Best treatment – weight loss if overweight Clues to tx: Headache worse in recumbent, pulsatile tinnitus, papilledema CSF pressure >250 mm CSF Can be straightforward, can resist treatment

Intracranial Hypotension

HA MUCH worse upon arising – pt prefers to lie down Antecedent LP, surgery, barotrauma CSF pressure <60 mm CSF Goal – Find the sight of leak and perform targeted blood patch

DIAGNOSING SIH

MR myelogram demonstrating myeloceles and leak

7 Medication-overuse headache (MOH)

A.Headache occurring on ≥15 d/mo in a patient with a pre-existing headache disorder B.Regular overuse for >3 mo of one or more drugs that can be taken for acute and/or symptomatic treatment of headache C. Not better accounted for by another ICHD-3 diagnosis

Secondary Headaches - When to look for them

RED FLAGS IN HA

New or Change in pattern Onset in middle age or later Effort induced or Positional Febrile or Systemic illness - AIDS, Cancer Change in personality or cognition Neurological findings

CHALLENGING HA MANAGEMENT SITUATIONS

• Treating migraines in patients with vascular disease or risk factors • Managing migraine in pregnancy • Managing medication overuse headache • Treating intractable cluster headache • New daily persistent headache • Migrainous vertigo • ED approach to treatment of acute severe headache

Levin UCSF

8 TREATING MIGRAINES IN PATIENTS WITH VASCULAR DISEASE OR RISK FACTORS

Case – 72 year old woman with longstanding migraine, HLD, borderline DM and a lacunar stroke seen on MRI. She is using sumatriptan 1-2x per week.

Levin UCSF

TREATING MIGRAINES IN PATIENTS WITH VASCULAR DISEASE OR RISK FACTORS

• Migraine usually begins in early adulthood but not always; migraine often persists into old age – 3-10% of elderly have migraine. (Fasted growing demographic) • Triptans are mildly vasoconstrictive and if risks are high, should probably be avoided. But often risks are exaggerated. • Risk factor stratification based on Framingham study data using gender, Total Chol, HDL, DM, HTN, and tobacco is more logical.

Levin UCSF

TREATING MIGRAINES IN PATIENTS WITH VASCULAR DISEASE OR RISK FACTORS

• Roberto et al - systematic review of observational data of use of triptans: • “…intense consumption of ergotamines may be associated with an increased risk of serious ischemic complications. As for triptans, available studies do not suggest strong CV safety issues”.

Roberto, G., Raschi, E., Piccinni, et al. (2014). Adverse cardiovascular events associated with triptans and ergotamines for treatment of migraine. Cephalalgia 2014 Levin UCSF

9 TREATING MIGRAINES IN PATIENTS WITH VASCULAR DISEASE OR RISK FACTORS

Alternatives to triptans include • NSAIDs and acetaminophen which can become more useful as pts age • Magnesium 200 mg • Short acting barbiturate butalbital – caution in elderly • Occipital nerve blocks • Low dose opioids – hydrocodone 5 mg • Neuroleptics – metoclopramide 10 mg, prochlorperazine 25 mg • Hydroxyzine 25-50 mg

Levin UCSF

TREATING MIGRAINES IN PATIENTS WITH VASCULAR DISEASE OR RISK FACTORS

• Use of triptans in “basilar migraine” (migraine with brainstem aura), and hemiplegic migraine (migraine with motor aura – contraindicated? • Mathew, PG., et al. "A retrospective analysis of triptan and DHE use for basilar and hemiplegic migraine." Headache: 56.5 (2016): 841-848. •  no clear evidence that BM and HM carry an actual elevated risk for vascular events compared with migraine with aura.

Levin UCSF

TREATING MIGRAINES IN PATIENTS WITH VASCULAR DISEASE OR RISK FACTORS

• Migraine is associated with increased risk of stroke, and possibly with increased risk for cardiovascular disease • Migraine with aura is associated with an increased risk of ischemic stroke (OR approx. 3) • (Mig without aura – 1.8x) • Risk is particularly increased in women, especially women using oral contraceptives, peripartum period, younger than 45 • Especially in smokers

Levin UCSF

10 STRUCTURAL BRAIN LESIONS IN MIGRAINE

Migraine particularly in women is associated with an increased risk of brain lesions, mostly in white matter (1,2,3) These tend to increase although can disappear (more likely in low frequency headaches) (4)

1. Kruit, MC et al. JAMA 2004;291:427 2. Kruit, MC et al. Brain 2005;128:2068 3. Scher, AI et al. JAMA 2009;301:2563 4. Erdélyi‐Bótor, S et al Headache 2015;55:55‐70.

STRUCTURAL BRAIN LESIONS IN MIGRAINE

Management of WML’s in migraine patients If asymptomatic – no workup May follow imaging...

MANAGING MIGRAINE IN PREGNANCY

• Most proph meds contraindicated in pregnancy including botulinum toxin • Case – • 29 year old with migraine since her late teens is now having more frequent and more severe HAs with nausea and vomiting in her 2nd trimester.

Levin UCSF

11 MANAGING MIGRAINE IN PREGNANCY

• First steps – • Rule out preechlampsia, gestational HTN, gestational diabetes, cerebral venous thrombosis, reversible cerebral vasoconstrictive syndrome • BP • Glu • CVT usually produces persistent severe HA often with increased ICP or focal signs or both – MRV without gad, LP – will also help to R/O RCVS

Levin UCSF

MANAGING MIGRAINE IN PREGNANCY

Medication FDA category TERIS risk rating

Acetaminophen BNo risk

Ibuprofen B (D in 3rd Trimester) Minimal

Naproxen B (D in 3rd Trimester) Undetermined

Oxycodone B (D near term)

Magnesium B Unlikely

Metoclopramide B Unlikely C in 1st trimester; Prednisone ?2nd/3rd trimesters Minimal

Promethazine CNone

MANAGING MIGRAINE IN PREGNANCY

• Triptans are contraindicated in pregnancy – but very few reports of • Nezvalová-Henriksen, K, Spigset, O, and Hedvig Nordeng, H. "Triptan safety during pregnancy: a Norwegian population registry study." European journal of epidemiology 28.9 (2013): 759-769. •  found no associations between triptan use during pregnancy and congenital malformations. Second trimester use was associated with postpartum haemorrhage (adjusted OR 1.5)

Levin UCSF

12 MANAGING MIGRAINE IN PREGNANCY

• Magnesium on the other hand becoming controversial – • Fetal calcium depletion – small but real risk • Respiratory distress in newborn – very small risk

Levin UCSF

MANAGING MIGRAINE IN PREGNANCY

• Occipital and other nerve blocks – Lidocaine and Bupivicaine category C, Ropivicaine B • Evidence is anecdotal but some small studies support its efficacy

Suproaorbital Greater and Lesser Auriculotemporal supratrochlear occipital

MANAGING MEDICATION OVERUSE HEADACHE

• Case – • 45 year old executive began having HAs in 30s, initially infrequent, now nearly daily leading her to use butalbital-acetaminophen-caffeine tablets (Fioricet ®) 2-6 tablets most days, frequent NSAIDs, occasional hydrocodone (Norco®) and other OTC meds. Triptans have not helped, nor have a number of prophylactic medications. “I am not addicted! I only take enough medication to function!”

Levin UCSF

13 MANAGING MEDICATION OVERUSE HEADACHE

• Mechanisms are unclear but consensus holds that use of analgesic or abortive headache medications >2x a week tends to worsen migraine frequency and severity • Reducing the use of medications will tend to further worsen headaches, leading to an impasse. • Physical and psychological dependency may be occurring simultaneously • Allowing MOH to continue seems to be associated with conversion of migraine to chronic migraine

Levin UCSF

MANAGING MEDICATION OVERUSE HEADACHE

Solution = “Bridge Therapy” • Steroid “burst” – prednisone 60 mg x 4 days reducing over the next 6 days to 0 • IV Dihydroergotamine x 5 d • IV Chlorpromazine Coupled with discontinuation of previous analgesics Replacement with rescue meds less likely to cause MOH Preemptive treatment of withdrawal

Levin UCSF

MANAGING MEDICATION OVERUSE HEADACHE

Analgesic hierarchy – • Opioids (hydrocodone, oxycodone) • Ergotamine • Barbiturates (Fioricet®) • Caffeine containing combination meds (Excedrin®) • Triptans • NSAIDS, acetaminophen • Antihistiminics

Levin UCSF

14 MANAGING MEDICATION OVERUSE HEADACHE

Preemptive treatment of withdrawal • Opioids – clonidine .1 mg – titrate dose to sx • Barbiturates – lorazepam .5-1 mg on a schedule titrated to sx • Triptans – DHE, NSAIDs

Levin UCSF

DOES OVERUSE OF TRIPTAN MEDICATION REALLY CAUSE MOH?

• Yes. • Katsarava, Z, et al. Clinical features of withdrawal headache following overuse of triptans and other headache drugs Neurology 2001 57: 1694-1698 • Pathophysiology of medication overuse headache: Insights and hypotheses from preclinical studies Cephalalgia 2011 31:851-860 • Triptan overuse in the Dutch general population: A nationwide pharmaco-epidemiology database analysis in 6.7 million people Cephalalgia 2011 31: 943-952

MANAGING INTRACTABLE CLUSTER HEADACHE • Case – • 48 year old accountant has had cluster cycles once yearly since his 20s. This cycle began 2 months ago and has not responded to the usual interventions

Initial step: Establish diagnosis with certainty • R/o hemicranias continua, intracranial pathology especially pituitary regions neoplasms, sinus or ocular pathology, and chronic paroxysmal hemicranias

Levin UCSF

15 MANAGING INTRACTABLE CLUSTER HEADACHE Traditional approach to CH • Break cycle: Prednisone • Prophylaxis: . Calcium channel blockers – Verapamil . Lithium . Antiepileptics – Valproate • Acute treatment . Oxygen 8-10 L/min . Sumatriptan subcutaneous

Levin UCSF

MANAGING INTRACTABLE CLUSTER HEADACHE • Break cycle: Prednisone • Prophylaxis: . Verapamil – consider high dose – up to 480 mg and avoid SR . Antiepileptics - also high dose Valproate; Consider Lamotrigine, remembering to up titrate the dose gradually • Acute treatment . Oxygen 8-10 L/min  25 L/min . Sumatriptan subcutaneous, IV . Occipital nerve blocks with steroid . Sphenopalatine ganglion blockade . Sphenopalatine ganglion stimulation Levin UCSF

NEW DAILY PERSISTENT HEADACHE

• Case – • 24 year old grad student has unremitting headaches which she distinctly recalls having begin one day during a “flu” and have been essentially constant since then. The pain is diffuse, not associated with much nausea, photosensitivity or phonosensitivity, and there are no other features. Exam and MRI are normal.

Levin UCSF

16 NEW DAILY PERSISTENT HEADACHE

• Definition – an unremitting headache that began at a clearly recalled time, unassociated with typical migraine features. • Perhaps not a homogenous group – Postinfectious, posttraumatic, migrainous, etc – • Therefore treatment responses may vary.

• Step 1 – exclude secondary causes – mass, inflammation, thrombosis, IIH, intracranial hypotension, etc. MRI, LP, Screening labs incl TSH, Lyme. • When NDPH confirmed – treatment generally fails

Levin UCSF

CHOICES IN MIGRAINE PROPHYLAXIS – GOOD OPTIONS

Anticonvulsants – topiramate 100-200 mg hs Beta blockers – propranolol 80 mg bid Cyclic antidep – nortriptyline 25-75 mg hs

CHOICES IN MIGRAINE PROPHYLAXIS – GOOD OPTIONS

Anticonvulsants – topiramate 100-200 mg hs Beta blockers – propranolol 80 mg bid Cyclic antidep – nortriptyline 25-75 mg hs Calcium channel bl – amlodipine 2.5-10 mg/d Angiotensin receptor bl – candesartan 4-16 mg Memantine 10 mg daily

Noruzzadeh, R, et al. Memantine for prophylactic treatment or migraine w/o aura: a RDBPC study. Headache 2016, 56:95-103.

17 OTHER CHOICES IN MIGRAINE PROPHYLAXIS

B2 Magnesium Feverfew Co Q 10 Melatonin Ginger Boswellia

NEW DAILY PERSISTENT HEADACHE

• Botulinum toxin • Inpatient DHE or chlorpromazine • Nerve blockade • Address MOH • Address depression • Persistence

Levin UCSF

BOTULINUM TOXIN FOR CHRONIC MIGRAINE

31 injections 5U each in forehead, temples, occiput, neck, trapezius Repeated every 3 mo AE’s – facial asymmetry, neck pain

18 MIGRAINOUS VERTIGO AKA VESTIBULAR MIGRAINE

• Case – • 39 year old teacher who had recurring headaches during her. They improved during her 2 pregnancies and she is now having only rare headaches. She does not remember auras. • Over the past 3 years she has had many episodes of nausea and a sensation of being pulled to the side along with some sensation of movement. These can last for hours.

Levin UCSF

MIGRAINOUS VERTIGO AKA VESTIBULAR MIGRAINE Definition:

• Current or previous history of migraine with or without aura • One or more migraine features with at least 50% of the vestibular episodes

• Vestibular migraine affects up to 1% of the general population* • 7% of patients in specialized dizziness clinics; • 9% of patients in HA Centers

*Neuhauser, et al. Migrainous vertigo: prevalence and impact on quality of life, Neurology 67 (2006), 1028–1033. Levin UCSF

Migraine with Aura ICHD III

With headache Migraine with typical aura Without headaches Migraine with Migraine with aura brainstem aura

Migraine with hemiplegia

Retinal migraine

Vestibular migraine

19 DDX VESTIBULAR MIGRAINE • Mal de Debarquement • Benign Paroxysmal Vertigo of Childhood • Benign Positional Vertigo • Meniere’s Disease • Migraine with brainstem aura • Vestibular pathology

Levin UCSF

CHRONIC VERTIGO

BPPV Meniere’s Vestib MdeD Migraine Positionality ++ + Hearing loss + Ear Fullness ++ Tinnitus ++ Photo/Phonoph ++ Vestib testing +

Levin UCSF

MIGRAINOUS VERTIGO AKA VESTIBULAR MIGRAINE

Acute treatment Zolmitriptan RCT 38% relief v 22% placebo Rizatriptan prevented motion sickness in the VM group better than placebo

20 MIGRAINOUS VERTIGO AKA VESTIBULAR MIGRAINE

Pharmacologic Prophylaxis – best evidence • Flunarizine • Propranolol • Lamotrigine

Lepcha A, et al. (2014) Flunarizine in the prophylaxis of migrainous vertigo: a randomized controlled trial. Eur Arch Otorhinolaryngol 271:2931–2936 Van Ombergen A, et al. (2015) Vestibular migraine in an otolaryngology clinic: prevalence, associated symptoms, and prophylactic medication effectiveness. Otol Neurotol 36(1):133–138 Bisdorff AR (2004) Treatment of migraine related vertigo with lamotrigine, an observational study. Bull Soc Sci Med Luxemb 2:103–108

MIGRAINOUS VERTIGO AKA VESTIBULAR MIGRAINE

Other options: • caffeine cessation, nortriptyline and topiramate • Vestibular rehabilitation • Even less evidence – though suggested ‐ prophylaxis: benzodiazepines, cinnarizine, SSRIs, pizotifen, dothiepin, acetazolamide, and behavioral modification

Mikulec AA, et al (2012) Evaluation of theefficacy of caffeine cessation, nortriptyline, and topiramate therapy in vestibular migraine and complex dizziness of unknown etiology. Am J Otolaryngol 33:121–127 Vitkovic J, et al (2013)Vestibular rehabilitation outcomes in patients with and without vestibular migraine. J Neurol 260:3039–3048

Levin UCSF

MIGRAINOUS VERTIGO AKA VESTIBULAR MIGRAINE Pharmacologic Symptomatic Tx

Anticholinergic Meclizine 12.5‐25 mg po tid Scopalamine patch 1q3d Anti‐DA Promethazine (phenergan) 12.5‐25 mg po tid, 25 mg IM for acute attack Sedative Diazepam 2‐5 mg po tid prn

21 EMERGENCY DEPT APPROACH TO ACUTE SEVERE HEADACHE

Case – 52 year old man developed the worst headache of his life while hiking. 2 hours later in the ED he is in a great deal of pain. He has had migraine headaches in the past. Exam is normal, but he complains of some “neck stiffness” CT of the head is normal

Levin UCSF

ED APPROACH TO ACUTE SEVERE HA STEP 1 - DDX

• Intracerebral hemorrhage • Subarachnoid hemorrhage • Pituitary Apoplexy • Cerebral Venous Thrombosis • Arterial Dissection • CNS Vasculitis, RCVS • Intracranial hypotension • Primary Thunderclap Headache • Sex related Headache • Meningitis • Acute Sinusitis

Levin UCSF

ED APPROACH TO ACUTE SEVERE HA R/O SAH, DISSECTION, INFECTION

• 5% of SAH may be missed by CT • In the 6 hours following subarachnoid hemorrhage, fluid may not be xanthochromic • Traumatic tap leads to uncertainty

Typical approach: • If CT is normal, LP should be done • If LP is not conclusive, or concerned about dissection – head and neck vessel imaging (CTA)

Levin UCSF

22 ED APPROACH TO ACUTE SEVERE HA

Ketotolac15-60 mg IM, IV Chlorpromazine – 25 mg IV with Benadryl [Opioids – avoid – particularly meperidine]

Triptans - sumatriptan injectable 6 mg Ergots – DHE – 1 mg IV with antinauseant

Other options: Valproate 250 mg IV Magnesium 1-4 g IV

Levin, M. "Approach to the Workup and Management of Headache in the Emergency Department and Inpatient Settings." Seminars in neurology.Vol. 35. No. 6. 2015.

DO WE NEED NEW INTERVENTIONS IN MIGRAINE? • Abortive migraine tx relieve pain in 60% pts (in 2 h) and eradicate pain completely in only 30% • Prophylactic migraine tx reduce HA freq by 50% in only 20-40% of patients • Abortive tx of cluster headache works about 75% of the time in 15 min (pain free in 50%) • Proph tx of cluster reduce HA freq by 50% in 70% of patients

NEW TREATMENT OPTIONS IN HEADACHE

• New forms of triptans & other older meds • CGRP as a target • Monoclonal antibodies • Neurostimulation

23 A NEW CLASS OF TRIPTANS – SEROTONIN 1F RECEPTOR BLOCKERS

• lasmiditan, the first “ditan”, has clear proof of principle in 2 studies • It is nonvascular so safer

CALCITONIN GENE RELATED PEPTIDE –CGRP –A NEW TARGET IN MIGRAINE • Small molecule antagonists were developed but not finalized due to adverse effects • Humanized and fully human monoclonal antibodies against CGRP and its receptor now in development

RATIONALE FOR CGRP MODULATION IN MIGRAINE

. Released from trigeminovascular afferents . Causes perivascular plasma protein extravasation and nociceptive pain . CGRP levels elevated in migraineurs between attacks and during (even higher) . Triptans and Onabotulinum toxin block CGRP release . CGRP induces migraine-like headache in susceptible individuals . CGRP enhances transmission of pain signals in CNS

Buchanan T, et al. Expert Rev Neurotherapeutics 2004; Edvinsson L. Expet Opin Ther Targets 2003; Buzzi MG, et al. Cephalalgia 1995; Goadsby PJ, et al. Ann Neurol 1988; Edvinsson L, et al. J Auton Nerv Syst, 1998; Ashina M, et al. Pain 2000.

24 4 MABS BEING DEVELOPED FOR MONTHLY INJECTION TO PREVENT MIGRAINE • LY2951742 (Lilly galcanezumab) – humanized mAb anti-CGRP – aimed at preventing episodic migraine - SC monthly • ALD403 (Alder fremanezumab)– humanized mAb anti-CGRP – aimed at preventing episodic migraine -IV q3mo • TEV 48125 (Labrys LBR-101 Teva ) - humanized mAb aimed at preventive treatment of chronic migraine - SC monthly • AMG 334 (Amgen erenumab) – Human anti GCRP receptor Ab – SC monthly

CGRP MABS - EVIDENCE TO DATE GENERALLY VERY POSITIVE AT HIGH DOSE

MAB target EM (12 wks) CM Other

LY ligand -4.2 d v -3.0 humanized ALD ligand −5.6d v −4.6 humanized

AMG receptor −3.4 d−2.3 -6.6 v -4.2 d human -75h v -57 h

TEV ligand -6 d v -3.5 -67h v -37h humanized

NEUROSTIMULATION IN HA

Non-invasive Supraorbital n Vagal n Transcranial magnetic stimulation

More Invasive Sphenopalatine ganglion stim Occipital nerve stim Deep brain stim

25 THE UCSF HEADACHE CENTER • Intractable migraine, cluster headaches, post-traumatic headaches and other unusual or difficult headache disorders • Outpatient treatment • Nerve blocks • Neurostimulation • Inpatient treatment • Telemedicine • Research

INPATIENT TREATMENT OF REFRACTORY HEADACHES

• Intravenous Dihydroergotamine (DHE) • Intravenous Chlorpromazine • Intravenous Lidocaine • Safe discontinuation of pain medications

CHALLENGES IN HEADACHE MEDICINE

• Challenging Issues in Headache Diagnosis • Primary and secondary headaches • Some common Management Impasses • Cardiovascular risks, Pregnancy, Medication overuse, Cluster HA, NDPH, Vestibular migraine, ER management • New treatment options • CGRP as a target • Neuromodulation • Inpatient treatment

26 RAIN 2017: Ischemic Stroke

Wade S. Smith, MD, PhD Chief UCSF Neurovascular Division Professor and Vice Chair, UCSF Department of Neurology

Disclosures •NIH •U10 NS 086494 (PI) NorCal RCC •U10 NS058931 (Co-PI) NETT • Consultant or stock ownership: • DSMB: Stryker Inc.

Wade S. Smith, MD, PhD Chief UCSF Neurovascular Division Professor and Vice Chair, UCSF Department of Neurology

MR CLEAN REVASCAT SWIFT-Prime N=1287 Randomized Patients EXTEND IA ESCAPE

1 Good Outcomes

50

45

40 19.1 35

30

25 Percent 20 13.6 16.9 15

10 7.9 5 10 5 0 Control Intervention 0 1 2

2 3 4 5 •DAWN – 6-24 hours trial – Carotid T or M1 occlusion – Favorable imaging – Randomized 1:1 embolectomy vs. best medical therapy – Started 7/2014 – N= 500 (~200)

• DEFUSE-3 – 6-12 hours trial – Carotid T or M1 occlusion – Favorable imaging – Randomized 1:1 embolectomy vs. best medical therapy – Start Feb 2016 – N = 476 (~100)

UCSF Acute Stroke Protocol

6 JAMA. 2016;316(19):1986-1996

JAMA. 2016;316(19):1986-1996

7 JAMA. 2016;316(19):1986-1996

JAMA. 2016;316(19):1986-1996

Major Conclusions

• Embolectomy with stent retrievers improve clinical outcome if done with 6 hours of symptom onset for anterior circulation ischemia • It is safe to combine embolectomy with IV t-PA treatment • The results are robust across a broad range of NIHSS scores and ages; NNT 2-3 to make someone have a good outcome • Earlier treatment improves outcome • Intubation does not appear to negatively impact outcome

8 1/27/2017

2017 Stroke Advances: Secondary Prevention: Be Aggressive

S. Andrew Josephson MD Carmen Castro Franceschi and Gladyne K. Mitchell Neurohospitalist Distinguished Professor Senior Executive Vice Chair, Department of Neurology Director, Neurohospitalist Program Medical Director, Inpatient Neurology University of California, San Francisco The speaker has no disclosures

Standard Large-Vessel Stroke Workup

• Cardioembolic: afib, clot in heart, paradoxical embolus • 1. Telemetry • 2. Echo with bubble study • Aortic Arch • 2. TEE (or CTA, MRA) • Carotids • 3. Carotid Imaging (CTA, US, MRA, angio) • Intracranial Vessels • 4. Intracranial Imaging (CTA, MRA, angio) And evaluate stroke risk factors

Approach to Stroke Treatment

Acute Stroke Therapy?

No

Anticoagulants?

No

Antiplatelets

1 1/27/2017

Shrinking Indications for Anticoagulation in Arterial Stroke 1. Atrial Fibrillation 2. Some other cardioembolic sources – Thrombus seen in heart –?EF<35 – ?PFO with associated Atrial Septal Aneurysm 3. Vertebral or Carotid dissection 4. Rare hypercoagulable states: APLS

Atrial Fibrillation Detection

•EKG • 48 Hours of Telemetry • Long-term cardiac event monitor (>21d) – 15-20% of patients with cryptogenic stroke otherwise unexplained have afib detected – Clearly changes management – Probably cost effective • Newer data suggest up to 25% when using a

Gladstone D et al: N Engl J Med 370:2467, 2014 stepwise approach Sposato LA et al: Lancet Neurol 14:377, 2015

Atrial Fibrillation Detection

• Advantages of devices to choose from – CardioNet and LifeWatch: real time monitoring – Zio Patch: ease of use – Implantable devices: extended duration

2 1/27/2017

The Bottom Line

1. Long term monitoring essential to screen for afib in cryptogenic stroke

TEE vs. TTE

• 231 consecutive TIA and stroke patients of unknown etiology underwent TTE and TEE • 127 found to have a cardiac cause of emboli, 90 of which (71 percent) only seen on TEE

• TEE superior to TTE for: LA appendage, R to L shunt, examination of aortic arch

De Bruijn S et al: Stroke 37:2531, 2006

TEE vs. TTE

• 263 consecutive stroke patients older than 50 of unknown etiology w/ normal TTE underwent TEE • An etiology of stroke was found in 42% – But only 1 patient did it directly change management

Marino B, et al: J Hosp Med 11:95, 2016

3 1/27/2017

TEE vs. TTE

• 61 patients with cryptogenic stroke with negative TTE and full workup for etiology underwent TEE • Additional findings found in 52% • Changed management in 16% (but included some patients who underwent PFO closure)

• Meta-analysis: pooled rate of anticoagulation therapy attributed to TEE findings: 8.7%

Katsanos AH, et al: Neurology 87:988, 2016

The Bottom Line

1. Echocardiography is low yield in stroke workup across multiple studies 2. TEE improves yield over TTE alone 3. When to employ TEE in workup remains unclear but should be part of all algorithms for cryptogenic stroke

Antiplatelet Options

• 1. ASA – 50mg to 1.5g equal efficacy long-term – ***At least 160mg in the acute period • 2. Aggrenox – 25mg ASA/200mg ER Dipyridamole • 3. Clopidogrel (Plavix) – Multiple secondary prevention studies (CHARISMA, SPS3) show no long-term benefit in combination with ASA

4 1/27/2017

PRoFESS Trial

• Randomized, double-blind trial of Aggrenox versus Plavix in over 20,000 patients with ischemic stroke • Recurrent 4-year event rates basically identical between the two medications – HR for Aggrenox 1.01 (95% CI, 0.92-1.11) – Composite of stroke, MI, vascular death: 13.1% in each – Major hemorrhagic events higher in Aggrenox group

Sacco RL et al: N Engl J Med 359:1238, 2008

Law of Transitivity: Secondary Prevention

• Aggrenox is better than ASA

• Aggrenox and Clopidogrel are equal

• Therefore, Clopidogrel is likely better than ASA

Antiplatelet Options

• If on no antiplatelet medication – Plavix vs. Aggrenox (or ASA) • If already on ASA – Switch to Plavix vs. Aggrenox • If already on Plavix or Aggrenox – ??? – Definitely NOT anticoagulants

5 1/27/2017

Clopidogrel + ASA: Ever A Winning Combination?

• CHANCE trial – 5170 TIA or Minor Stroke patients assigned to daily ASA + Placebo versus daily ASA + Clopidogrel following 300mg load – Primary outcome was stroke at 90 days • NNT=29 to prevent 1 stroke • Similar safety endpoints • Generalizability? – Await POINT trial results

Wang Y et al: N Engl J Med 369:11, 2013

CHANCE Reanalysis

• Three major CYP2C19 major alleles were genotyped in all patients in the trial • 58.8% of these Asian patients were carriers of loss of function alleles (*2 *3) • In these loss of function carriers, the trial was completely negative (no benefit of clodiogrel plus ASA over ASA alone) • Lower carrier rates in non-Asians Wang Y et al: JAMA 316:70, 2016

The Bottom Line

1. Would wait for POINT results before employing dual antiplatelets widely, but this likely will become standard 2. Until then, use only in those with large vessel intracranial atherosclerosis (>70%) and those with fresh stents (carotid, coronary) 3. Assume genotyping will play an important role in the future in these patients

6 1/27/2017

A Future Option?: P2Y12 Receptor Antagonists

Johnston SC et al: N Engl J Med 375:35, 2016

What about Insulin Resistance?: IRIS Trial • Nearly 4000 patients with recent TIA or stroke were assigned to pioglitazone or placebo for almost 5 years • Patients did not have diabetes but were found to have insulin resistance • Primary outcome of stroke or MI significantly reduced in the pioglitazone group (HR 0.71, P=0.007)

Kernan WN et al: N Engl J Med 374:14, 2016

Insulin Resistance in 2017

• The Problem: Nearly impossible to define insulin resistance as they did in the trial • Take home: – We don’t pay attention to insulin resistance – By modifying this risk factor we could make a reasonably big difference for our patients – We have no idea how to define this problem, but if we could, we now have guidance on how to help solve it

7 1/27/2017

TIA Aggressive Therapy: A Modern Look • 2009-2011 TIA registry of nearly 5000 patients • Population at baseline was high risk comparable to historical cohorts • 78% saw a stroke specialist within 24 hours – Most neurologists likely • 1-year stroke rate was 5.1% • Rates at 2d, 7d, 30d, 90d, 1y were all less than half of that in historical cohorts

Amarenco P, et al: N Engl J Med 374:1533, 2016

The Bottom Line

1. Continue to be ultra-aggressive in TIA workup and treatment 2. This is our version of unstable angina and likely we have more to gain in TIA than in post-stroke secondary prevention

8 Intracerebral Hemorrhage 2017

Nerissa U. Ko, MD, MAS

University of California, San Francisco Recent Advances in Neurology

Slides courtesy of J. Claude Hemphill III, MD, MAS UCSF Disclosures: Research Support NIH/NINDS, HHMI, AHA, Edge Therapeutics NEUROCRITICAL CARE PROGRAM

ICH 2017 – Practical Management Issues

1. Coagulopathy Reversal

2. Blood Pressure Control

3. Surgery

4. Outcome Prediction

Oral Anticoagulants and ICH

64 yo woman with atrial How to keep that from fibrillation, hypertension ending up like this – On warfarin, INR 4.5

Initial CT 10 hours later

Page 1 Reversal of Anticoagulation

• Principle – any ICH in patient on anticoagulation should be considered “life-threatening”

• Does urgent reversal of warfarin coagulopathy improve outcome in ICH? – No pivotal randomized trials – Prothrombin complex concentrates (PCC) reverse INR faster than fresh frozen plasma (FFP) and have fewer cardiopulmonary side effects (Sarode Circulation 2013) • Does urgent reversal of NOAC coagulopathy improve outcome in ICH? – Not studied. Very early in experience with these medications

Saraf Postgrad Med J 2014

Warfarin-related ICH

• Lots of experience • ~10% of spontaneous ICH has been associated with warfarin – Increase in incidence with aging of population and more use in atrial fibrillation stroke prevention and DVT treatment – Caused by warfarin or a hypertensive ICH in a patient on warfarin? Probably does not matter. • Warfarin use is associated with worsened outcomes – More hematoma expansion – Longer duration of bleeding (over a day or more)

Page 2 INCH Trial

• 54 subjects; trial terminated early by regulatory due to differences in hematoma expansion • 1o Endpoint – INR < 1.2 by 3 hours – PCC 67% v. FFP 9% (P=0.0003) • Mortality – 35% FFP (5 hematoma expansion, 19% PCC (none hematoma expansion)

NOACs

• Dabigatran – direct thrombin inhibitor (DTI) • Rivaroxaban – anti Xa • Apixaban – anti Xa • Edoxaban – anti Xa

• Demonstrated equivalence or superiority to warfarin for – Stroke prevention in atrial fibrillation – Deep venous thrombosis treatment • Safer than warfarin (apixaban)

NOAC Reversal – initial approaches

• Dabigatran – Dialysis – Charcoal – FEIBA (activated PCC) – rFVIIa

• Rivaroxaban, apixaban, edoxaban – Charcoal – PCC

• Vitamin K has no effect • FFP? (probably not)

Page 3 Idarucizumab

• Monoclonal antibody fragment that binds dabigatran with 350 times the affinity as thrombin • Binds free and thrombin-bound dabigatran and neutralizes its activity • Made by same company that makes dabigatran • Open-label single arm study of 90 patients with – Group A -Serious bleeding – Group B - Peri-procedure • Hemostasis restored in Group A at median 11.4 hours • Group B with normal intraop hemostasis in 92% • Approved for use in US

Pollack NEJM 2015

Frontera CCM 2016

When to Restart Warfarin

• In amyloid, generally never • No prospective randomized trials • Majeed (Stroke 2010) followed 234 warfarin- related ICH patients for a median of 34 weeks – Risk of rebleeding with early resumption of anticoagulation exceeded the risk of thromboembolism from withholding it, whereas later, the opposite was true – Survival model based on these data found that the total risk of ischemic plus hemorrhagic stroke was minimized when anticoagulation was reinitiated after ≈10 weeks • Are NOACS safer after warfarin-related ICH? – Nobody knows

Page 4 2015 American Heart Association Guidelines for Management of Spontaneous Intracerebral Hemorrhage

• Relatively mild non-operated ICH • Platelet transfusion not beneficial and may be harmful • Reason? Not clear

Page 5 Blood Pressure and Perihematoma Ischemia in ICH

• Initial animals models suggested a zone of perihematoma “ischemia” based on findings of low CBF – Bullock (1988) - blood injection into primate caudate; CBF below ischemic threshold of 18 ml/100 gm/min Current– Mendelow Thinking (1993)- neuroprotection - ongoing with ischemia nimodipine in rodentin the ICH perihematoma region is neither common nor the major mechanism of perihematoma injury

2015 AHA Guidelines for ICH

Published online May 29, 2013

• Randomized 2839 subjects • Same protocol as INTERACT (SBP <140 vs. <180mmHg) • Outcome at 90 days tested 2 ways • Rankin scale dichotomized at 2/3 • Proportional odds analysis across entire Rankin scale • 68% of subjects from China

Page 6 3.6%

No difference in hematoma expansion between groups

1. So does it work? 2. Is it a clinically meaningful effect?

(used IV nicardipine infusions)

•Difference in Blood Pressure •No difference in outcome

Qureshi NEJM 2016

Page 7 JAMA 2015

• Observational study of 1176 patients; 854 for hematoma expansion • Hemorrhage enlargement in 36%

JAMA 2015

Synergistic Effect of • Reduced hematoma“Combination enlargement Therapy”were associated – with reversal of INR levels <1.3 within 4 hours after admission (19.8%) vs INR of 1.3 (41.5%; P < .001)Blood and Pressure systolic BP Lowering <160 mm Hg and at 4 hours (33.1%) vs 160 mm Hg (52.4%;Coagulopathy P < .001). Reversal • The combination of INR reversal <1.3 within 4 hours and systolic BP of <160 mm Hg at 4 hours was associated with lower rates of hematoma enlargement (18.1% vs 44.2%; P<0.001) compared with those not achieving these and lower rates of in-hospital mortality (13.5% vs 20.7%; P=0.03)

Page 8 What We Know About BP in Acute ICH

• No trial has looked at treating BP versus ignoring it and allowing it to go untreated • Therefore, BP lowering to at least systolic < 180 mmHg should be considered in all patients • Lowering to systolic BP < 140 mmHg appears safe in most patients • At UCSF we have adjusted to a < 160 mmHg goal

BP lowering: how to do it

• Labetalol – 5‐10 mg IV bolus every 10‐15 minutes – Infusion, begin at 5 mg/hr and titrate up • Nitroprusside – Infusion, start at 2 μg/kg/min and titrate – Theoretical issues of increase in ICP (not a big deal) • Nicardipine – We don’t bolus – Start IV infusion at 2.5 mg/hr and titrate up by 0.5 mg/hr increments Stroke 2007;38;2001-2023; – We use central lines for prolonged usage

2015 AHA Guidelines for ICH

Page 9 Surgical Trial for ICH (STICH)

• Largest study of surgery in ICH (>1000 pts) • Does a policy of “Early Surgery” improve outcome in patients with spontaneous supratentorial ICH compared with a policy of “Initial Conservative Treatment”? – Randomisation within 72 hours of ictus – Surgery within 24 hours of randomisation – Selection based on “uncertainty principle” • No Difference in mortality or functional outcome • 26% of patients randomized to Initial Conservative Treatment later had surgery • Conclusion – early surgery is not harmful

Mendelow Lancet 2005

• Lobar ICH within 1 cm of cortical surface • Hematoma volume 10-100 cc • Randomized within 48 hours of onset • Best motor score on GCS of > 5, conscious, no IVH

• Randomly assigned to surgery within 12 hours or not • 6 month GOSE “Prognosis-based” outcome • 21% of non-surgical group received delayed surgery

• No difference in outcome • “Poor prognosis” group benefited from surgery (post-hoc analysis)

Minimally Invasive ICH Surgery

• Concept has existed since 1980s • Variation in techniques based on – Interest of investigator/clinician – Technology

• 3 basic types of approaches – Endoscopic removal – Stereotactic aspiration – Addition of thrombolytics

• Increased attention to technique refinement

Page 10 MISTIE

• Minimally invasive surgery plus recombinant t-PA for intracerebral hemorrhage evacuation (Mould Stroke 2013) (n=118) • Dose-ranging and safety study for image- guided catheter placement with subsequent t-PA instillation and clot aspiration • ICES group – endoscopic hematoma removal • Hematoma removal associated with decreased peri-hematomal edema

• MISTIE phase 3 NIH-funded and ongoing

Endoscopic Hematoma Evacuation

1. Image-guided navigation (framed or frameless stereotaxy); MR most often used; CT also possible – Pathway designed to minimize injury to brain 2. Endoscope to allow visualization of hematoma cavity 3. Irrigation and aspiration apparatus

Orakcioglu Neurocritical Care 2014

Orakcioglu Neurocritical Care 2014

Page 11 If there is no proven treatment, does it matter what you do?

• Many different clinical grading scales for ICH • Some use these for outcome prediction • Concern for self-fulfilling prophecy of poor outcome with early care limitations such as DNR orders on day 1

Prospective ICH Outcomes Study

• Prospective observational study of outcome in ICH • Patients with intent to treat without DNR orders for at least initial 5 days • GCS < 12, no pre-existing DNR order • N=109, 5 centers

• Specific Aim 1 – assess whether 30 day mortality is less than predicted by ICH Score • Specific Aim 2 – if so, does this result in unacceptably high rate of disability at 90 days

Morgenstern Neurology 2015

Mortality much lower than predicted in all severity categories

Morgenstern Neurology 2015

Page 12 3 Month mRS in ICH Patients 70% Predicted 60% Observed Many patients who would have died 50% had good functional outcomes and many were left severely disabled

40% Is the glass half-full or half-empty?

30%

20%

10%

0% 0123456

Morgenstern Neurology 2015

ICH 2017

• Have a protocol for warfarin and NOAC reversal • Blood pressure – Lowering to < 140 mm Hg systolic BP is safe in most patients – Target for aggressive Rx still open to discussion – No evidence that allowing very high BP (> 180 mm Hg SBP) is good • Surgery (for supratentorial ICH) not clearly beneficial, but new studies of minimally invasive surgery ongoing – Cerebellar ICH is a surgical disease! • Even in the absence of specific highly effective treatments, nihilism is an ineffective treatment strategy

Page 13

Liza Ashbrook, MD February 10, 2017

Recent Advances in Neurology

Patient 1 A 70-year-old man with a history of obstructive sleep apnea and right hip replacement presents with trouble falling asleep. He complains of leg discomfort that keeps him up at night. He feels his legs (R > L) begin to move on their own. He cannot sit still causing him to get up and walk around overnight-often for hours. He first noticed this leg discomfort on airplanes years ago. Symptoms have been worsening over the past several months and are now hard to tolerate despite treatment. He does not complain of numbness or pain in the legs or feet. He does get intermittent hip pain but no back pain.

On general examination, he has full range of motion at the right hip and no hip pain. On neurologic examination his mental status and cranial nerves are normal. On motor exam, there is normal bulk, tone, and power in the arms and legs. Coordination, reflexes and gait are normal. Sensation is intact to light touch, pin and vibration.

References 1. Aurora RN, Kristo DA, Bista SR, Rowley JA. Zak RS; Casey KR; Lamm CI; Tracy SL; Rosenberg RS. Sleep. 2012;35(8):1039-62. 2. Cho YW, Allen RP, Earley CJ. Sleep Medicine. 2013;14(3):274-277. 3. Garcia-Borreguero D, Silber MH, Winkelman JW, Högl B, Bainbridge J, Buchfuhrer M, Hadjigeorgiou G, Inoue Y, Manconi M, Oertel W, Ondo W. Sleep Medicine. 2016 May 31;21:1-1. 4. Silver N, Allen RP, Senerth J, Earley CJ. Sleep Medicine. 2011 May 31;12(5):440-4 5. Trenkwalder C, Beneš H, Grote L, García-Borreguero D, Högl B, Hopp M, Bosse B, Oksche A, Reimer K, Winkelmann J, Allen RP. The Lancet Neurology. 2013 Dec 31;12(12):1141-50.

Patient 2: A 20-year-old woman with a history of chronic hip pain and chronic migraine presents with trouble falling asleep and staying asleep for 1.5 years. She gets in bed between 10 and 11:30 pm but does not fall asleep until 4-5 am. She often does not get out of bed until 3-5 pm. Overnight she awakens 6-7 times, related to physical discomfort such as hip pain, headache, need to urinate, or no known cause. It takes minutes to hours to fall back to sleep. When not sleeping but in bed at night she watches Netflix, colors, and talks on the phone. She never feels well rested. She snores occasionally. There are no reported breathing pauses and she does not awaken overnight gasping or choking. She does awaken with dry mouth. She does not complain of an urge to move the legs and there are no abnormal behaviors overnight. Her goal sleep schedule is 11:30 pm – 7:30 am.

She has a normal neurologic exam.

References 1. Auger RR, Burgess HJ, Emens JS, Deriy LV, Thomas SM, Sharkey KM. J Clin Sleep Med. 2015 Oct 15;11(10):1199-236. 2. Brainard GC, Hanifin JP, Greeson JM, Byrne B, Glickman G, Gerner E, Rollag MD. Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor. Journal of Neuroscience. 2001 Aug 15;21(16):6405-12. 3. Magee M, Marbas EM, Wright KP, Rajaratnam SM, Broussard JL. Diagnosis, cause, and treatment approaches for delayed sleep-wake phase disorder. Sleep Medicine Clinics. 2016 Sep 30;11(3):389-401. 4. Saxvig IW, Wilhelmsen-Langeland A, Pallesen S, Vedaa Ø, Nordhus IH, Bjorvatn B. A randomized controlled trial with bright light and melatonin for delayed sleep phase disorder: effects on subjective and objective sleep. Chronobiology international. 2014 Feb 1;31(1):72-86. 5. St Hilaire MA, Gooley JJ, Khalsa SB, Kronauer RE, Czeisler CA, Lockley SW. Human phase response curve to a 1 h pulse of bright white light. The Journal of physiology. 2012 Jul 1;590(13):3035-45.

Jenny Clarke, MD February 10, 2017

Recent Advances in Neurology

Patient 1 A 57 yo RH man presented to the ER with worsening expressive aphasia. His medical history was notable for a left temporal glioblastoma 8 years prior, at the age of 49. At that time, he had presented with temporal lobe seizures consisting of taste/smell abnormalities and “auditory hallucinations”. He underwent aggressive subtotal resection via awake language mapping, followed by enrollment in a phase I clinical trial adding enzastaurin (an oral protein kinase C inhibitor) to standard radiation and temozolomide chemotherapy. He did very well, remaining on adjuvant chemotherapy without evidence of tumor progression for 45 cycles after completion of radiation. At that time, he voluntarily stopped treatment, and was monitored for 4 years.

9 months prior to presentation in the ER, he was seen in clinic with stable imaging. At that time, seizures were well-controlled on Keppra 500 mg BID. A week later he started to have episodes of acute-onset expressive aphasia that would gradually resolve over 30-60 minutes, without clear alteration of consciousness or other associated symptoms. These were suspected to be seizures and Keppra was increased to 750 mg BID. Three months later, he was still having the episodes, without appreciable change in frequency or severity on the higher dose of Keppra. Imaging remained stable and routine EEG showed no epileptiform discharges. A further increase in Keppra dose was discussed, but the episodes were not disabling and he wished to avoid further worsening of Keppra-related side effects.

Five days prior to presentation in the ER, he began to have increased frequency of the acute aphasic episodes, with an associated rising epigastric sensation, occasional music/other auditory symptoms, and cognitive changes. By the time of evaluation in the ER, the aphasia was persistent without discrete episodes or return to baseline between. There were no missed doses of medication, signs of symptoms of infection, or history of specific precipitating events.

On initial evaluation in the ER, neurological examination revealed that he was alert and oriented, but speech was halting with significant word-finding difficulty, frequent phonemic and semantic paraphasias, and inability to read. Auditory comprehension, memory, and ability to provide history were intact. Cranial nerves were unremarkable aside from a baseline right surgical pupil. Strength, coordination, gait and reflexes were all normal. Sensory examination was normal.

He was admitted to the neurology service, and additional tests were performed.

References 1) Cole AJ. Epilepsia 45:72-77, 2004 2) Lansberg MG, O’Brien MW, Norbash AM, et al. Neurology 52:1021, 1999 John Engstrom, MD February 10, 2017 Recent Advances in Neurology

Patient A 75 yo woman was referred for consultation in the spine neurology practice with low back pain (LBP) and left leg pain.

She first remembers low back and right leg pain beginning around 2003. She had deep, dull, and aching right buttock pain that spread to the posterior thigh. The pain was much worse with sitting and better when walking. She was seen by a chiropractor with some modest benefit. An epidural injection at L5 in 2005 was associated with some benefit for a year. Another injection in 2008 was associated with less pain relief of shorter duration. She started Pilates in 2010 with mild benefit. She was also given ibuprofen and gabapentin that she took as needed with modest results. She also noted that even without treatment her symptoms tended to fluctuate over time.

By 12/13 she developed new LBP that was sharp and prickly, spreading over the right hip, lateral thigh, and lateral calf. There was tingling on the sole of the right foot. The pain worsened over months so she had a right L5 epidural block in 4/14 that helped the back pain, but was not helpful for the right leg pain. A right gluteal trigger point injection in 6/14 helped by more than 50%. Neurologic exam showed only a mild decrease in the right knee reflex, but was otherwise normal. Lumbar spine MRI showed a right lateral L4-5 disk protrusion with narrowing of the right L4-5 neural foramen. She elected conservative management at that time.

She presented again in 1/16 with left dull and aching low back, lateral thigh, lateral calf and ankle pain. She developed worsening pain at Christmas and very severe pain 3 weeks later when trying to get out of bed. She fell to the ground and had to drag herself to the bathroom due to pain. As the pain subsided, she noted that sitting was the best position while standing and walking were the worst. (Yes…the pain switched sides and the relationship of the pain to posture changed completely!) Straight-leg raising and reverse-straight leg raising signs were absent. Neurologic examination was normal.

Diagnostic studies were reviewed and performed.

References 1. Engstrom JW and Deyo RA. Harrison’s Principles of Internal Medicine (18th ed.) McGraw-Hill Inc., New York, 2015. 2. Tarulli AW, Raynor EM. Neurol Clin. 2007; 25(2):387. 3. Beutler WJ, Fredrickson BE, Murtland A, Sweeney CA, Grant WD, Baker D. Spine 2003 May 15;28(10):1027-35; discussion 1035. 4. Hammerberg KW. Spine 2005 Mar 15;30(6 Suppl):S4-11.

Heather Fullerton, MD February 10, 2017

Recent Advances in Neurology

Patient A previously healthy 14-year old boy presented with recurrent arterial ischemic strokes and a rapidly progressive cerebral arteriopathy.

While playing basketball with friends, he had a witnessed convulsion lasting six minutes. Afterwards he had a mild headache and right-sided weakness. He was transported by EMS to a hospital where he was found to be aphasic with a right hemiparesis. An emergent MRI revealed small acute infarcts in the left middle cerebral artery (MCA) territory, with involvement of the internal capsule. An MRA showed mild narrowing of his left supraclinoid internal carotid artery (ICA).

He was admitted to the hospital. His general physical exam was unremarkable. His neurological exam was notable for aphasia, a right hemiparesis (face=arm=leg), and normal sensation. He was placed on IV heparin. An echocardiogram was normal. His deficits improved dramatically over the next few days.

Three days after his stroke, he had a severe left frontal headache. The next day, 4-days post- stroke, he was found to be agitated with worsened aphasia and right hemiparesis. His deficits were positional, improving when placed flat, and responded to IV hydration and pressors. Repeat MRI showed new infarction in the left MCA territory and severe narrowing of his left distal ICA and proximal MCA.

He was transferred to UCSF Benioff Children’s Hospital-San Francisco where additional diagnostic studies were performed and treatment provided.

References 1. Chabrier S, Rodesch G, Lasjaunias P, Tardieu M, Landrieu P, Sebire G. J Child Neurol 1998;13:27-32. 2. Wintermark M, Hills NK, deVeber GA, et al. Stroke 2014;45:3597-605. 3. Elkind MS, Hills NK, Glaser CA, Lo WD, Amlie-Lefond C, Dlamini N, et al. Circulation. 2016;133:732-741. Nicholas Galifianakis, MD, MPH February 10, 2017

Recent Advances in Neurology

Patient A 45 year old man was referred for neck ”spasms” and involuntary movements. He had been athletic his whole life, though he remembered walking “pigeon-toed” as a child. In his 20s, co- workers noted that his left arm twisted when walking. At age 35, posturing of the left foot impaired his gait and he was first seen by a neurologist. By age 40, he developed painful tilting of the head to the left. Over the next five years, the symptoms progressed and trihexyphenidyl, levodopa, lorazepam and tramadol provided only modest benefit. By age 45 (2010, the year of his presentation) the movements and pain prevented his work as a high school basketball coach and substitute teacher. He went on disability. He had mild memory complaints attributed to his medications, but denied imbalance or other neurologic symptoms. He was otherwise healthy. He was a college graduate, lived with his wife and five adopted children (no biological children). Family history was significant for a younger brother (age 41) with recent stiffness in his left leg and abnormal movements in his left arm.

Prior work-up included a normal MRI brain, but an MRI cervical spine showed a “bone spur compressing a nerve”. “Spine surgery” temporarily relieved his neck and shoulder pain, but not the abnormal movements. Subsequent labs (metabolic and thyroid panels, vitamin E level, ceruloplasmin, anti-GAD antibodies) were all normal.

General examination was unremarkable. Memory, language, attention, executive function, and visuospatial function were normal on mental status examination. Cranial nerve examination (including voice and facial expression) was normal. Normal aspects of the motor exam included strength, coordination and flexor plantar responses. Deep tendon reflexes were brisk throughout. Sensory examination was normal.

On movement examination, his head was tilted to the left. The left splenius capitis, SCM, trapezius, and levator scapulae were clearly hypertrophied relative to the right. Range of motion was limited for right lateral tilt. Tone was minimally increased in the neck, left arm and leg (only brought out with distraction). No rest or action tremor was noted. Rapid repetitive movements (finger taps, hand movements, heel stomps) were normal on the right. Left bradykinesia was difficult to assess due to the intrusion of abnormal movements. On gait examination, he was able to stand out of chair normally. He had normal turns, no shuffling, and no retropulsion on pull testing. During walking, the left arm twisted into a posture with the elbow mildly flexed and the palm facing outward. The left foot inverted slightly.

References 1. Albanese A et al. Movement Disorders 28: 863-873, 2013 2. Frucht SJ. Movement Disorders 28: 884-888, 2013 3. Marras C et al. Movement Disorders 31: 436-457, 2016 Nancy Ann Oberheim-Bush February 10, 2017 Recent Advances in Neurology

Patient A 66 yo man with a history of papillary thyroid cancer as well as right MCA stroke was seen due to the development of low back pain, weakness, and numbness.

In 2009 he had acute onset left-sided weakness and was found to have right MCA stroke in the setting of a carotid artery dissection. Due to persistent left hemiparesis he sought treatment with stem cell therapy. In 2011, he underwent intrathecal injection of embryonic stem and mesenchymal stem cells in China without improvement in his weakness. In 2012, he underwent arterial injection of autologous iliac crest cells in Argentina again with no clinical improvement. In 2014 he traveled to Mexico when he had intrathecal injection of mesenchymal and neuronal stem cells which was associated with improvement of his left hemiparesis for about 1 month. He then underwent a second treatment 6 months later with improvement in his hemiparesis for a few weeks. In February of 2015 he then developed progressive low back pain, weakness and numbness in his right arm and leg.

On general exam he is a well appearing man in no acute distress, but in a wheelchair. General examination is normal.

Mental status exam reveals normal cognition and language. He has left hemi neglect.

Cranial nerve exam is significant for an upper motor neuron left facial droop and is otherwise normal.

Motor exam reveals a spastic left hemiparesis with a paretic right leg. His left arm is 4- /5 proximally with 2/5 in the triceps muscle and clonus at the wrist. His right arm has full strength. His left leg is 2/5 in power throughout. His right leg flexion is 2/5 at the hip, 4+/5 at the quadriceps, 2/5 in the hamstrings, and 0/5 in the distal foot for dorsiflexion and plantar flexion at the ankle and great toe extension. His reflexes are symmetric and normal at biceps and triceps, and his knee jerks were 3+ bilaterally, there was clonus in the ankles bilaterally. Plantar responses were extensor bilaterally. His coordination with finger-nose-finger is normal bilaterally and was unable to be tested in the legs due to weakness.

Sensory exam is significant for marked hyperesthesia/paresthesias in the left arm and leg with a T4 sensory level on right. He has no vibratory sensation in the legs.

Diagnostic tests were performed.

References 1. Berkowitz AL et al. N Engl J Med. 2016 Jul 14;375(2):196-8. 2. Bowman M, Racke M, Kissel J, Imitola J. AMA Neurol 2015;72:1342-1345 3. Amariglio N, Hirshberg A, Scheithauer BW, et al. PLoS Med2009;6:e1000029- e1000029 4. Fox IJ, Daley GQ, Goldman SA, et al. Science 2014;345:127391-127391

Jeffrey Ralph, MD February 10, 2017

Recent Advances in Neurology Patient A 61-year-old man with a history of hypertension presents with 1 year of progressive muscle stiffness, weakness, and numbness in all limbs. One year ago, he first developed tingling in both hands, which then spread to the neck, arms and legs. He was diagnosed with Vitamin B12 deficiency (149 ng/L), and his sensory symptoms improved somewhat with treatment. However, he slowly developed weakness and difficulty rising from a chair. He describes that any movement leads to constant muscle contraction and he can't relax his muscles until 30 seconds later. This problem has been getting progressively worse, and now involves all extremities, trunk and abdomen, neck muscles, and facial muscles. He has difficulty swallowing and notes changes to his voice. He has had difficulty with speech and swallowing for four months and lost about 20 lbs. since this problem began. Evaluation by his local neurologist included normal CNS imaging and elevated anti-GAD antibodies. He was diagnosed with stiff person syndrome and started on benzodiazepines and then given IVIg treatment with no improvement in his symptoms. He came to ED two days ago because of worsening symptoms, respiratory difficulty, and worsening dysphagia such that he was unable to eat. On mental status exam, he is awake and alert, oriented to person, place, and time. He has significant dysarthria. On cranial nerve exam, visual fields are normal. Pupils are equal, round, and reactive to light. There is bilateral restriction of eye abduction, but no ptosis or bifacial weakness. The tongue is midline without fasciculations. The tongue protrudes to the right. He has labial dysarthria when talking that markedly fluctuates. He has difficulty opening his mouth after minutes and then it improves with 15-20 seconds of rest. On motor exam, there is normal muscle bulk and tone, and a chronic contracture of the left 4th and 5th fingers. He has apparent grip myotonia but no percussion myotonia. There is mild neck flexion weakness. He has mild-to-moderate proximal weakness in bilateral arms and legs, though it is difficult to assess strength fully in the context of severe stiffness and myotonia. Plantar responses are mute bilaterally. Finger-to-nose movements are accurate bilaterally. Reflexes are absent in all limbs. Sensory exam is notable for decreased pinprick distal to bilateral mid-calves. There is decreased position sensation at the IP joints of both great toes. References 1. Ahmed A et al. Muscle Nerve 52: 5-12, 2015. 2. Lancaster et al. Ann Neurol 69:303-311, 2011. 3. Rana SS et al. J Clin Neuromuscul Dis 13(4): 228-33, 2012. Liliana Ramirez-Gomez, MD February 10, 2017

Recent Advances in Neurology

Patient A 59 yo woman was referred for difficulties with gait and speech. Her symptoms had a subacute onset, first with lower back pain and left leg pain, followed by progressive loss of balance and frequent falls. Concurrently, she noted changes in her speech including slurring her words and changes in her handwriting. A few months later, her husband noted that she started enacting her dreams at night. She had a sleep study that revealed obstructive sleep apnea and REM sleep behavior disorder. She was started on clonazepam, gabapentin and began using CPAP at night. She denied any weakness or swallowing difficulties. Per her husband, she demonstrated changes in her mood including irritability, frustration, depression and shame as a result of her condition. She denied any hallucinations or changes in cognition. Her past medical history was significant for gastric bypass surgery in 2006, and back pain which improved with epidural injections and facet blocks. Her mother suffered from rheumatoid arthritis and late onset Alzheimer’s disease. Her father passed away at age 83 and suffered from ALS and myelodysplasia. Her younger sister was healthy. On general examination, there were no abnormal findings.

Mental status exam was normal for language, speech, attention, recent memory, abstractions and calculations. MoCA was 29/30-missing one point in phonemic fluency. Cranial nerve exam revealed EOMI, saccadic intrusions to smooth pursuits, no nystagmus, and mild dysarthria. The other cranial nerves were normal. Motor exam demonstrated normal bulk and tone, no pronator drift, and no fasciculations. There was no cogwheel rigidity, tremor or spasticity. Power testing was normal in all limbs. Gait was wide-based, unsteady, and ataxic. She was unable to tandem walk. Reflexes were 2+ throughout except for 1+ bilateral Achilles. Plantar responses were not extensor. Coordination revealed moderate dysmetria with FTN (L > R), ataxic finger taps, and mild-to-moderate dysdiadochokinesia (L > R). Sensory exam was normal. Romberg sign was absent. Prior to her evaluation at UCSF, brain MRI and EMG/NCS were normal. HIV testing was negative. Additional diagnostic tests were performed.

References 1. Nachbauer W., Eigentler A., Boesch S. J Neurol (2015) 262:1385–1393 2. Sarah Kalus, John King, Elaine Lui, Frank Gaillard. Case Reports / J Clin Neurosci 23 (2016) 162–164 3. Jones AL, McKeon et al. JAMA Neurol. 2015;72(11):1304-1312

The New Anatomy of Language

Edward F. Chang, MD, PhD

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Clinicopathologic Conference RAIN 2017

Case History: A 68 year‐old left‐handed man presented for evaluation of cognitive changes that began 5 years prior. The patient’s initial symptoms included difficulty in performing skilled tasks such as simple automobile repairs despite being a former mechanic. He then 1 year later began having difficulty understanding his wife in conversation, which led to an evaluation of his hearing. Hearing aides were prescribed but he exhibited no improvements. His language declined over the next 3 years. He began to mispronounce words and repeated previous conversations often. His speech output diminished, and he spoke in short sentences with a soft voice. He then eventually had more difficulty expressing himself verbally, and used mainly hand motions during conversation. By this time, he was no longer able to read and could only write his own name.

Throughout the course of this illness, he also developed a progressive lack of motivation. He no longer pursued his hobbies of restoring cars and playing virtual poker, and he eventually quit his job as a part‐time dishwasher. His wife had to encourage him to perform personal hygiene tasks such as showering and brushing his teeth. He began sleeping 12 hours a night (compared with 9 hours typically) and frequently took daytime naps. He had poor insight into his condition, yet his mood remained content.

Four years into his illness, he began to exhibit new behaviors. He repetitively paced in his yard in a particular pattern, and would occasionally walk outside of his house in only underwear. He displayed a lack of control while eating and consumed large meals, which led to a significant amount of weight gain.

Review of Symptoms: The patient had a several year history of difficulty swallowing pills as well as coughing during meals. He occasionally had urinary incontinence. Approximately 10 years ago, he had a recurrent delusion in which he suspected his wife of infidelity, but this resolved with marriage counseling. There were no hallucinations.

Past Medical History: He had a long‐standing history of benign prostatic hyperplasia status post laser surgery.

Medications: His only medication was tamsulosin daily. No known drug allergies.

Social History: He was raised in foster care and lost his foster parents at a young age. He grew up in central California and completed the twelfth grade. He most recently worked a part‐ time job as a dishwasher, but was previously employed at an auto shop. The patient did not smoke tobacco and rarely consumed alcohol. He denied illicit drug use.

Family History: He had two healthy sons. His biological parents were not known.

Physical Examination: Vital Signs: BP 133/77, HR 56, 137 lbs., 5’7” General: He was well groomed and cooperative. His lungs were clear to auscultation. The remainder of his general exam was unremarkable. Mental Status: He was alert but very slow, responding to only a few questions. He stared at the examiner for the entirety of the encounter. Mini‐Mental State Exam score was 8 out of 30. He was oriented to self, city, month, and date, but could not state the season, year, or medical center. He could not spell WORLD backward. He had a digit span forward of 4 and backward of 0. His speech content was sparse with up to 4‐word sentences that were grammatically correct. When he began to say some words he would instead perform hand gestures but not speak. He did not appear frustrated by his speech impairment. When requested to touch his right hand to his left ear, he touched his left hand to his right ear, and was unable to perform more complex tasks. He was able to repeat some simple sentences. He was not able to blow a kiss or whistle. Cranial Nerves: His visual fields were full and pupils were equal and reactive to light. He had no extinction to double simultaneous visual stimuli. He had limited up‐ gaze and normal down‐gaze. Horizontal eye movements appeared normal, but he had some gaze impersistence. Saccades appeared normal and there was no nystagmus. Facial sensation was intact. His voice was mildly hypophonic and guttural dysarthria was present. He had moderate hypomimia but facial strength was full and equal on both sides. Hearing was mildly diminished bilaterally and he was wearing hearing aids. The palate elevated symmetrically. Sternocleidomastoid and trapezius muscles were full strength. Tongue protrusion was midline without fasciculations. Motor: He had occasional fasciculations throughout his upper extremities, but none were visualized on his back, trunk, or legs. Paratonia was present moderately in his arms and mildly in his legs, and no rigidity or spasticity could be detected. He demonstrated bradykinesia with all limb movements, although his right‐sideright side was slower than his left. Power was full in all extremities. There was no obvious tremor. Sensory: He had normal sensation to all modalities, and no extinction to double simultaneous tactile stimuli. He was able to identify objects placed in both of his hands. Romberg sign was absent. Reflexes: Reflexes were symmetric, and 2+ in the arms, 3+ at the patellae, and 2+ at the ankles. Plantar response was extensor on the right and equivocal on the left. The jaw jerk was normal. Coordination: He had a right‐sided intention tremor on finger‐nose‐finger testing. Gait: His gait was slow and cautious with short steps and decreased arm‐swing bilaterally. He was able to walk on his toes and heels. During tandem gait, he took 1 side‐step out of 10. He took 1 step backward during retropulsion testing.