August 2016 by San Francisco Marin Medical Society

SAN FRANCISCO MEDICINE J O U R NA L O F T H E S A N F R A N C I S C O M E D I CA L S O C I E T Y

NEURONS AND NEW HORIZONS WHAT’S NEW IN NEUROLOGY? Alzheimer’s

ALS Migraine Stroke Neuroethics Toxins Plus: Opioids: Pain, Addiction - and Responsibilities

SFMS General/All Member Meeting September 12 - Details on Page 30

VOL.89 NO.6 August 2016

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IN THIS ISSUE

SAN FRANCISCO MEDICINE August 2016 Volume 89, Number 6

What’s New in Neurology? FEATURE ARTICLES

MONTHLY COLUMNS

Membership Matters

President’s Message Richard Podolin, MD

A Half Century of Experience: Personal Reflections on Neurology Eric H. Denys, MD

12 Neurosurgery in San Francisco: Continuing a Legacy Mitchel S. Berger, MD

28 Medical Community News

13 Alzheimer’s and Anosognosia: Seeing the Stigma of Dementia Catherine Madison, MD

30 Upcoming Events

16 A New Era: Advances in Acute Ischemic Stroke Therapy Alan Yee, MD

Welcome SFMS New Members

19 Polysubstance Users in Treatment: Do They Differ from Alcoholics? Dieter J. Meyerhoff, Dr.rer.nat. and Thomas P. Schmidt, MS

HOUSE OFFICERS

15 Chemicals Are Hurting Brain Development Ted Schettler, MD, MPH

17 ALS: What’s New and Exciting? Robert G. Miller, MD

20 Clinical Neuroethics: A New Frontier Gil Palchik, PhD

22 Migraine: Current Management Practices Morris Levin, MD

OF INTEREST 25

Medical Student Perspective: Pharmaceutical Industry-Sponsored Meals for Physicians Are Associated with Increased Brand-Name Prescribing in Medicare Part D Colette DeJong, BA, and R. Adams Dudley, MD, MBA

27 Opinion: Please Disarm the Deranged Steve Heilig, MPH

Editorial and Advertising Offices: 2720 Taylor St, Ste 450 San Francisco, CA 94133 Phone: (415) 561-0850 Web: www.sfms.org

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REGULAR MEMBERS

MEMBERSHIP MATTERS Activities and Actions of Interest to SFMS Members

Key Changes the New Medicare Payment System Needs Physicians have submitted comments to the Centers for Medicare & Medicaid Services (CMS), detailing the changes that need to be made to the draft rule for the new Medicare payment system so it works for physicians and their patients. The AMA is urging changes across the reformed program as well as revisions that are specific to the Merit-based Incentive Payment System (MIPS) and the alternative payment model (APM) option. Three of the overarching program recommendations call on CMS to: • Create a transitional reporting period in the first year, beginning July 1, to allow sufficient time to prepare physicians and have a successful launch of the new payment system. • Provide more flexibility for solo physicians and small group practices, such as modifying the low volume threshold, lowering reporting burdens, comparing practices to their peers, and providing education, training and technical assistance to these practices. • Provide physicians with more timely and actionable feedback in a more usable and clear format. The AMA offers an action kit and other resources to help your practice get ready for the upcoming transition and learn more about the new Medicare payment system. Visit http://www. ama-assn.org/ama/pub/advocacy/topics/medicare-physicianpayment-reform.page.

SFMS Supports The Following:

Yes on 63 Gun Control Initiative - “Safety for All” would: prohibit the possession of large capacity military style magazines, treat ammunition sales like gun sales, ensure people prohibited from owning guns do not possess them, require reporting lost or stolen guns, and share data with federal system on prohibited people. For more information see: safetyforall.com Screen at 23 Campaign - Screen at 23 seeks to reveal

the undiagnosed cases of diabetes among Asian Americans. By screening Asian American patients using a body mass index of twenty-three as per the 2015 ADA recommended guideline, thousands of cases of diabetes and even more of pre-diabetes will be unmasked. For more information, visit www.screenat23.org.

Yes on 56 Tobacco Tax Initiative - The California Healthcare, Research and Prevention Tobacco Tax Act of 2016 will increase California’s cigarette tax by two dollars per pack, with an equivalent increase on products containing nicotine derived from tobacco, including e-cigarettes. Nearly one million Californians have signed a petition to get this initiative on the November ballot. For more information, visit www.savelivesca.com. 4

San Francisco vs. Big Soda - A November 2016 Ballot Measure will tax distributors of sugar sweetened beverages a penny per ounce. These revenues can be used to support health education programs and efforts to improve children’s health across San Francisco. The soda tax was placed on the ballot by Supervisor Malia Cohen with the support of Supervisors Scott Wiener, Mark Farrell and Eric Mar. For more information, visit www. sfunitedtoreducediabetes.com. SFDPH Health Advisory: FluMist® Not Recommended for 2016-2017 Influenza Vaccination

CDC’s Advisory Committee on Immunization Practices (ACIP) voted that live attenuated influenza vaccine (LAIV), also known as the “nasal spray” flu vaccine FluMist®, should not be used during the 2016-17 flu season. Data from the U.S. Influenza Vaccine Effectiveness Network on the effectiveness of LAIV among children aged two to seventeen years during 2015-16 influenza season showed just three percent efficacy in preventing laboratory-confirmed influenza disease, meaning that no protective benefit could be measured, while in comparison, IIV (injectable flu vaccines) were sixty-three percent effective. These data were supported by other non-CDC studies for 2015-16 as well as studies from the 2013-14 and 2014-15 seasons that LAIV worked less well than IIV. Resources: For local San Francisco Department of Public Health recommendations and guidance on influenza prevention, visit http://sfcdcp.org/flu.html. SFDPH Vaccine Update: http:// www.sfcdcp.org/vaxfax.html. CDC Media Statement: http://www. cdc.gov/media/releases/2016/s0622-laiv-flu.html.

SFDPH Health Advisory: Outbreak of Meningococcal Disease involving Men who Have Sex With Men in Southern California; Recommendations for San Francisco

Due to higher risk of invasive meningococcal disease (IMD) among HIV-infected persons, on 6/22/2016 the CDC’s Advisory Committee on Immunization Practices (ACIP) expanded its recommendation for immunization with quadrivalent meningococcal vaccine (MenACWY; Menactra ® or Menveo ® ) to include all HIV-positive persons age 2 months and above. In addition, on 6/24/2016 CDPH announced an outbreak of IMD in May-June 2016 in Los Angeles and Orange Counties. Among 9 reported cases, most were in men who have sex with men (MSM), and meningococcal serogroup C is the strain identified thus far. Therefore CDPH and SFDPH also recommend vaccination with MenACWY for MSM who are not HIV-infected but who have other risk factors for meningococcal disease: • Regularly have close or intimate contact with multiple partners, or who seek partners through the use of online websites or

SAN FRANCISCO MEDICINE AUGUST 2016 WWW.SFMS.ORG

digital phone applications. • Regularly visit crowded venues such as bars, parties, etc. • Smoke cigarettes, marijuana, hookahs, or illegal drugs or spend time in smoky settings. In 2015, a single case of IMD in a San Francisco MSM was reported, the only such case in the past five years. Actions Requested of SF Clinicians: 1. Routinely vaccinate all HIV-positive persons age > two months with MenACWY vaccine. 2. Recommend MenACWY vaccine for MSM and transgender persons who have sex with men, particularly those with the risk factors listed above. 3. Immediately report all San Francisco residents with suspected or confirmed meningococcal disease to the 24/7 Communicable Disease Control Unit (CDCU) of SFDPH at (415) 554-2830. After hours follow instructions to page the on-call MD. Do not wait to report until the diagnosis is cultureconfirmed; any delay in reporting compromises the ability to identify close contacts and ensure they receive timely antibiotic prophylaxis. SFDPH can assist with coordinating Polymerase Chain Reaction (PCR) testing.

Federal Medical Advocacy Summary Available

The CMA's veteran federal health policy Vice President, Elizabeth McNeil, has prepared a new summary of CMA and AMA advocacy on current issues facing medicine. It includes: • Medicare MACRA Implementing Regulation • Medicare 2017 Physician Fee Schedule Regulation + CA GPCI/Locality Update • Veteran’s Administration Advanced Practice RN Scope of Practice Expansion • Department of Education Medical Student Public Service Loan Forgiveness Program • Physician Reimbursement Rate Reduction for Medicare Part B Drugs • Opioid Update: Congressional and HHS Action • Additional Legislation For a copy or for more information, contact Steve Heilig at the SFMS, heilig@sfms.org.

CMA’s Practice Management Tip of the Month

The new provider directory accuracy law took effect July 1. Make sure your practice isn’t penalized. The new law not only requires payors to maintain accurate and current directories, but it also requires physicians to do their part in keeping the information up-to-date. Failure to comply with the new requirements may result in payment delays, removal from directories and even contract termination. For more information on physicians’ obligations under the new law, visit http://cal.md/directory-accuracy.

Calling all SFMS Members - Join us for the SFMS General/ All Member Meeting on 9/12

6:00 p.m. to 7:30 p.m., Golden Gate Yacht Club. Join SFMS at our annual General Meeting at the Commodore Room inside the Golden Gate Yacht Club. Featured speakers include Mayor Ed Lee (invited) and CMA president, Steven E. Larson, MD, MPH. Dinner will be provided. Members are welcome to stay for the board meeting immediately following the General Meeting. This is a great opportunity to meet with SFMS leadership and to learn firsthand the issues for which SFMS and CMA are advocating on behalf of physicians and their patients in San Francisco and California. RSVP Required. Please RSVP to Posi Lyon at plyon@sfms.org or (415) 561-0850, extension 260.

WWW.SFMS.ORG

August 2016 Volume 89, Number 6 Editor Gordon Fung, MD, PhD Managing Editor Steve Heilig, MPH Production Editor Amanda Denz, MA Copy Editor Amy LeBlanc, MA EDITORIAL BOARD Editor Gordon Fung, MD, PhD Obituarist Erica Goode, MD, MPH Michel Accad, MD Erica Goode, MD, MPH Stephen Askin, MD Shieva Khayam-Bashi, MD Payal Bhandari, MD Arthur Lyons, MD Toni Brayer, MD John Maa, MD Chunbo Cai, MD David Pating, MD Linda Hawes Clever, MD SFMS OFFICERS President Richard A. Podolin, MD President-Elect Man-Kit Leung, MD Secretary John Maa, MD Treasurer Kimberly L. Newell, MD Immediate Past President Roger S. Eng, MD SFMS STAFF Executive Director and CEO Mary Lou Licwinko, JD, MHSA Associate Executive Director, Public Health and Education Steve Heilig, MPH Associate Executive Director, Membership and Marketing Erin Henke Director of Administration Posi Lyon Membership Coordinator Ariel Young BOARD OF DIRECTORS Term: Jan 2016-Dec 2018 Charles E. Binkley, MD Katherine E. Herz, MD Todd A. LeVine, MD Raymond Liu, MD David R. Pating, MD Monique D. Schaulis, MD Winnie Tong, MD

Term: Jan 2014-Dec 2016 Benjamin L. Franc, MD Benjamin C.K. Lau, MD Ingrid T. Lim, MD Keith E. Loring, MD Ryan Padrez, MD Rachel H.C. Shu, MD Paul J. Turek, MD

Term: Jan 2015-Dec 2017 Steven H. Fugaro, MD Brian Grady, MD Todd A. May, MD Stephanie Oltmann, MD William T. Prey, MD Michael C. Schrader, MD Albert Y. Yu, MD

CMA Trustee Shannon Udovic-Constant, MD AMA Delegate Robert J. Margolin, MD AMA Alternate Gordon L. Fung, MD, PhD

AUGUST 2016 SAN FRANCISCO MEDICINE

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PRESIDENT’S MESSAGE Richard Podolin, MD

Opioids, Pain, Addiction, and Responsibility In 1995 Purdue Pharma introduced OxyContin, and between 1996 and 2002 funded more than 20,000 educational programs to encourage the long-term use of opioid pain relievers (OPRs) for chronic, non-cancer pain.1 As part of this campaign, the company provided financial support to the American Pain Society, the Federation of State Medical Boards, the Joint Commission, and pain-patient advocacy groups. In 1996, the President of the American Pain Society introduced the “Pain is the Fifth Vital Sign” campaign, and shortly after the Joint Commission adopted this campaign to encourage the aggressive treatment of pain, particularly with OPRs. In 2001, a jury in Alameda found an internist guilty of elder abuse and reckless negligence for not giving enough pain medication to an eighty-five-year-old man dying of lung cancer. In response, that year AB 487—requiring all physicians except pathologists and radiologists to complete twelve hours of CME related to pain management and often focused on the use of OPRs—was passed into California law. Prior to the introduction of OxyContin, physicians were generally reluctant to prescribe opioids for chronic pain because of concerns about addiction. To overcome this reluctance, physician-spokespersons for opioid manufacturers published papers and gave lectures claiming that “physical dependence” was distinct from addiction and clinically unimportant. A monograph published by the Joint Commission in 2003 stated: “Clinician’s misconceptions about pain treatments could include an exaggerated fear of addiction resulting from use of opioids; confusion about the difference between addiction, physical dependence, and tolerance; or unwarranted concerns about the potential for the side effect of respiratory depression.”2 In the United States, between 1999 and 2011 the use of hydrocodone more than doubled, oxycodone use increased nearly 500 percent, and deaths due to overdose of OPRs nearly quadrupled. This was despite the complete lack of highquality, long term clinical trials demonstrating the safety and efficacy of OPRs for chronic non-cancer pain. In 2014 opioid overdose caused over 47,000 deaths in the U.S., corresponding to approximately one death every eleven minutes. Contrary to the belief of many physicians, the majority of injuries and deaths occur in patients using opioids exactly as they are prescribed.3 Between 1997 and 2011, the number of patients seeking treatment for addiction to OPRs increased 900 percent. Four out of five current heroin users report that their use of opioids started with prescription OPRs. While physicians can take some comfort in the fact that we were not alone in creating this epidemic, our names are on the prescriptions and we must take ownership of the problem. In a recent review, Kolodny et al., offer a framework for curbWWW.SFMS.ORG

ing the prescription opioid and heroin epidemic, dividing the strategies into those aimed at primary, secondary, and tertiary prevention. Primary prevention aims to prevent new cases of opioid addiction. The strategies include limiting prescription of extended release OPRs, shortening the duration of treatment, and decreasing the quantity of opioids prescribed. Equally importantly, physicians must be given information about effective non-opioid, and non-pharmacologic strategies for managing their patients’ pain. The aim of secondary prevention is to identify and treat opioid addicted individuals before their condition causes serious complications. This can be difficult. These individuals may be unaware of, or motivated to conceal, their addiction. But when behaviors associated with addiction, such as requesting early refills or seeking prescriptions from multiple providers are discovered, too often the patients are simply turned away rather than referred for addiction treatment. Finally, once addiction is firmly established, tertiary prevention focuses on preventing serious complications such as progression to injection drug use, overdose, and death. This requires access to effective and affordable opioid addiction treatment. A bill under consideration by the California Legislature, SB 482, would require health care providers to consult the CURES database before giving an outpatient a new prescription for more than five days of a schedule II, III, or IV medication and to consult the database every four months if the medication is continued. Ten states have mandated the use of a prescription drug monitoring program, similar to the CURES database. Early reports from these states have shown a drop in opioid prescribing and a significant decline in visits to multiple providers. The CMA has opposed SB 482 over concerns about patient confidentiality and the technical readiness of the database to handle the volume of inquiries. These concerns are legitimate, but once addressed we should support this requirement. In other states, prescription monitoring databases have proven effective, but only when their use is mandated. Dr. Podolin is a cardiologist at St. Mary’s Medical Center where he has been chief of the medical staff. Connect with him via the SFMS LinkedIn Group or send him an email at podolin@sfms.org.

References 1. Kolodny, A et al. Annu. Rev. Public Health 2015. 36:559-74. 2. “Improving the Quality of Pain Management Through Measurement and Action”, JCAHO, 2003. 3. Manchikanti, L et al. Pain Physician 2012. 15:ES9-ES38. AUGUST 2016 SAN FRANCISCO MEDICINE

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Neurology

A HALF CENTURY OF EXPERIENCE Personal Reflections on Neurology Eric H. Denys, MD Fifty years ago, when I entered the field of Neurology, the specialty was considered a diagnostic one with few therapeutic options. At the same time, it was also the

last frontier to conquer offering lots of opportunities, and this appealed to me. Much has indeed changed since. I remember the day when the Computed Tomography (CT) scan penetrated the skull and showed us anatomical pictures of the brain, thus far only seen in textbooks or postmortem. Magnetic Resonance Imaging (MRI) transformed our abilities in even greater detail, and has never stopped to evolve, with MR angiography almost replacing conventional angiograms and tractography showing white matter fibers. New software programs allow us now to see the brain in action with functional imaging while performing a task such as reading and even experiencing emotions. As I was finishing my training, levodopa (L-Dopa) for Parkinson’s disease was released in 1971 with sometimes-dramatic improvement in symptoms. The word “miracle” was not an uncommon reaction by patients, and it even inspired moviemakers to produce the film “Awakenings” in 1990. There must also be something special in the air of San Francisco. We knew of the existence of bacteria and viruses, but certain chronic “degenerative” neurological diseases continued to elude us. Dr. Stanley Prusiner at UCSF began his research in 1974, and by 1982 discovered that a “naked” protein was able to transmit a chronic spongiform encephalopathy as seen in sheep scrapie (or mad cow disease in Great Britain) as well as in dementia of Creutzfeldt-Jakob Disease. He called the protein a “prion” (a creative combination of the words protein and infectious). I have never, to my dismay, encountered so many skeptics in the scientific world, yet Dr. Prusiner did not relent and was finally awarded the Nobel Prize for Physiology and Medicine in 1997. Around the same time, a human form of mad cow disease (bovine spongiform encephalopathy) was discovered in Great Britain. Could Alzheimer’s disease and Parkinson’s disease also be “prion” diseases? Meanwhile, Dr. Alan Scott at the Smith-Kettlewell Institute at California Pacific Medical Center was using dilute amounts of botulinum toxin to weaken eye muscles in animals with the aim of treating strabismus non-surgically. The first patients were treated under research protocol in 1977. I recall receiving twenty-five dollars for the required neurological exam prior to its administration in the hospital, just in case something untoward happened. The rest is history. His “Oculinum” encountered a regulatory nightmare, but Allergan was happy to produce it as Botox in 1991, once Dr. Scott’s patent had run out. The applications expanded to blepharospasm, torticollis, spasticity, chronic migraine, achalasia and others, not to mention the explosion into cosmetic enhancements. New therapeutic innovations took a while, but one of the most anticipated discoveries was certainly in multiple sclerosis, WWW.SFMS.ORG

a disease affecting many young patients. The first treatment, Betaseron, was released in the U.S. in 1993 but required a subcutaneous injection. This treatment reduced relapses by thirty-four percent and has since proven to play a crucial role in preventing later disease progression. Several other drugs followed along the same line. Currently, potent oral agents are available, dramatically improving the prospect for newly diagnosed patients and markedly reduced long-term disability. Who would have thought that a stroke could be reversed if treated in time? A colleague at my Alma Mater, the University of Leuven, Belgium, Dr. Desire Collen, discovered the action of tissue plasminogen activator (tPA), first used in myocardial infarction. Its application for stroke took a while because of the potential for brain hemorrhage, but is now part of all stroke centers. Because the treatment window of three hours is narrow, treatment is being offered in remote hospitals thanks to tele-medicine. With the help of special imaging protocols, the treatment window can even be expanded, but public awareness and access need more development. We should not forget the contribution of our neurosurgical colleagues in the area of deep brain stimulation for neurological diseases. Before L-Dopa, thalamus cauterization for Parkinson’s disease tremor had gained increasing acceptance, only to be cut short by the appearance of L-Dopa. However, none of the treatments arrested progression of the disease. The advent of Deep Brain Stimulation (DBS) opened up new and useful ways to intervene when medications are losing their effectiveness or are associated with troubling side effects such as involuntary movements. DBS is also used in other movement disorders such as essential (familial) tremor. One of the most remarkable “miracles” was seen in the treatment of a very rare genetic dystonia (DYT2). These very young patients suffer from contortions of their body, yet are able to run when a brain implanted simulator is turned on. Epilepsy is another common neurological disease with great impact on people’s life. Epilepsy has existed since ancient times and in the early nineteenth century was treated with bromides. When I started neurology, medications consisted of barbiturates, diphenylhydantoin, mesantoine, and a few others. New drugs with less side effects were eagerly awaited for the patient who did not achieve full control, and in recent decades these medicines have flooded the market. However, each new drug has brought only limited incremental improvement at high prescription cost. Therefore, if a cocktail of three drugs has failed to achieve control, it is current practice to consider in-hospital monitoring to find the location of the excitatory tissue and perform a neurosurgical ablation. Neurostimulators are also employed in other patients in order to suppress emerging epileptic excitation in the brain via implanted brain electrodes. Even the easily accessible vagus

Continued on the following page . . .

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Personal Reflections on Neurology Continued from page 9 . . . nerve in the neck has not escaped attention for interference with brain activity via stimulation. Some neurological diseases are relatively rare compared to others, but all patients yearn for relief, especially if the ability to move is affected. Myasthenia gravis was supposedly an easy to understand disease, as the neuromuscular synapse had been studied for years by neurophysiologists and was always the stepping-stone for unraveling the mysteries of the synapses in the central nervous system. I was actively studying the neuromuscular synapse at Stanford when the accepted wisdom considered myasthenia gravis a presynaptic disease. However, in 1973, Patrick and Lindstrom, researchers at the Salk Institute, working with post-synaptic receptors of an electric eel, almost accidentally created a rabbit model of myasthenia gravis, demonstrating the presence of a circulating antibody and its attachment to the post synaptic membrane. The tables turned, and by 1976, I was fortunate to be part of the San Francisco team that performed, for the first time, successful plasma exchanges, washing out the antibodies in patients with myasthenia gravis, providing a rescue treatment for severely affected patients. Early in my career, I spent many years in clinical care and research on ALS. It was one disease where I thought a solution would be found because we were only dealing with one type of cell, the motor neuron. How disappointed we have been. Hope has reigned eternal and persistence in searching for a cure has not failed. But, alas, we continue to be on the cusp of a new discovery every day, which, I am sure, will eventually come to fruition. While neurology may not be well understood by the layperson, Alzheimer’s disease has certainly captured center stage. Increasing longevity and other factors are raising the number of people at risk, causing a tremendous burden for families and society. A massive research attack is underway, in part fueled by the prospect of huge pharmaceutical profit, but will we be able to bear the cost? Let’s not forget more common afflictions like migraine, a familial disorder responsible for a major loss in productivity and personal suffering. No specific treatments existed when I began neurology. Then came the triptans in 1991, first injectable and soon by mouth, as well as new preventive medications for recalcitrant cases. The list of innovations goes on, with genetic elucidation of familial and genetic diseases, gene therapy, bone marrow transplantation and subjects covered in more detail elsewhere in this issue. Neurology is no longer the last frontier but the new and exciting frontier drawing a wave of young scientists into the field. It is now “the place to be”. Dr. Denys trained in neurology at Leuven, Stanford University, and the Mayo Clinic. He was active in San Francisco for thirty-eight years at CPMC, Associate Clinical Professor of Neurology at UCSF, the recipient of the Elliott Royer Award in Neurology and the Charlotte Baer Award for excellence in teaching from the School of Medicine at UCSF. He is the Past President of the Association of the Clinical Faculty at UCSF and of the San Francisco Neurological Society. He has been a lifetime member of the San Francisco Medical Society. Dr. Denys is currently retired. WWW.SFMS.ORG

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Nonrandomized Intervention Study of Naloxone Coprescription for Primary Care Patients Receiving Long-Term Opioid Therapy for Pain Phillip O. Coffin, MD, et al., San Francisco. Ann Intern Med. Published online 28 June 2016 doi:10.7326/M15-277 Background: Unintentional overdose involving opioid analgesics is a leading cause of injury-related death in the United States. Objective: To evaluate the feasibility and effect of implementing naloxone prescription to patients prescribed opioids for chronic pain. Setting: six safety-net primary care clinics in San Francisco, California. Intervention: Providers and clinic staff were trained and S.F. Medicine supported in naloxone prescribing. Results: 38.2% of 1985 patients receiving long-term opi02-20-14 oids were prescribed naloxone. Patients who received a naloxone prescription had 47% fewer opioid-related ED visits per month in the six months after receipt of the prescription and 63% fewer visits after one year compared with patients who did not receive naloxone. There was no net change over time in opioid dose among those who received naloxone and those who did not. Conclusion: Naloxone can be coprescribed to primary care patients prescribed opioids for pain. When advised to offer naloxone to all patients receiving opioids, providers may prioritize those with established risk factors. Providing naloxone in primary care settings may have ancillary benefits, such as reducing opioid-related adverse events. AUGUST 2016 SAN FRANCISCO MEDICINE

Neurology

NEUROSURGERY IN SAN FRANCISCO Continuing a Legacy Mitchel S. Berger, MD The history of neurosurgery in Northern California goes back over one hundred years, and San Francisco in particular has been a major hub of innovation. In 1912, Howard Naffziger, MD, began performing the first neurosurgical procedures at the University of California, San Francisco (UCSF). He also established the first surgical residency training program in the United States, which continues to attract top talent and has been rated the best neurosurgical residency program in the nation. Neurosurgeons from all over the world travel to UCSF to observe our surgeons in the operating room and take home skills to advance their own practices. Most of our faculty are involved with publishing guidelines for treatment in their respective subspecialties as members of leading professional organizations like the American Association of Neurological Surgeons and Congress of Neurological Surgeons. Read on to discover the latest advances in neurosurgery and how UCSF continues to lead the world in expertise and innovation.

Image-Guided Therapy

In the last twenty-five years we have seen major advances in the operating room that have made neurosurgery more accurate and safe, but perhaps none have been more impactful than those in imaging. Intraoperative Magnetic Resonance Imaging (MRI) was introduced in the early 1990s, followed by sophisticated surgical navigation software that guides us around critical structures of the brain. Today and into the future, further integration of advanced imaging techniques with therapeutic tools and drug delivery will improve treatment across the spectrum of neurosurgical disorders. An interventional MRI (iMRI) platform called ClearPoint, developed by the surgical movement disorders group at UCSF in 2008, allows image-guided placement of electrodes for deep brain stimulation (DBS). Patients can now be under general anesthesia during the procedure instead of having a traditional awake surgery, which is less stressful for the patient, allows the most accurate placement of DBS leads, and shortens surgery time. ClearPoint is now used at select medical centers across the country and can be especially useful for treating children who cannot tolerate awake procedures. UCSF is home to one of the nation’s most experienced surgical teams using DBS to treat pediatric dystonia and other movement disorders—approximately sixty-five cases have been performed, and it may provide life-long control for some symptoms. iMRI is also being used for real-time monitoring of drug and gene therapy infusions. Previously, direct infusion to bypass the blood-brain barrier was essentially a blind process and there was no way to know how much of the therapeutic agent reached its 12

target. We are currently using real-time imaging in two clinical trials: one studying convection-enhanced delivery (CED) of a liposome-encapsulated chemotherapeutic drug for brain tumors and the other studying CED of a gene therapy for Parkinson’s disease. These and other studies that incorporate surgery are part of a large clinical trials portfolio (of over forty trials) run by physicians with extensive experience in translational research, the importance of which cannot be overstated. For chronic and severe pain, MRI-compatible spinal cord stimulation devices that incorporate wireless technology to adjust stimulation settings are simplifying these procedures and reducing potential side effects. In functional neurosurgery, implantable devices with a brain recording capability also have a wireless component for downloading information on brain activity, and can automatically program their stimulation settings based on abnormal activity. For movement disorders like Parkinson’s disease, this will essentially create a closed-loop stimulation system similar to pacemakers for the heart that detect arrhythmias. Implanted stimulation devices are also being examined for the treatment of psychiatric disorders such as obsessive-compulsive disorder and depression, based on the premise that they result from disruptions in neural networks that can be automatically detected.

Multidisciplinary Teams

Another key ingredient to the success of neurosurgery at UCSF is the multidisciplinary collaboration we enjoy as members of a large academic center, and the knowledge brought by our colleagues from other fields has enabled us to form centers of excellence for many complex diseases. The Pediatric Brain Center (PBC), for example, contains a depth and breadth of expertise that is unmatched. To provide comprehensive care in one place, there are specialized clinics for the entire spectrum of central nervous system disorders, including epilepsy, movement disorders, brain and spinal cord tumors, hydrocephalus, craniofacial abnormalities, cerebrovascular disorders and stroke, spasticity, complex spine disorders, and others. The PBC is based at a new state-of-the-art hospital at our Mission Bay Campus, which is outfitted with intraoperative MRI to give our surgeons instant feedback during their procedures. Outside the operating room, the UCSF Sports Concussion Program is the region’s premier center for evaluating and treating head injuries in young athletes. The team includes experts from specialties such as sports medicine, physical medicine and rehabilitation, neuropsychology, neuroradiology, neurology and neurosurgery. We are able to diagnose and manage all types of sports concussions and help athletes safely return to school and sports.

Continued on page 14 . . .

SAN FRANCISCO MEDICINE AUGUST 2016 WWW.SFMS.ORG

Neurology

ALZHEIMER’S AND ANOSOGNOSIA Seeing the Stigma of Dementia Catherine Madison, MD The road appears misty through unfamiliar turns and my eyes struggle to clearly see Hopes and dreams changed over so many years As now the bell tolls for Thee. . .

The practice of medicine is changing so quickly that those of us with decades under our belt are struggling to maintain balance. Through our own experiences, we are

increasingly familiar with the complaint lists of our patients. Clinicians have become quietly subservient to complicated electronic health records (EHR), and our ability to navigate complicated tasks wanes with aging. The environmental shift to EHR can disrupt one’s ability to fully interact with a patient and sift through their comments to detect underlying questions and observe changes. The exchange is further complicated when patients themselves are not aware of brain deterioration that may cloud their presentation of information. Anosognosia is a deficit of self-awareness frequently associated with right hemisphere injury and present in about ten percent of stroke patients. It is recognized in dementias such as Alzheimer’s disease, but impact on decision-making and daily life has not been well studied. Measuring regional brain metabolism with 18-Fluoro-deoxyglucose positron emission tomography (FDG PET) scans has demonstrated hypometabolism in the orbital frontal and posterior cingulate cortices. These findings suggest that the lack of awareness of deficits in Alzheimer’s disease stems from a disruption in communication within and between self-related and memory-related brain networks. While a left hemi-paresis is obvious to a physician, cognitive impairment may not be. And why would we want to search for a condition that we cannot cure? The statistics of Alzheimer’s Disease are sobering yet dull. The grey tsunami is an accepted fact that we are quick to acknowledge—and then move on. Quite understandable, considering that between 2002-2012 Alzheimer’s Disease drug trials claimed the highest failure rates of any disease area—ninety-nine point six percent compared with eighty-one percent for cancer.1 Providers must personally tackle the stigma surrounding cognitive impairment and diagnose earlier to enable treatment trials to be more effective. The public generally recognizes that a deficit in memory is frequently seen in dementia, and this might prompt a query to their provider. But other important cognitive domains are also compromised. In fact, one does not meet criteria for dementia without documented impairment of cognition in two of the following domains: • The ability to acquire and remember new information • Impaired reasoning and handling of complex tasks or poor judgment WWW.SFMS.ORG

• Impaired visual spatial abilities • Impaired language function • Changes in personality, behavior or comportment.

These deficits need to represent a decline from prior level of function, interfere with usual daily activities, and not be present in the setting of delirium or major psychiatric disorder. Average perperson Medicare spending for those with Alzheimer’s and other dementias is three times higher than average per-person spending across all seniors. Beyond these costs to the medical system, if patients are not cognizant of their intellectual limitations, their ability to effectively make decisions may be compromised. This inadvertently places clinicians and/or family members in a position where they could be inserting their own judgment. Whether providers can distinguish between views of a patient’s former competent self and incompetent current self has been debated with no clear directions.2 Prospection is the ability to mentally simulate potential events at a future point in time. This requires one to retrieve autobiographical details from their past to consider scenarios that can evolve based on their medical condition. This is especially pertinent for

Continued on the following page . . .

AUGUST 2016 SAN FRANCISCO MEDICINE

Alzheimer’s and Anosognosia Continued from page 13 . . . individuals with cognitive impairment who will need more assistance as their limitations increase. Careful documentation of what medical interventions an individual does—and does not—want implemented is an important process that providers should facilitate with platforms such as the prepareforyourcare.org site offers. For individuals with a dementia, cognitive weakness can be further muddled by anosognosia with altered prospection. Research into impairment of prospection in dementia syndromes is limited, but a review of the literature up to October 2014 collectively showed marked impairments in the ability to simulate personally relevant events at a future point in time.3 The impediment of anosognosia is severe in almost one third of patients newly diagnosed with Alzheimer’s disease and associated with advanced age, lower educational level and more neuropsychiatric symptoms.4 Not surprisingly, this then leads to increased burden and distress of care partners. With someone developing Alzheimer’s Disease every sixty-six seconds, prevalence of this conundrum is only proliferating. But with shrinking schedules and expanding distractions, a clinician’s ability to consider subclinical impairment is reduced. It is also difficult for providers to question the patient’s self report as this can threaten a trusting relationship. Perhaps with our own aging, the possibility itself is threatening. The lack of prospection and prevalence of anosognosia make starting this conversation more difficult, but we must be the catalyst to break through the stigma of dementia. For if we continue to neglect its existence and our own risk—it may become our reality. Catherine Madison, MD, Medical Director of the Ray Dolby Brain Health Center, is a neurologist and memory loss specialist. She completed her medical School training at St. Louis University in Missouri and her neurology residency at George Washington University Medical Center in Washington has been practicing at CPMC since 2001. References available at www.sfms.org.

Neurosurgery in San Francisco Continued from page 12 . . .

Minimally Invasive Treatment The Minimally Invasive Skull Base Surgery Center at UCSF is a collaboration with our Otolaryngology–Head and Neck Surgery colleagues. As with other medical fields, minimally invasive procedures have been a major trend in all subspecialties of neurosurgery. With surgery for brain tumors, minimally invasive techniques using the endoscope are allowing us to use narrow corridors such as the nasal passages to access tumors extending into the ventricular system or along the anterior skull base—sites that were either inaccessible or only accessible through invasive craniotomies just a decade ago. It is also being increasingly used throughout the country for pituitary surgery; use of the endoscope has been shown to maximize resection while reducing trauma to the normal gland, improving postoperative endocrine 14

function in these patients. Minimally invasive techniques for conditions of the spine have been nothing short of revolutionary, and many of them have been pioneered at UCSF. There are a shrinking number of procedures that cannot be performed through smaller incisions and retractable tubes, minimizing blood loss and postoperative pain and speeding recovery times. Spinal stenosis, spinal tumors, and spinal deformity can all be tackled with minimally invasive methods. We have recently opened an outpatient spine service at our Mt. Zion campus where most patients who come in for microdiscectomies, laminectomies, and foraminotomies can go home the same day. Our pediatric and adult epilepsy surgeons have begun using stereoelectroencephalography (stereoEEG) to diagnose seizures and laser ablation to target epileptogenic zones, both of which involve very small incisions. This has begun to transform the field for patients who have been reluctant to undergo traditional brain surgeries. I hope that this will encourage more patients to be evaluated for surgery, as there is clear evidence in the literature that there are many patients who could be permanently free of seizures but who instead continue to take life-long medication and cannot always fully participate in activities of daily living.

Specialized Regional Care

Several studies have recognized that advanced minimally invasive techniques for both brain and spine have a steep learning curve and are best accomplished at centers of excellence that perform these operations frequently and can achieve reduced length of stay and reduced morbidity. For vascular neurosurgery in particular, specialized care is becoming increasingly necessary. In the last decade, endovascular devices and techniques have evolved to treat an increasing number of aneurysms and arteriovenous malformations. The Pipeline flow diverter is an example of a new device that has had such an impact. However, these devices cannot be used to successfully treat every case, and at UCSF we have maintained a commitment to excellence in open surgery while other centers are moving away from this important branch of neurosurgery. Overall, this is a very exciting time to be in the field of neurosurgery as we are beginning to see breakthroughs in the treatment paradigms for many disorders that have long had limited treatment options or were considered untreatable. The nature of many central nervous system diseases makes them difficult to treat with systemic drug therapy and other conservative options; therefore, I think surgery will remain a mainstay of treatment delivery. Mitchel S. Berger, MD, FACS, FAANS, is the Berthold and Belle N. Guggenhime Professor and Chair of the Department of Neurological Surgery at the University of California, San Francisco (UCSF) and Director of UCSF’s Brain Tumor Center. Dr. Berger is a pioneer of intraoperative brain mapping—a technique used to avoid functional areas of the brain during surgical resection of a tumor. His work has enabled surgeons to perform more extensive resection of tumor with less chance of producing sensorimotor or language deficit. During his career, Dr. Berger has served as President of the American Association of Neurological Surgeons (AANS) and been a director of the American Board of Neurological Surgery and a member of the Board of Directors of the AANS. Most recently, he was selected by Vice President Joe Biden to serve as one of twenty-two members of a Blue Ribbon Panel for the National Cancer Moonshot Initiative.

SAN FRANCISCO MEDICINE AUGUST 2016 WWW.SFMS.ORG

Neurology

CHEMICALS ARE HURTING BRAIN DEVELOPMENT Ted Schettler, MD, MPH An unprecedented alliance of leading scientists, health professionals, and children’s health advocates has come together to publish a consensus state-

ment concluding that scientific evidence supports a causal link between exposures to toxic chemicals in food, air and everyday products and children’s risks for neurodevelopmental disorders. The alliance, known as Project TENDR, is calling for immediate action to significantly reduce exposures to toxic chemicals to protect brain development for today’s and tomorrow’s children. Neurodevelopmental disorders include intellectual disability, autism spectrum disorder, attention deficits, hyperactivity, other maladaptive behaviors, and learning disabilities. The consensus statement is available on the Project TENDR website: http://projecttendr.com/consensus-statement. The alliance concentrated primarily on examples of chemicals and pollutants for which the causal contribution to children’s learning, intellectual and behavioral impairment is clear and unequivocal. They include: • Organophosphate (OP) pesticides • Polybrominated diphenyl ether (PBDE) flame retardants • Combustion-related air pollutants • Lead • Mercury • Polychlorinated Biphenyls (PCBs) The effort was led by TENDR co-directors Irva Hertz-Picciotto, environmental epidemiologist at UC Davis, and Maureen Swanson, with the Learning Disabilities Association of America. They assembled a team of scientists who extensively scoured the published literature to identify candidate chemicals and pollutants for which the evidence of neurodevelopmental impacts is strongest. The broader alliance then developed the consensus statement over more than a year of intensive work. This initial effort was not intended to address a longer list of candidate chemicals for which existing evidence is highly concerning but not yet firmly established. Beyond that the alliance recognizes that a list of chemicals and pollutants known or suspected to have adverse neurodevelopmental impacts is probably the tip of an iceberg. Thousands of chemicals to which people are exposed have not undergone any evaluation of their impacts on the developing brain. The statement underscores the urgent need for a better approach to developing and accessing scientific evidence and using it to make decisions. According to Irva Hertz-Picciotto, “This is truly an historic agreement. Ten years ago, this consensus wouldn’t have been possible, but the scientific research is now abundantly clear: toxic chemicals are harming our children’s brain development. As a society, we can eliminate or significantly lower these toxic chemical exposures and address inadequate regulatory systems WWW.SFMS.ORG

that have allowed their proliferation. These steps can, in turn, reduce high rates of neurodevelopmental disorders.” Maureen Swanson added, “This national problem is so pressing that the TENDR scientists and health professionals will continue their collaboration to develop and issue recommendations aimed at significantly reducing exposures to toxic chemicals that are harming children’s brain development. Calling for further study is no longer a sufficient response to this threat.” See Project TENDR’s website for recommendations for steps that individuals can take to protect themselves and their families from the worst of these exposures. Ted Schettler, MD, MPH, is Science Director of the Collaborative on Health and the Environment (healthandenvironment.org), an international network founded at the SFMS in 2012.

Organizations Endorsing or Supporting the TENDR Consensus Statement

American College of Obstetricians and Gynecologists Alliance of Nurses for Healthy Environments American Nurses Association Child Neurology Society Developmental Neurotoxicology Society Endocrine Society International Neurotoxicology Association International Society for Children’s Health and the Environment International Society for Environmental Epidemiology National Association of Pediatric Nurse Practitioners National Council of Asian Pacific Islander Physicians National Hispanic Medical Association National Medical Association Physicians for Social Responsibility

AUGUST 2016 SAN FRANCISCO MEDICINE

Neurology

A NEW ERA Advances in Acute Ischemic Stroke Therapy Alan Yee, MD Stroke is a leading cause of disability in the United States; a devastating disease some fear greater than death.1,2 For-

tunately, recent advancements in acute neurovascular imaging and endovascular stroke care have revolutionized the therapeutic options historically limited by a time-sensitive impasse. In 1996, the U.S. Food and Drug Administration approved the first effective treatment for acute ischemic stroke when administered within three hours from symptom onset.3 Recombinant tissue plasminogen activator (rtPA), an intravenous (IV) fibrinolytic agent, improves the likelihood for neurologic recovery and is considered first-line treatment.3,4 Yet, only a minority of candidates receive thrombolytic therapy despite the beneficial effects when administered up to four and a half hours from time last well.5,6,7 Delayed time to presentation, overly conservative exclusionary treatment criteria, and concerns about the risk of cerebral hemorrhage are among numerous factors leading to this low utilization.8 Compounding this issue is that those with the most severe symptoms are also most likely to possess a large artery occlusion that in turn is least likely to respond to IV rtPA alone. Such major large artery occlusions occur in one-third to one-half of all acute ischemic strokes cases.9 These patients are frequently left with devastating neurologic disability and remain at high risk for morbidity and death.10 These facts beg the question: could expeditious endovascular recanalization of an otherwise disabling cerebral arterial thrombosis detected by modern advanced neuroimaging minimize the severity of stroke burden? Early endovascular stroke trials tested the feasibility and effectiveness of local intra-arterial (IA) fibrinolytic administration either at the face of the thrombotic occlusion or within its proximal segment.11 Unfortunately, recanalization rates were not substantially better and overall benefit not realized.11,12 Fortunately, despite humbling results from early catheter-based trials, persistent research and technological advances gave rise to a new generation of endovascular thrombectomy devices.17,18 These devices, called stent retrievers, trap the thrombus between the arterial wall and a metal stent allowing simultaneous withdrawal of both the stent system and clot. In 2015, five landmark endovascular trials defined a new gold standard for acute ischemic stroke: in patients who present with disabling stroke symptoms from a proximal anterior circulation occlusion, mechanical thrombectomy with a retrievable stent definitively improves neurologic functional outcome.19-23 Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN), Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE), Extending the Time for Thrombolysis in Emergency Neurological Deficits–Intra-arterial (EXTEND-IA), Solitaire with the Intention 16

for Thrombectomy as Primary Endovascular Treatment (SWIFT PRIME), and Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset (REVASCAT) consistently showed that endovascular therapy was safe and effective with or without prior IV rtPA use at least six hours and as long as twelve hours after symptom onset.16,19-23 Many but not all of these trials relied on advanced neuroimaging to identify appropriate targets for treatment. The optimal imaging parameters for treatment remain unclear and are an active area of investigation. The ideal imaging modality should identify the patients at greatest risk for severe ischemic injury. It should precisely localize the arterial occlusion as well as establish the presence or absence of collateral circulation. Importantly, the test should differentiate cerebral ischemic tissue at risk (“penumbra”) from that which has infarcted. At the California Pacific Medical Center, we have been long time advocates of this approach, and routinely perform complex cerebral imaging for all patients with suspected ischemic stroke. In our experience, favorable functional outcomes are still attainable even for those who present many hours after symptom onset. We are currently participating in the DAWN (Diffusion Weighted Imaging (DWI) or Computerized Tomography Perfusion (CTP) Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention) clinical trial, which is enrolling patients up to twenty-four hours after time last well and selecting patients for treatment based upon neuroimaging identification of viable brain tissue. We welcome colleagues with appropriate patients to participate in this pioneering study.24 In summary, acute ischemic stroke is now an eminently treatable disease, and with a realistic chance of a good outcome. Timely reperfusion remains the primary goal, and appropriate imaging selection has broadened our understanding of stroke pathophysiology. Many patients who previously would be left in a severe disabling condition now have a chance to return to functional independence. These new techniques have left us with the long-awaited evidence that endovascular therapy definitively improves outcome in patients with acute ischemic stroke. Dr. Yee is a Stroke and Critical Care Neurologist at California Pacific Medical Center and Clinical Assistant Professor of Neurology at Geisel School of Medicine at Dartmouth. He directs the CPMC Neurosciences Education Program and is the Medical Director for the Clinical Neuroethics Fellowship in the Program in Medicine and Human Values. A full list of references is available at www.sfms.org.

SAN FRANCISCO MEDICINE AUGUST 2016 WWW.SFMS.ORG

Neurology

ALS What’s New and Exciting? Robert G. Miller, MD Amyotrophic Lateral Sclerosis (ALS), or Lou Gehrig’s disease, is a lethal neurodegenerative disease characterized by motor neuron cell death and progressive paralysis. Most patients die in less than three to

five years of respiratory failure. Although considered rare (one and a half new cases per hundred thousand population), the lifetime risk of developing ALS is one in three hundred, comparable to the risk of multiple sclerosis. Only one drug, riluzole, has been approved for disease modifying therapy enhancing survival to a modest degree.1 In the last few years, there have been significant advances. New genes have been discovered at an exponentially increasing rate. It is now likely on the basis of twin studies that ALS is sixty percent genetic and forty percent due to environmental factors. The environmental factors are still poorly understood, which is true of Alzheimer's and Parkinson's also, but new technology is opening up the genetics of ALS in an unprecedented fashion. The most exciting genetic breakthrough was the recent elucidation of the expansion mutation in the C9orf72 gene responsible for up to forty percent of familial and up to ten percent of sporadic ALS, and also for cases of ALS linked to Frontotemporal dementia.2 The mechanisms of toxicity of the mutation upon motor neurons are unfolding, and a new animal model has been described which is much needed to move the field forward. Moreover, it appears likely that antisense oligonucleotides will be a potential therapy for patients with this mutation. Studies of the first known ALS mutation, SOD1, in mutant mice and in humans with this mutation, also appear to show benefit from knocking out the protein product of the mutation with antisense oligonucleotides. Phase 2 trials are underway directed against the SOD1 mutation. These new approaches to treatment, which involve newly identified targets that appear responsive to therapy, is indeed a welcome step forward in the battle against ALS. Neuroinflammation is emerging as an important component of ALS, as well as Alzheimer’s and Parkinson's. Recently, we completed a clinical trial of a novel anti-inflammatory agent that blocks monocyte and macrophage activation.3 A subset of patients in the study who had evidence of systemic inflammation showed no progression of ALS during six months of treatment, a finding not previously observed in any ALS trial. A larger follow-up study is underway to seek to confirm these findings, and other trials are beginning to focus on novel anti-inflammatory agents. Oxidative stress also appears to be important in ALS and a new antioxidant, edaravone, has been licensed in Japan on the basis of slowing the functional decline of ALS with Food and Drug Administration review pending for approval in the U.S.4 A very innovative approach to treating ALS is being pioWWW.SFMS.ORG

neered by a biotech company in south San Francisco, Cytokinetics. This agent increases force production in fast skeletal muscle by increasing the sensitivity to calcium in the troponin complex. A large trial recently showed significant slowing of the decline in respiratory and limb muscle function in patients with ALS.5 The pivotal trial is underway, and results eagerly awaited. There has also been progress in symptomatic therapy for ALS. Treatment of pseudobulbar affect, which consists of episodic outbursts of emotion in patients with pseudobulbar palsy, is now treatable with dextromethorphan and low dose quinidine. The drug combination, Nuedexta, was approved by the FDA on the basis of two controlled trials showing more than a ninety percent reduction in emotional outbursts.6 Effective treatment for respiratory insufficiency with noninvasive ventilation at night extends life, improves sleep, quality of life and alleviates dyspnea. Dysphagia and weight loss shorten life for these patients, but a percutaneous gastrostomy (PEG) stabilizes weight and improves nutrition. In specialized multidisciplinary clinics, patients with ALS receive comprehensive care from a neurologist, respiratory physician, gastroenterologist, rehabilitation medicine physician, social worker, occupational therapist, speech therapist, respiratory therapist, specialized nurse case manager, physical therapist, dietitian, psychologist, and palliative care expert.7 The whole spectrum of care is available from a team of experts, with one stop shopping. Specialized clinics coordinate care and interface with a primary care physician, local neurologist and communitybased services. Three studies show that multidisciplinary clinics specializing in ALS care, like the one we have at the Forbes Norris Center, are effective in several ways: increased use of adaptive equipment; increased utilization of riluzole, PEG, and noninvasive ventilation; improved quality of life; and lengthened survival.8 Thus, while we await more definitive disease modifying therapy for ALS, we are able to utilize a variety of treatments to ease the burden of this terrible disease. Robert G. Miller, MD, is director of the Forbes Norris ALS Treatment and Research Center at California Pacific Medical Center, San Francisco. A full list of references is available at www.sfms.org.

AUGUST 2016 SAN FRANCISCO MEDICINE

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Neurology

POLYSUBSTANCE USERS IN TREATMENT Do They Differ from Alcoholics? Dieter J. Meyerhoff, Dr.rer.nat. and Thomas P. Schmidt, MS A large body of research has shown that both treatment-seeking individuals with an alcohol use disorder (AUD) and treatment-seeking individuals with a stimulant

use disorder exhibit rather wide ranges of neurocognitive deficits and inhibitory control deficits (e.g., impulsivity, decision-making, risk-taking). Most often observed are deficits in the neurocognitive domains of executive function, learning and memory, and processing speed. Todayâ&#x20AC;&#x2122;s treatment centers, however, are full of clients who are not simply dependent on a single substance, but who abuse more than a single substance at a time (most often alcohol, psychostimulants, cigarettes, and/or marijuana), representing the exceedingly large fraction of polysubstance users (PSU) among treatment seekers. Little is known about the degree to which their neurocircuitry or their purported cognitive and inhibitory control deficits might differ from those of monosubstance users. Any such differences are not a question of pure academic interest or theoretical value, but they are of practical value in the treatment setting: neurocognitive and inhibitory control deficits may negatively impact activities of daily living (such as managing finances and holding employment) and they have been shown to relate to a greater risk of relapse and poor treatment adherence, thus impeding successful and meaningful recovery after substance use. A better understanding of potential neuropsychological differences between distinct subgroups of substance users is important for designing appropriate treatment interventions that align with the specific learning capabilities and behavioral deficits of such subgroups. We recently published a paper in The Journal of Clinical and Experimental Neuropsychology that describes how groups of PSU and AUD differ on neurocognitive functioning and inhibitory control at one month of abstinence.1 In that paper, we also demonstrate that PSU show dramatic improvements in neurocognitive function and inhibitory control between one and four months of abstinence, despite their many years of chronic substance abuse. This is a brief synopsis of our main findings and their implications for treatment approaches. Not unexpectedly, the one-month-abstinent PSU as a group (n = 36) showed a wide range of deficits across several cognitive domains when compared to age-matched norms. In all domains, the PSU showed numerically more severe deficits than the ageequivalent one-month-abstinent AUD (n = 69). PSU performed especially worse than AUD on measures assessing auditoryverbal memory and learning as well as general and premorbid verbal intelligence. These differences suggest that PSU may have a diminished capacity (compared to AUD) of learning, memorizing, and integrating new skills presented in clinical settings, where psychoeducational material is typically presented verbally. In addition, our analyses showed that PSU differed from AUD WWW.SFMS.ORG

on several measures of inhibitory control: PSU exhibited worse decision-making and higher self-reported impulsivity; those PSU who smoked cigarettes showed higher motor impulsivity than the smoking and nonsmoking AUD; and being on a prescribed psychoactive medication at the time of study (primarily an SSRI or benzodiazepine) significantly predicted higher impulsivity within the PSU group only. These inhibitory control findings at one month of sustained abstinence suggest that PSU as a group are at greater risk for making poorer decisions and acting impulsively than AUD, behaviors that place them at a greater relapse risk than AUD during early recovery. Collectively, these neuropsychological group differences may explain why relapse rates are often higher in PSU than AUD. Treatment plans that are dependent on psychoeducation to reduce or eliminate chronic substance use should consider that PSU may be less able than AUD to learn new skills, interpret information accurately, and remediate maladaptive behavioral patterns that are impeding a successful course of treatment. We and others showed previously that AUD successfully recover from most cognitive deficits over a few months of abstinence. A secondary aim of our study was therefore to determine if the neuropsychological deficits in PSU recover with sustained abstinence from all substances (except tobacco). Thus, we re-studied those PSU who remained abstinent for at least three months after their initial one-month-assessment (n = 17, forty-seven percent of initial sample). During these four months, the research participants were engaged in outpatient treatment programs and abstinence was assessed with self-report and confirmed via medical chart review. We observed statistically significant improvements across several neurocognitive functions that are important for treatment adherence and for a reduced relapse risk, including improvements in executive functioning, cognitive efficiency, working memory, and reductions in impulsivity. Learning and memory remained deficient after four months of abstinence. The improvements we observed within this PSU group during abstinence, together with several positive correlations between substance use quantities and cognitive deficits, suggest that specific deficits are to some extent a consequence of long-term chronic substance use, but also that there is the potential for remediation and dramatic resolution of initial deficits with prolonged abstinence. In other words, the neuropsychological deficits observed in PSU during early abstinence are not all traits (inherited) that remain relatively unchanged with time, but there rather is clear evidence for successful neuropsychological recovery in long-term addicted individuals. In order to try to identify potential predictors of relapse, we assessed for neuropsychological and behavioral differences at one month of abstinence between the seventeen PSU individuals who

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AUGUST 2016 SAN FRANCISCO MEDICINE

Neurology

CLINICAL NEUROETHICS A New Frontier Gil Palchik, PhD Although ethical issues at the intersection of clinical medicine and the brain have a long history stretching back for centuries, the field of Neuroethics as

a separate discipline has only been recognized for little more than a decade. Following the landmark 2002 conference describing the emerging discipline of Neuroethics, neuroscientist and philosopher Adina Roskies divided this neologism into two useful components: “ethics of neuroscience” and “the neuroscience of ethics.”1,2 The ethics of neuroscience includes the scope of clinical bioethics, insofar as it deals with ethical issues such as how brain disorders can affect a person’s decision-making and consent, clinical trial design, cloning, and privacy. The second major subdivision, the neuroscience of ethics, is more conceptual and deals with how findings from neuroscientific research inform our notions of morality and issues germane to philosophy such as concepts of the self, free-will, intentionality, and the nature of consciousness. A common thread among neuroethicists is defining neuroethics and outlining which topics the field should address. Many of the issues posited by efforts to define what’s “hot” in neuroethics, either philosophical or scientific, are often so conceptual that they become irrelevant to clinicians and thus fail to be incorporated into their practice. The literature contains a plethora of work pertaining to the neuroscience of ethics, but much less addressing the ethics of neuroscience as it pertains to the clinical setting. The view presented here is that rather than a primarily theoretical discipline, to be of practical use, neuroethics should be able to be incorporated into the physician’s toolbox and applicable at the bedside. For that reason, I will present below what I believe are some key neuroethical issues that are relevant to physicians. A detailed analysis of the ethical issues presented is beyond the scope of this short article and will not be addressed here.3 Altering brain function, either via pharmacological or prosthetic means, is already routinely implemented in a clinical setting. Most physicians would not object to prescribing methylphenidate (Ritalin®) to individuals with attention deficit/hyperactivity disorder (ADHD), nor would they have qualms about placing a cochlear implant for patients who are deaf or hard of hearing. These treatments are common and socially accepted examples of using psychotropic drugs for brain enhancement and the application of Brain-Computer Interfaces (BCI). However, even within these benign examples, ethical issues can arise pertaining to both treatments. The topic of enhancement—using drugs to improve cognitive function (nootropic drugs)—is much debated in neuroethics today, due in part, to the ethical issues when an individual uses nootropics 20

without medical indication. Neuroenhancement is not limited to theoretical speculation, and in the clinic physicians are increasingly being faced with requests for the eugeroic modafinil (Provigil®) or amphetamines from non-narcoleptic patients seeking improved alertness or memory. It is important that beyond medical safety considerations, clinicians inform themselves of the benefits and burdens associated with such therapies as well as the ethical implications of their decisions before making a recommendation. Issues stretching from the effects of social pressure as a motive, to improving and maintaining certain mental states, to the long term effects of altering neurotransmitter levels in a healthy brain are essential in guiding a physician’s course of action. As mentioned above, another area receiving considerable attention involves BCIs. Physicians should be aware of the neuroethical implications of interfacing brains and machines, even when it comes to the treatment of severely paralyzed patients. For one, the definition of a person’s condition as a “disability” is by far not absolute, and a drive towards “normalization” might interfere with cultural and subcultural notions of neurodiversity. The fact that lack of hearing is not seen as a debilitating condition among the deaf and hard of hearing community is a good example. Additionally, physicians should be aware of the potential benefits of restoring sensorimotor function against the potential harm caused by the physical implantation of a device, such as with cochlear implants or deep brain stimulation (DBS). The consequences of providing information to the brain, either de novo or after a hiatus in communication might yield unprecedented consequences; for example, the efficacy of DBS in treating pathologies may often result in psychological and social maladaptation in ways unanticipated by patient and families. While neuroenhancement using engineered prostheses for the purpose of sensory augmentation, or improving cognition/memory is still at its infancy, it is nevertheless already being implemented. With the advance of medicine and research, the use of these tools will become increasingly relevant or even acceptable, and there will be an ever-growing number of people in need of treatment or rehabilitation who can potentially benefit from them. The role of neuroethics is not to pass judgment, but to assist the clinician by highlighting and analyzing the increasing complexity of their accompanying ethical issues. There are numerous other topics that could be considered: from how we should evaluate the informed consent in patients with consciousness or psychiatric disorders who can benefit from neurosurgery, to whether the treatment of psychogenic disorders using placebo, surgery, or drugs are ethically justifiable, to how should we handle predictive biomarkers of late-onset neurodegenerative diseases. The list goes on. As mentioned,

SAN FRANCISCO MEDICINE AUGUST 2016 WWW.SFMS.ORG

the purpose of this article is not to provide a comprehensive list of neuroethical issues, but rather make this growing field relevant to the clinician. With neuroscientific research leading to new, and often controversial, medical approaches, exploring how the findings of brain science should best be applied at the bedside becomes not only increasingly complex and challenging, but a necessity. We are only now beginning to see the array of complex ethical dilemmas being posed by neuroscience that have a direct impact on the lives of patients in the real world. These dilemmas were hitherto unknown, and present the clinician with a whole new set of opportunities and challenges. In an effort to address these issues, the Program in Medicine and Human Values at Sutter Health’s California Pacific Medical Center (CPMC) has developed the “Clinical Neuroethics Initiative” (CNI), directed by Thomasine Kushner, PhD, and Alan Yee, DO, to provide training in neuroethics consultation, develop teaching methodologies, foster collaboration between scientists, ethicists and clinicians, and establish a distinguished Visiting Scholars Program. As the first Fellow in Clinical Neuroethics, I believe that clinical neuroethics will be most useful as a practical approach in providing an applied application grounded in actual medical situations. CNI is already making an impact. We’ve partnered with ICM (Institut du Cerveau et de la Moele Epinière), the noted Brain and Spine Institute, in Paris, France, to coordinate the annual Neuroethics Network conference, and Cambridge University Press is publishing “Clinical Neuroethics,” an issue of the Cambridge Quarterly of Healthcare Ethics, edited by Dr. Thomasine Kushner of CPMC and Steve Heilig of the San Francisco Medical Society. As neuroscience makes discoveries about the human brain and mind at an incredibly fast rate, physicians are being presented with new clinical options as well as burgeoning ethical dilemmas. The goal of CNI is to identify these emerging issues and to assist healthcare providers and patients in dealing effectively with their increasingly complex clinical challenges. Gil Palchik, PhD, is a neuroethics specialist with the program in Medicine and Human Values at California Pacific Medical Center, Sutter Health. If you wish more information on CPMC’s Clinical Neuroethics Initiative or would like to be placed on the list for Visiting Scholar presentations; contact Dr. Thomasine Kushner: kushnertk@gmail.com. Acknowledgements: thank Dr. William Andereck, Director of the Program in Medicine and Human Values, for his valuable input in preparing this article.

References 1. Marcus, S. J. “Neuroethics: Mapping the Field - Conference Proceedings” (1st ed.). Dana Press (2002). 2. Roskies, A. “Neuroethics for the New Millennium.” Neuron, 35(1), 21–23. 3. Readers interested in additional information on these topics are encouraged to review: John Harris, “How to be Good,” Oxford University Press, 2016; James Giordano, “Scientific and Philosophical Perspectives in Neuroethics,” Cambridge University Press, 2010; Joseph Fins, “Rights Come to Mind: Brain Injury, Ethics, and the Struggle for Consciousness,” Cambridge University Press, 2015; and Martha Farrah, “Neuroethics: An Introduction with Readings,” MIT Press, 2010. WWW.SFMS.ORG

Polysubstance users in treatment Continued from page 19 . . . continued to abstain and the nineteen PSU who relapsed between one and four months of abstinence. In comparisons to the abstaining PSU, the relapsing PSU had more years of cocaine use over lifetime (twenty-four vs. fifteen years) and they performed worse on tasks of cognitive efficiency, processing speed, and visuospatial learning. These classifiers, if confirmed in future prospective studies of relapse, could help identify those treatment-seeking PSU individuals who are at greatest risk of relapse, and subsequently, allow more tailored treatment approaches to help reduce the risk for relapse later in treatment. Practically, this means, that treatment efforts could be maximized for those PSU with specific characteristics and cognitive deficits; identifying those at greatest relapse risk requires using a brief but targeted neurocognitive battery during an intake assessment. Our study identified clear differences in neurocognitive function and inhibitory control between PSU and AUD groups, and it further demonstrated beneficial changes of neurocognition and inhibitory control during sustained abstinence in the PSU group. It is important for substance abuse treatment providers to consider the greater neuropsychological deficits of PSU relative to AUD and the specific differences in neuropsychological performance between PSU and AUD in early abstinence. These deficits negatively impact an individual’s ability to benefit from general treatment approaches. Furthermore, the neuropsychological differences between different substance using groups are likely to influence a successful course of treatment and they may demand more specific treatment that targets specific subgroups of substance users. Furthermore, the improvements observed in PSU who maintained abstinence for four months is likely to be of psychoeducational relevance for treatment providers and the client alike. More generally, the results of our study have the potential to collectively reshape public opinion about the possibility of successful recovery even in individuals highly addicted to several substances for many years. Dieter J. Meyerhoff, Dr.rer.nat., is Professor of Radiology and Biomedical Imaging at UCSF and Director of Substance Use Imaging at the Center for Imaging of Neurodegenerative Diseases at the San Francisco Veterans Affairs Medical Center, San Francisco, California. For more than thirty years, he has been continuously National Institutes of Health- and Department of Defense-funded to use neuroimaging, neurocognitive, and neurogenetic methods to help understand the impact of substance use, comorbid conditions, and recovery on the human brain. Thomas P. Schmidt, MS, is Study Coordinator and Assessor at the Center for Imaging of Neurodegenerative Diseases. For almost five years, he has been instrumental in recruiting and assessing participants for Dr. Meyerhoff’s research studies.

Reference 1. Schmidt, T.P., Pennington, D.L., Cardoos, S.L., Durazzo, T.C., Meyerhoff, D.J. “Neurocognition and Inhibitory Control in Polysubstance Use Disorders: Comparison with Alcohol Use Disorders and Changes with Abstinence.” The Journal of Clinical and Experimental Neuropsychology. 2016, in press. AUGUST 2016 SAN FRANCISCO MEDICINE

Neurology

MIGRAINE Current Management Practices Morris Levin, MD

Migraine is a serious public health concern affecting millions of people, and leading to a great deal of suffering, dis-

ability and cost. Proper headache diagnosis, as well as identification of comorbid conditions, is essential. Acute treatments are reasonably good when prescribed appropriately, yet there are patients who do not have a reliable migraine antidote. Prophylactic options are available but far from satisfactory. This article reviews these, but also highlights some much needed new developments that look promising for migraine management in the near future and beyond.

Epidemiology Migraine was found to be the third most prevalent,

and seventh most disabling illness in the world by the World Health Organization.1 Some thirty-six million people in the United States suffer from migraine, and approximately ten percent of these have, or are progressing to, the more frequent and disabling form–chronic migraine (defined as having headaches on fifteen or more days per month, most of which are migraines). And when one considers that migraines are underdiagnosed and undertreated, we are talking about a major worldwide public health problem. Acute treatments are reasonably good when prescribed appropriately, but prophylactic options are far from satisfactory. In fact, satisfaction across the spectrum of migraine patients regarding their treatment is not good–with around forty percent expressing clear unmet needs.2 And satisfaction is even worse in patients with chronic migraine.

Diagnostic Considerations and Other Barriers to Effective Treatment Barriers to care in migraine patients are diverse and include the following: Incorrect diagnosis (or incomplete diagnosis), incorrect treatment, intolerable treatment, poor adherence to treatment for other reasons, and finally, intractable migraine. This last category is like refractoriness in other medical areas—somewhat mysterious and highly frustrating. Diagnosis is crucial, of course. Secondary causes of headache such as vascular causes, high and low intracranial pressure, otolaryngological and ophthalmological disease, cervical spine pathology and certain neuralgias can mimic migraine. Other primary headache entities such as cluster headache (and its relative, Paroxysmal Hemicrania), exercise-related headaches and Hemicrania Continua (a persistent side-locked headache, also with cluster headache-like features) are also misdiagnosed as migraine, and respond to very different treatments. And a number of patients with migraine are wrongly classified sometimes for years as sinus headache, tension headache and psychogenic headaches. A quick scan of the table of contents of the International Classification of Headache Disorders (third ed.) will put any clinician on alert to possible missed diagnoses in patients presenting as migraine.3 22

Acute Treatments Triptans remain the mainstay of treatment

in acute migraine. They are well tolerated, generally effective, and several are available in generic forms (sumatriptan, naratriptan and rizatriptan). Yet, a fairly significant proportion of migraine sufferers do not find them helpful consistently. Class adverse effects of the triptans include jaw, neck and chest muscle tightness, fatigue and paresthesias. The mild chest discomfort is not uncommon but almost never a sign of cardiac dysfunction. However, because of their potential vasoconstrictive effects, triptans are considered to be contraindicated in patients with coronary or cerebrovascular disease. This is, however, a theoretical risk and risk-versus-benefits for this class must be considered on an individual basis. Non-steroidal anti-inflammatory medications are effective, with good evidence in particular for naproxen sodium, ibuprofen and diclofenac. Opioids, the short-acting barbiturate butalbital (the major ingredient of Fioricet® and Fiorinal®) and isometheptene (found in Midrin®) have little evidence to support them. However, used very sparingly, these might provide viable options in certain patients, as long as they are used sparingly to avoid medication overuse headache (aka analgesic rebound, defined as the worsening of migraine due to excessive use of analgesics or other migraine abortives). The ubiquitous combination formulations of acetaminophen, aspirin and caffeine (e.g. Excedrin®, Goodies powder®) have reasonably good evidence for their effectiveness but should be used with caution, as this combination medication may be a significant promoter of medication overuse headache as well. In an urgent care or emergency department setting, several other options are available. Intravenous or intramuscular kerorolac 30-60 mg is quite useful. Intravenous dihydroergotamine in a dose of 1 mg infused over thirty minutes is effective for many patients. Likewise, IV chlorpromazine at a dose of 12.5-25 mg infused slowly is quite helpful, but care must be taken to monitor blood pressure and oversedation. Magnesium sulfate 1-2 g IV is also supported by reasonably good evidence for the acute management of migraine.4

Preventive Treatment The best evidence for the prevention

of episodic migraine has emerged for beta-blockers, valproate, and topiramate.5 Yet, tricyclic antidepressants such as amitriptyline and nortriptyline are generally felt to be very useful for many migraine sufferers, supported by fairly good evidence. Calcium channel blockers such as verapamil and amlodipine, and the angiotensin-receptor blocker candesartan have also been shown to be useful. Recent evidence supporting memantine as a migraine prophylactic in a dose of 10 mg bid has been reported. Angiotensin converting enzyme inhibitors, venlafaxine and Selective Seratonin Reuptake Inhibitor (SSRI) medications have been promoted as having benefit in preventing migraines but results have not been widely seen. Botulinum toxin in a dose of 155-185 units injected in the face and scalp in a specific

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pattern has been shown to have some benefit in reducing migraine frequency in chronic migraineurs. In some, these benefits are clinically quite significant. Intravenous dihydroergotamine given over several days (a method first developed at University of California, San Francisco by Dr. Neil Raskin), can be quite helpful in breaking a stubborn cycle of migraine headaches. Corticosteroids such as prednisone can provide similar benefits in some patients.

Alternative and Complementary Treatment Petasites (butterbur) has been shown to be effective in preventing migraine. Unfortunately, some components of this plant are hepatotoxic and/ or carcinogenic, and while it has been claimed by some manufacturers that these elements can be excluded in their preparations, this is not a certainty, hence this herbal supplement should probably not be recommended anymore. Riboflavin (vitamin B2–dose 400 mg) and magnesium in a dose of about 500-600 mg daily are probably effective in migraine prophylaxis.6 The evidence for feverfew, generally used as leaves or powder, is less robust. Progression to Chronic Migraine and Risks for Brain Changes One of the most unsettling issues in Headache Medicine

is the transformation of episodic migraine to chronic migraine with its significantly higher disease burden on patients, families and society. The rate of transformation of episodic migraine to the chronic form is about two point five percent annually. Risk factors for this are: high headache frequency, high use of analgesic medications, poor success with acute treatment options, obesity, and depression.7 It is impossible to know whether a) any of these risk factors is causal in the transformation, and b) whether attacking these risk factors (e.g. improving acute treatment success) might reduce the odds of transformation (something of clearly great interest).

New Directions – Use of Older Options in New Forms for Acute Therapy Several new formulations of sumatriptan

are being promoted for the acute treatment of migraine. One utilizes a novel intranasal delivery system actuated by exhaling into a twonozzle device (Onzetra®). This recently approved device seems promising, but whether it will be more popular than the currently available sumatriptan and zolmitriptan nasal spray devices remains to be seen. Another route of delivery for sumatriptan was made available last year as an iontophoretic patch (Zecuity®). This seemed useful in select patients, but some developed skin irritation and even burns, which led to its being taken off the market. A microneedle array transdermal delivery system is also being developed for sumatriptan. An inhaled form of Dihydroergotamine (DHE) (Semprana®) is being awaited with optimism by the headache community, since most see DHE as a highly effective agent in migraine and were somewhat disappointed with the nasal spray formulation (Migranal®).

Injections for Migraine After years of use empirically, occipital nerve blocks seem to be acquiring evidence for use in preventing migraine. The procedure is easy to learn and of low risk in the right hands. Most practitioners use lidocaine 1%, bupivacaine .25-50% or a combination of the two, with or without the addition of corticosteroid like triamcinolone. Sphenopalatine ganglion blockade is being promoted via the transnasal transmucosal route (needleless) using devices which aim to deliver a small amount of local anesthetic to the posterior nasal cavity in hopes of diffusion across mucosal tissue to the pterygopalatine fossa. Trigger point injections in the head WWW.SFMS.ORG

and neck are also regaining some popularity for migraine, despite a paucity of evidence.

New Directions–CGRP Antagonists Calcitonin gene related protein (CGRP) seems to be a key neurotransmitter in pain and has become a target in migraine on the basis that 1) elevated venous CGRP is seen during migraine attacks, 2) resting levels of CGRP are higher in migraine patients than in the general population, and 3) injecting CGRP induces migraine in susceptible individuals. A class of small molecule antagonists, including olcegepant and telcagepant, was developed by Merck but these both were found to be hepatotoxic and had to be abandoned. Much work has recently been done by a number of pharmaceutical companies and investigators to find monoclonal antibodies against CGRP (either the molecule itself or its receptor) in hope that this could be a viable migraine preventive treatment option. Four monoclonal antibodies (mAb’s) are now in, or nearing, phase 3 trials, and it is the hope, based on very encouraging Phase 2 data, that one or more will be available by 2018.8 Cost may be prohibitive for many patients but one can imagine the potential for intractable chronic migraine sufferers. Neuromodulation Using electrical stimulation of superficial

nerves of the head to treat head pain is not a new concept. Transcutaneous nerve stimulation in particular has been promoted for migraine, and a recent study supported the use of a device Cefaly®, which consists of a plastic headband containing electrodes which overly the supraorbital nerves. This is supposed to be worn and used twice daily in hopes of preventing migraine. Non-invasive vagal nerve stimulation is being studied for its potential migraine potential (one device seeking approval is gammaCore®). These devices are intended to be used by patients preventively or perhaps at the time of migraine, and will target the vagus nerve in the neck or in the periauricular region. Transcaranial magnetic stimulation, in the milder “single pulse” format, has been shown to abort acute migraine and is now available for rent by prescription (SpringTMS®). A more invasive neurostimulation technique involves the transoral surgical placement of a tiny electrode array adjacent to the sphenopalatine ganglion. This can be stimulated by the patient by means of an external triggering device. Implanted occipital nerve devices have led to mixed results, but have helped selected patients.9

More distant future Newer pharmacological targets have

emerged, including serotonin receptors other than the 5HT1B,D receptors bound by triptans, orexin receptors, pituitary adenylate cyclase-activating peptide (PACAP), and glutamate receptors, longtime targets in pain management. Research into the mechanisms underlying migraine are yielding much new data, although as is typical in research, more questions are being raised than answered.

Conclusions The landscape for intractable migraine sufferers is beginning to look more encouraging. Pharmacotherapy aimed at new targets, as well as using new routes, injection therapy, calcitonin gene-related peptide (CGRP) antibody therapy, and neuromodulatory devices all seem promising at this point. Keep an eye on the headache and general medical journals as well as CNN. Morris Levin, MD, is professor and chief of the Division of Headache Medicine in the Department of Neurology at UCSF. A full list of references is available at www.sfms.org. AUGUST 2016 SAN FRANCISCO MEDICINE

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MEDICAL STUDENT PERSPECTIVE Pharmaceutical Industry-Sponsored Meals for Physicians Are Associated with Increased Brand-Name Prescribing in Medicare Part D Colette DeJong, BA, and R. Adams Dudley, MD, MBA The U.S. Sunshine Act reveals that in the last five months of 2013, over half of American physicians received

free meals, gifts, or payments from the pharmaceutical industry. Research shows that physicians who receive large industry payments—such as speaking fees and royalties—are more likely to prescribe brand-name drugs over generics. In our recent study in JAMA Internal Medicine, we found that physicians who received a single industry-sponsored meal—with an average value under twenty dollars—were up to twice as likely to prescribe the brandname drug being promoted.1 Our study contributes evidence to a long-standing debate around industry-sponsored meals. Although an inexpensive meal certainly cannot financially influence physicians, it is possible that physicians feel obliged to listen to a five-minute pitch when pharmaceutical representatives bring in refreshments for physicians and their staff. While these meals may be opportunities for physicians to learn about new therapies and guidelines, some argue that they lead to over-prescribing of brand-name drugs. In response to concerns, a majority of teaching hospitals and several state legislatures have taken steps to restrict meals or gifts to physicians from industry. These policies have been controversial; Massachusetts’ ban on sponsored meals outside of clinical settings was overturned in response to appeals from pharmaceutical companies, some physician groups, and restaurateurs, some of whom reported a twenty percent decline in revenue as a result of the ban. In surveys, most physicians deny that pharmaceutical representatives influence their prescribing decisions, but believe they may influence their peers. To examine the association between sponsored meals and physician prescribing patterns, we linked August-December 2013 industry payment records, from the U.S. Sunshine Act’s Open Payments Program, with 2013 prescribing data from Medicare Part D. We then identified physicians who wrote Medicare prescriptions in any of four common drug classes: statins, β-blockers, angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), and selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRIs and SNRIs). We identified the most-prescribed brand-name drug in each class in 2013 (rosuvastatin, nebivolol, olmesartan, and desvenlafaxine, respectively), and flagged physicians who received industry-sponsored meals promoting one of the drugs. There is mixed evidence around the superiority of these drugs over generic alternatives, and all four are excluded from the Veterans Affairs (VA) National Formulary. 279,669 physicians received 63,524 payments associated with the four target drugs. Ninety-five percent of payments were meals, averaging under twenty dollars. The study found that receipt of a single industry-sponsored meal was positively associated with the rate at which physicians prescribed the promoted drug over alternatives within the drug class. Physicians who reWWW.SFMS.ORG

ceived a single meal promoting the drug of interest had higher rates of prescribing rosuvastatin over other statins (odds ratio [OR], 1.18; 95% CI, 1.17-1.18), nebivolol over other β-blockers (OR, 1.70; 95% CI, 1.69-1.72), olmesartan over other ACE inhibitors and ARBs (OR, 1.52; 95% CI, 1.51-1.53), and desvenlafaxine over other SSRIs and SNRIs (OR, 2.18; 95% CI, 2.13-2.23). Analyses were adjusted for prescribing volume, physician specialty, practice setting, and demographic characteristics. The more meals or the costlier meals a physician received, the stronger the association with prescribing the promoted drug. We were unable to draw causal inferences in this analysis. It is possible that physicians attend meals about drugs they tend to use, and thus the associations we observe are not indicative of influence. If, alternatively, meals change physicians’ prescribing practices as a result of promotional influence, either by encouraging future use or rewarding an ongoing preference for the promoted drug, this would be cause for concern. Increased use of generics is a national priority. Between 2010 and 2012, the U.S. could have saved seventy-three billion dollars if brands were exchanged for equally effective generics. Twenty-five billion dollars of that cost was borne by patients, who pay a median Part D co-pay of one dollar for generics and eighty dollars for non-preferred brand-name drugs. With their lower out-of-pocket costs, generics have been linked to improved adherence and better outcomes for certain chronic conditions. We hope that our study leads to further examination of the impact of pharmaceutical detailing—positive or negative—on the cost and quality of prescribing. Although our findings raise questions about current practices, it’s worth noting that industry detailing is one of the only systems through which drug information is actively distributed to prescribers. It’s possible that the Food and Drug Administration or Medicare could reduce spending through greater investment in systems that get drug information out to doctors and give equal footing to brands and generics. In the interim, individual physicians have the task of deciding their practice’s stance on pharmaceutical detailing, and seeking out independent sources of drug information that directly compare the safety and cost-efficacy of current treatment options. Colette DeJong is a fourth-year medical student at University of California, San Francisco (UCSF) and a Research Fellow at the UCSF Center for Healthcare Value. R. Adams Dudley is the Director of the UCSF Center for Healthcare Value and a Professor of Medicine and Health Policy at UCSF.

Reference:Colette DeJong, BA;Thomas Aguilar, MS;Chien-Wen Tseng, MD, MPH; Grace A. Lin, MD, MAS; W. John Boscardin, PhD; R. Adams Dudley, MD, MBA. “Pharmaceutical Industry–Sponsored Meals and Physician Prescribing Patterns for Medicare Beneficiaries”. JAMA Intern Med. Published online June 20, 2016. doi:10.1001/jamainternmed.2016.2765 AUGUST 2016 SAN FRANCISCO MEDICINE

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OPINION Please Disarm the Deranged Steve Heilig, MPH When the twin towers fell on 9/11, at first it was thought that as many as ten thousand people might have been inside. When the twin towers fell on 9/11, at first

it was thought that as many as ten thousand people might have been inside. A national call for blood donors went out in case there were many injured. By the time I got to my local blood bank in San Francisco, a line of people stretched around the block. My pent-up horror over what had just happened in New York came out in tears over the goodness of humans, reaching out in the best way they could to help people they did not know. To top it off, Robin Williams showed up, stood in line and quietly offered to buy meals for everyone there. The first photo I saw from Orlando on Sunday morning was of a similar line at that city’s blood bank; it recalled that same mix of emotion—pain over senseless slaughter and suffering, mixed with a strong sense of the essential good within almost all people. Our first impulse is one of empathy, and a hope to help. It’s the best thing about our species. It’s both heroic and normal. But these mass shootings can bring out the worst in some of us as well. Beyond the countless gun-loving trolls online, Donald Trump jumped on Twitter to crow, “I told you so.” Nothing he has proposed would have prevented this or any other such incident. What is known so far is that the shooter was an American-born citizen who had long threatened to kill people out of unfocused anger. In other words, he was, at least to some degree, deranged. And he was able to legally buy whatever guns he wanted. Gun injuries and deaths are vastly more prominent in the United States than in any other remotely comparable nation, even though general violent crime rates have declined substantially in recent decades. About ninety people die each day from guns in our nation. Many are children. So what to do? We already know much. The kind of “combat mode” weaponry used in too many of these murders, including Orlando, should be banned; no citizen needs them. Background checks and registration for both guns and ammunition purchases should be universal; likewise safety courses. Taxes on guns and ammo would pay for these and other gun-related social costs. None of this is “gun grabbing”—unless you are demonstrably unstable. As President Obama has said: “We respect the rights of responsible gun owners.” And most are responsible. The vast majority of gun owners support rational gun policies. And the law permits those; the Second Amendment does have limits, as even the late Justice Scalia wrote in his Heller ruling upholding it: “Nothing in our opinion should be taken to cast doubt on long-standing prohibitions on the possession of firearms by felons and the mentally ill, or laws forbidding the carrying of firearms in sensitive places such as schools and government buildings, or laws imposing conditions and qualifications on the commercial sale of arms.” But here is a crucial point: With more than three hundred million guns in private hands, the problem is not going away WWW.SFMS.ORG

anytime soon. The real effect of more rational policies will take decades to be felt. It will be the work of generations, and thus policies such as the assault weapons ban will need to be in place longer than has been tried so far. A new normal, where our madness will gradually come into view, much as the denormalization of tobacco use has cut smoking rates by more than half in a couple of generations. Until then, we will line up at blood banks. Again, that is a beautiful impulse, but it would be so much better if we did not have to.

The SFMS Board of Directors has voted to endorse the California “Safety for All” gun control ballot initiative, Proposition 63, which would: Prohibit the possession of large capacity military style magazines, treat ammunition sales like gun sales, ensure people prohibited from owning guns do not possess them, require reporting lost or stolen guns, and share data with federal system on prohibited people. For more information see: safetyforall.com Steve Heilig works with the San Francisco Medical Society and is co-editor of the Cambridge Quarterly of Healthcare Ethics. A different version of this appeared in the San Francisco Chronicle. He is an NRA-certified Junior Marksman.

AMA Calls Gun Violence “A Public Health Crisis,” Pledges to Actively Lobby Congress to Lift Ban on CDC Gun Violence Research June 14, 2016 | In the wake of the worst mass shooting in American history and with more than 6,000 deaths already in 2016 from gun violence, the American Medical Association (AMA) today adopted policy calling gun violence in the United States “a public health crisis” requiring a comprehensive public health response and solution. Additionally, at the Annual Meeting of its House of Delegates, the AMA resolved to actively lobby Congress to overturn legislation that for twenty years has prohibited the Centers for Disease Control and Prevention (CDC) from researching gun violence. “With approximately 30,000 men, women and children dying each year at the barrel of a gun in elementary schools, movie theaters, workplaces, houses of worship and on live television, the UnitedCHICAGO—In the wake of the worst mass shooting in American history and with more than 6,000 deaths already in 2016 from gun violence, the American Medical Association (AMA) today adopted policy calling gun violence in the United States “a public health crisis” requiring a comprehensive public health response and solution. Additionally, at the Annual Meeting of its House of Delegates, the AMA resolved to actively lobby Congress to overturn legislation that for twenty years has prohibited the Centers for Disease Control and Prevention (CDC) from researching gun violence. A longer version of this press release was originally posted on the AMA website: http://www.ama-assn.org/ama/pub/news/ news/2016/2016-06-14-gun-violence-lobby-congress.page. AUGUST 2016 SAN FRANCISCO MEDICINE

MEDICAL COMMUNITY NEWS Saint Francis Robert Harvey, MD, MBA

In 1967, a ten-year-old girl was standing in front of the fireplace in her family’s Crescent City home when suddenly her nightgown caught fire. In a matter of seconds, the flames were out but the damage was done. Burned over forty percent of her body, she was taken to the local hospital. Meanwhile in San Francisco, the final stages of construction were underway on the first burn unit west of the Rockies. Recognizing the extent of her injuries were too much to treat in Crescent City, the girl was brought to Dignity Health Saint Francis Memorial Hospital, becoming the first patient in the Bothin Burn Center. Nearly fifty years later, the unit received another first patient—this time to an all-new Bothin Burn Center. The new Burn Center opened in June. Now the largest burn unit in Northern California, the Burn Center features the most advanced medical technology and equipment, including a dedicated Operating Room, stateof-the-art life support, monitoring equipment, and ultrasonic hydrotherapy for bathing wounds. The Burn Center treats approximately seventy children each year. Much thought went into creating a new space that is engaging and comforting to children. In addition to dedicated pediatric treatment rooms, there is a play area complete with gaming consoles and iPads. The Bothin Burn Center is led by Medical Director Jeffrey DeWeese, MD, and Richard Grossman, MD, who, along with David Malone, MD, Fred Hom, MD, Kathleen Jordan, MD, and Mel Blaustein, MD, treat more than five hundred patients each year. We are proud to be the first burn unit in the Bay Area to be verified by the American Burn Association and the American College of Surgeons, Trauma Division, and look forward to our continued legacy delivering the highest quality care for burn victims.

St. Mary’s

Robert Weber, MD

Summer is both a busy and exciting time at Dignity Health St. Mary’s Medical Center as we welcome a new group of hospitalists, launch a new intensivist program, and break ground on a new advanced hybrid surgical suite. These big changes mean more coordinated and collaborative care to improve clinical outcomes and enhance patient experience. New Hospitalist Partnership - St. Mary’s recently expanded our partnership with CEP America, a physician owned and operated health care company based in Emeryville. CEP America already manages our emergency medicine program and will now provide inpatient care through its hospitalist program. CEP America physicians also serve as faculty for our internal medicine residency. By providing inpatient acute care and consultative expertise for our subspecialists, CEP America hospitalists closely collaborate with our patients’ primary care providers to ensure seamless transitions of care. New Intensivist Program - St. Mary’s has always embraced a team-based approach, and integrating a new intensivist program will help ensure our most critically-ill patients receive optimal life-saving care. Led by Jacob Adams, DO, our intensivists are all board certified and specially trained to treat a broad range of serious illnesses and complex diagnoses. By providing a critical care expert around the clock, our new intensivist program is expected to improve patient survival rates by proactively addressing changes in a patient’s condition, promoting medication safety, and decreasing procedure complications. Constructing a Hybrid Operating Room (OR) - We are excited to start construction on a new hybrid surgical suite, which will merge minimally invasive cardiac procedures and traditional open-heart surgeries with advanced imaging capabilities. The new hybrid OR will be integrated with the hospital’s existing cardiac catheterization lab, allowing clinicians to perform open-heart surgery, complex vascular surgery, and minimally invasive procedures in one location.

SPMF

Robert Osorio, MD, FACS

At Sutter Pacific Medical Foundation, our expert physicians not only care for patients with complex illnesses, but research the latest advances in treatment and even prevention. Neurologists Robert Miller, MD, and Jonathan Katz, MD, are making headway with new approaches and pioneering advances to improve the quality of life for people with amyotrophic lateral sclerosis (ALS). For the thirty thousand people in the U.S. with this neurodegenerative disease, progressive deterioration and death of motor neurons causes loss of control of voluntary muscles and resulting symptoms including muscle weakness, spasticity, slurred speech and respiratory difficulties. Currently, the only Food and Drug Administration-approved drug treatment for ALS (riluzole/ Rilutek®) reduces damage to motor neurons by decreasing the release of glutamate. The drug has established safety data and prolongs survival in patients by several months. Ongoing clinical trials led by Dr. Miller and Dr. Katz are assessing the efficacy and safety of a new drug (Neuraltus Pharmaceuticals’ NP001) that has shown promise in halting disease progression in a subset of patients. Results of a phase 2 trial published in Neurology: Neuroimmunology & Neuroinflammation suggest possible effects of the drug in slowing disease progression over six months. Dr. Miller and Dr. Katz are co-principal investigators of the Phase 2 study, conducted at twenty national sites. The Forbes Norris MDA/ALS Research and Treatment Center, under the direction of Dr. Miller, is the lead site. Other trials led by the ALS team will determine optimal use of non-invasive ventilation (NIV) machines to ease breathing in patients, and a multicenter, randomized study of the NeuRX® Diaphragm Pacing System—an approach to support patients with diaphragm weakness. The ALS group will be collaborating with Cedars-Sinai Regenerative Medicine Institute on a study funded by the California Institute for Regenerative Medicine (CIRM). The project will test the effects of combined stem cell and gene therapy, along with the protein GDNF (glial cell-derived neurotrophic factor) to promote the survival of damaged motor neurons in ALS patients.

SAN FRANCISCO MEDICINE AUGUST 2016 WWW.SFMS.ORG

MEDICAL COMMUNITY NEWS CPMC

Edward Eisler, MD

The Melanoma Research Foundation presented a Humanitarian Award to Dr. Kevin Kim, who serves as Director of Clinical Research for the Center for Melanoma Research and Treatment at California Pacific Medical Center (CPMC). The award recognizes his advanced work in melanoma research and treatment. Dr. Kim leads CPMC’s efforts to build a database and tumor bank of tissue samples from patients with melanoma. He and colleagues will use these samples to create new diagnostic tests and personalized therapies for all stages of the disease. Dr. Kim’s research was critical to early drug development of vemurafenib and dabrafenib (both BRAF inhibitors) and trametinib (a MEK inhibitor)—Food and Drug Administration-approved drugs that have greatly advanced the treatment of patients with BRAF-mutant metastatic melanoma. CPMC’s Ray Dolby Brain Health Center (RDBHC) is enrolling patients into an international study of a new oral experimental drug called idalopirdine, in patients with mild-to-moderate Alzheimer’s disease. Patients will be given the drug for six months in combination with currently approved medications for the illness. Changes in their cognition, daily function, and behavior will be assessed. This study represents the type of rigorous trial that will help advance treatment of the illness with more effective compounds used in “cocktail” combinations. Sutter Health was among the first hospitals nationally to enroll patients into the National Cancer Institute’s Molecular Analysis for Therapy Choice (MATCH) trial—a key study supporting Obama’s Precision Medicine Initiative. The trial links targeted cancer drugs to gene abnormalities, and will provide patients with faster, streamlined access to more effective therapies. Sutter Health Cancer Research Consortium will re-open the twenty-four-arm study this week at twenty sites system-wide and enroll patients with solid tumors or lymphomas (approximately one-quarter of which will include rare types of cancer) who have failed standard therapy and will be screened for common cancer-related genes known to drive tumor progression and matched to a targeted agent. WWW.SFMS.ORG

Kaiser

Maria Ansari, MD

Sometimes the field of medical research provides a rare confluence of breakthroughs that can be applied to current clinical practice and improve the lives of patients living today. Prion research has likewise presented us with breakthroughs for treating degenerative brain diseases. Prions are small, proteinaceous infectious disease-causing agents that are believed to be the smallest infectious particle known, and have been proposed as a potential root cause to several neurodegenerative disorders. As new discoveries are made through intensive brain research, it’s our challenge as physicians to develop and integrate clinical practice with the new findings. At Kaiser, our current approach is to prepare our general and specialty neurologists with the latest information so that when new treatments are available, we have the systems in place to immediately provide care to patients suffering from these devastating diseases. Additionally, we both support and author clinical research of prions and partner with other entities such as the University of California San Francisco Memory and Aging Center. As we redesign our specialty to be “on alert” for these new discoveries, we keep our focus on the needs of patients and their caregivers. We keep up to date on the basic science and clinical research so that when new medications or care models become available, we’re able to deliver them in a specialty-directed, efficient, and cost-effective manner. The approach is one of working on a continuum, where we are laying the foundation to improve the care delivery for diseases not yet treatable, but for which new discoveries are made at an increasingly rapid pace. As the population ages, we will rely on such new information and approaches to handle an increasing incidence of neurodegenerative illnesses, such as Parkinson’s and Alzheimer’s disease. At Kaiser, we have been constructing and implementing comprehensive specialty-focused care models. In neurology we have created reciprocal hub and spoke networks to support physicians and patients alike for diagnoses such as stroke, Parkinson’s, multiple sclerosis, neuromuscular disorders, and epilepsy.

SFVAMC

C. Diana Nicoll, MD, PhD, MPA

The prevalence of neurodegenerative diseases is increasing as our Veteran population ages. Many of these disorders, including Parkinson’s disease and Alzheimer’s disease, manifest intracellular accumulations of misfolded proteins that may themselves contribute to disease pathogenesis in a prion-like manner. The progressive decline in motor and cognitive function caused by these conditions impacts not only the affected individuals, but also the family and caregivers as they are increasingly relied upon for assistance. Our Veteran patients fiercely value their independence, and we endeavor to assist them in independent living as long as this is feasible. This assistance takes the form of medical treatment and home adaptations, and also involves helping patients and caregivers with difficult judgments concerning, for example, driving safety, financial control, and determining competency for decision-making. At the San Francisco Veterans Affairs (VA) Health Care System, this assistance is often provided by patient-oriented teams of professionals with overlapping expertise. A challenge, however, is how to provide this expertise to patients and families living in outlying rural areas, for whom travel to the main medical center at the San Francisco VA Medical Center (SFVAMC) is difficult. To address these challenges, we are employing a “hub and spoke” model of care, in which neurologists, geriatricians, social workers, and mental health professionals at the SFVAMC work together with our local community based outpatient clinics. This communication is increasingly augmented by video-telehealth conferencing to patients and local VA health care providers. A novel and highly successful part of this effort is a Parkinson’s disease palliative care program. This program applies the principles of palliative care to cancer and other terminal disorders and to patients with progressive neurodegenerative disorders, aiming to assist patients and caregivers in adjusting goals of care in relation to changing capacities and expectations.

AUGUST 2016 SAN FRANCISCO MEDICINE

MEDICAL COMMUNITY NEWS SF Health Network

Alice Chen, MD

UPCOMING EVENTS San Francisco vs. Big Soda Campaign Kick Off | August 16, 2016, 5:00 to 8:00pm. | An evening to support San Franciscans United to Reduce Diabetes in Children. For sponsorship levels or individual ticket information, contact annie@eaganconsult.com or (415) 269-5105.

5th Annual Asian Health Symposium | August 26 to 27, 2016 | Laurel Heights

The San Francisco Health Network has invested significant resources in creating a comprehensive treatment program for stroke patients from ambulance to home. Zuckerberg San Francisco General Hospital and Trauma Center (ZSFG) has been certified by the Joint Commission as a Primary Stroke Center since 2007. “Time is brain” is the philosophy that drives our 24/7 team consisting of certified stroke neurologists, neurosurgeons, interventional neuroradiologists, emergency medicine physicians, and stroketrained nurses. With the opening of our new hospital, we bring state-of-the-art equipment to the patient’s bedside in our combined XMR suite (3T Magnetic Resonance Imaging (MRI) coupled to biplane x-ray angio suite) and in our Neuroscience Intensive Care Unit equipped with the most advanced neuromonitoring, allowing us to diagnose and treat stroke patients in one place. Stroke stimulation training aimed at enhancing the Stroke Team’s skills and speed to provide treatment, and the availability of patient follow-up in our Stroke Clinic, ensures ongoing excellence in care that promotes brain health and stroke prevention. For patients requiring intensive rehabilitation prior to returning home, Laguna Honda Hospital and Rehabilitation Center’s (LH) Acute Rehabilitation Unit (ARU) provides a crucial bridge from hospital to home. With stroke as the most common diagnosis treated at the ARU, our program excels in poststroke care, offering rehabilitation services in a state-of-the-art rehabilitation environment conducive to recovery and wellness. Our interdisciplinary team of rehabilitation-trained physicians, nurses, and therapists develop and implement comprehensive stroke treatment plans along with patient and caregiver training so that we can help to maximize our patients’ functional abilities and safe return to the community. Across our Network, stroke patients are assured of the clinical expertise and latest advances in stroke care that will support them on their transition back to home. 30

Conference Center, 3333 California Street, San Francisco, CA - The 5th Annual Asian Health CME symposium will help bridge the knowledge and practice gaps in treating the many diseases and health issues that have significant impacts on the Asian community. The symposium will highlight specific areas for this unique community, including cancer, cardiovascular disease, integrative medicine, and infectious disease with special emphasis on the differences in Asian patients. For more information or to register online, visit www.cme.ucsf.edu.

SFMS General/All-Member Meeting | September 12, 2016, 6:00 to 7:30pm | Golden Gate Yacht Club - Calling all SFMS members – join us at our General Meeting on September 12, 2016. Members are welcome to stay for the board meeting immediately following the General Meeting. This is a good opportunity to meet with SFMS leadership and to learn firsthand the issues SFMS and CMA are advocating for on behalf of physicians and their patients in San Francisco and California. RSVP to Posi Lyon, plyon@sfms. org, (415) 561-0850 x260.

Building Healthy Communities Summit | September 16 to 18, 2016 | Marriott Hotel and Spa, 900 Newport Center Drive, Newport Beach, CA - The Network of Ethnic Physician Organizations (NEPO) 2016 Building Healthy Communities (BHC) Summit is a unique and exciting educational event for physicians, public health professionals, and community leaders. NEPO is a cornerstone program of the CMA Foundation consisting of over fifty ethnic physician organizations across California. Register for the Summit at https://www.eventbrite.com/e/2016-building-healthy-communities-summit-tickets-18979769000.

Classified Ads Alexander Valley Healthcare, a Federally Qualified Health Center, seeks up-andcoming family physician, DO, or internist to serve as Chief Medical Officer. Competitive salary and an opportunity to run a healthcare program for an entire community. Location is Cloverdale, CA. Inquiries may be directed to Heather Merriam 510-859-6621. SUBLET: SF FINANCIAL DISTRICT MEDICAL OFFICE. 22 Battery St at Bush and Market. 2 exam rooms, 1 or 2 days a week. J Binstock, MD. (415) 956-8686

Medical office for lease: 1000 South Eliseo Greenbrae; close to Marin General; large parking lot; 5 exam rooms; 1 consult room; 1 business office; waiting room/ reception areas. ~1350 SF. $4.6/SF/month. Available 12/2016. Contact: may. tam@aasthma.com Phone: 415-751-6800

FALL IN LOVE WITH PRACTICING MEDICINE AGAIN. For Sale: Well Established Medical Weight Loss Practice In Marin County. Enjoy work-life balance and financial freedom. This all cash practice offers a flexible schedule and provides multiple income streams. In addition, this practice presents a significant growth opportunity. This is and will continue to be an active ongoing practice. The seller will enable a smooth transition. Email now drgail@marinweightloss.com.

SAN FRANCISCO MEDICINE AUGUST 2016 WWW.SFMS.ORG

Premiums are based in part on age. The longer you wait, the higher your premium rate may be. You’ve worked hard all your life to provide a good standard of living for you and your family and KEEP your current lifestyle in retirement. But long-term care costs can get in the way. If you develop a debilitating long-term condition, you may need long-term care. Once you’re 65 years old, Medicare will help pay your medical costs. But Medicare does not pay full benefits for extended-care, assisted-care facilities, custodial care or nursing home facility expenses. If you need this type of care, you could face big expenses: • The average cost of a private room in a nursing home in San Francisco is $182,318 per year.* • The average cost of an assisted living, one bedroom apartment with private bath, or a private room with a bath in San Francisco is $71,400 per year.* Many of us think Medicare is going to cover long-term care expenses, but find the coverage very limited. That’s why millions of responsible Americans help protect their lifestyles with long-term care insurance. But finding the right protection isn’t easy. It’s tough to compare policies with different benefits, features, limitations, costs, spouse coverage and more. The San Francisco Medical Society/CMA can help, with a special benefit for members: Long-Term Care Resources, a unique long-term care buying service. This program allows you to work with a long-term care insurance representative who will give you all the information about benefits and rates of different, highly rated long-term care providers. Call Long-Term Care Resources today to receive information at 800-616-8759, or visit https://education.ltcr.com/sfms. * Compare Long Term Care Costs Across the United States https://www.genworth.com/about-us/industry-expertise/cost-ofcare.html, viewed 7/8/16

Call 800-616-8759 or visit https://education.ltcr.com/sfms Sponsored by: 74511 (7/16) Copyright 2016 Mercer LLC. All rights reserved. 777 South Figueroa Street, Los Angeles, CA 90017 • 800-842-3761 CMACounty.Insurance.service@mercer.com • www.CountyCMAMemberInsurance.com

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San Francisco Medical Society 2720 Taylor St, Ste 450 San Francisco, CA 94133

Find the best specialist for your patient with one call. We make it easy to transfer and refer your patients to specialists at CPMC, part of the Sutter Health network. One call allows you to match your patientsâ&#x20AC;&#x2122; needs with the right specialist, notify admissions, get authorizations and more. And weâ&#x20AC;&#x2122;re available 24/7, so you never have to wait to find the best possible care for your patients.

Referrals and Transfers 24/7 888-637-2762 cpmc.org