2021 May AANnews by American Academy of Neurology

VOLUME 34 · ISSUE 5 · MAY 2021

Visit AAN.com/Covid19 for the latest pandemic information and resources to support you and your crucial work.

PREPARING FOR OUR RENAISSANCE President's Column On April 23, I began my term as president of the American Academy of Neurology. I was deeply touched by the formal “passing of the gavel” from President Jim Stevens, MD, FAAN, with whom I have worked very closely for the past two years. He led this organization through what has been, arguably, the toughest period in our lifetimes, and he did so with compassion, grace, and fortitude. Most importantly, throughout myriad challenges, he maintained steadfast focus on the lodestar: emphasizing the best interests of this organization and its members. While his leadership took us through arduous times, as I take over as president, we are beginning to glimpse brighter days. Indeed, if historians were to compare the past pandemic year to the Middle Ages, they would invariably refer to the present time as a Renaissance period, marked by an eruption of ideas which reflect all we have learned and started to integrate into our post-pandemic future. Orly Avitzur, MD, MBA, FAAN

During the past year, we have taken advantage of the circumstances to reflect, refresh, and reimagine. Certainly, as an organization, we have learned a great deal. Continued on page 11

This Exclusive $500 AAN Member Benefit Closes May 14

Cerebral Palsy Advocate Gives First Congressional Briefing

Time is running out to complete your Neurology Compensation and Productivity Survey. Your participation ensures this survey continues to be the largest source of meaningful data from neurologists and advanced practice providers, representing up to 18 subspecialties and various practice settings including solo and private, government-based, and academic.

In March, the AAN co-hosted a virtual briefing with the Congressional Neuroscience Caucus to educate Capitol Hill staff on the critical need to improve our understanding of what causes neurodevelopmental disorders and share new approaches for treatment and Aravamuthan prevention. The event co-hosts included the American Brain Coalition, Autism Speaks, Cerebral Palsy Research Network, and the Society for Neuroscience.

This is a $500 AAN member value—if you complete the survey by May 14, 2021. By participating, you will be able to benchmark your value using the largest neurology compensation survey in the United States with FREE access to the empowering data dashboard when it becomes available this summer. Participation also includes instant access to the 2019 data report. With the data from the Neurology Productivity and Compensation Survey, you can: Filter neurologist compensation data by subspecialty, geographic region, and more Continued on page 13

12 New Quality Measures for

MS Added to Axon Registry

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AAN member Bhooma Aravamuthan, MD, PhD, associate professor of neurology at Washington University, joined a distinguished panel of speakers for this briefing to discuss the importance of cerebral palsy research. Aravamuthan also serves as vice chair of the AAN’s Adults with Intellectual and Developmental Disabilities Section, has attended a Neurology off the Hill meeting, and has recently participated in the Emerging Leaders Program.

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15 May 23 Is Last Chance to

Submit Online Evaluations for Annual Meeting CME

Continued on page 23

18 AAN Diversity Officer

Work Group Makes Progress on Goals

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Discover an oral therapy for your patients with relapsing forms of multiple sclerosis (MS)1…

ZEPOSIA—FOCUSED ON WHAT COUNTS ZEPOSIA was studied in the largest number of patients with RMS in 2 pivotal head-to-head trials against an active comparator (N=2659)2,3a:

POWERFUL Efficacy1a

Proven superior in reducing relapses vs Avonexc Proven superior in reducing GdE and T2 lesions vs Avonex

COMPARABLE

Safety Profile vs Avonex in Overall Incidence of Adverse Reactions1-3b Consistently low discontinuation rates vs Avonex Comparable rates of serious infections and malignancies vs Avonex

Study designs: SUNBEAM (1 year; N=1346) and RADIANCE (2 years; N=1313) were multicenter, randomized, double-blind, double-dummy, active treatment-controlled studies of daily oral ozanimod 0.46 mg (not approved for maintenance dose) or 0.92 mg vs weekly Avonex (interferon beta-1a), 30-μg intramuscular injection. Primary endpoint: ZEPOSIA reduced ARR vs Avonex by 48% at 1 year (0.18 vs 0.35, respectively) and by 38% at 2 years (0.17 vs 0.28, respectively). Secondary endpoints: ZEPOSIA reduced the number of new or enlarging T2 lesions by 48% at 1 year and by 42% at 2 years and reduced the number of GdE lesions vs Avonex by 63% at 1 year and 53% at 2 years. 9 of 10 patients showed no confirmed 3-month disability progression. There was no significant difference in 3-month confirmed disability between ZEPOSIA and Avonex.1-3 b Adverse reactions: Overall incidence of adverse reactions for ZEPOSIA vs Avonex at 1 year was 59.8% and 75.5%, respectively, and at 2 years was 74.7% and 83.0%, respectively. Across 2 head-to-head trials, the most common adverse reactions with an incidence of at least 2% in patients treated with ZEPOSIA and at least 1% greater than Avonex, respectively, were as follows: upper respiratory infection, 26% (vs 23%); hepatic transaminase elevation, 10% (vs 5%); orthostatic hypotension, 4% (vs 3%); urinary tract infection, 4% (vs 3%); back pain, 4%

The FIRST AND ONLY S1P With No First-Dose Observation Required1,4,5d

Full Prescribing Information for ZEPOSIA has NO FIRST-DOSE OBSERVATION required NO genetic testing required NO ophthalmic testing required for most patients6e

(vs 3%); hypertension, 4% (vs 2%); and abdominal pain upper, 2% (vs 1%). Data are not an adequate basis for comparison of rates between ZEPOSIA and the active control. Upper respiratory infection includes nasopharyngitis, upper respiratory tract infection, pharyngitis, respiratory tract infection, bronchitis, rhinitis, respiratory tract infection viral, viral upper respiratory tract infection, rhinorrhea, tracheitis, and laryngitis. Hepatic transaminase elevation includes alanine aminotransferase increased, gamma-glutamyl transferase increased, aspartate aminotransferase increased, hepatic enzyme increased, liver function test abnormal, and transaminase increased. Hypertension includes hypertension, essential hypertension, and orthostatic hypertension. Overall discontinuation rates for ZEPOSIA vs Avonex at 1 year were 6% and 8%, respectively, and at 2 years were 10% and 15%, respectively. Discontinuation rates due to adverse reactions for ZEPOSIA vs Avonex at 1 year were 2.9% and 3.6%, respectively, and at 2 years were 3.0% and 4.1%, respectively. Serious infections: The rate of serious infections at 1 year for ZEPOSIA was 1.1% vs 0.7% for Avonex and the rate at 2 years for ZEPOSIA was 0.9% vs 0.9% for Avonex. Malignancy rates: The rate of malignancies at 1 year for ZEPOSIA was 0.2% vs 0% for Avonex and the rate at 2 years for ZEPOSIA was 0.9% vs 0.5% for Avonex.1-3

Indication ZEPOSIA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

IMPORTANT SAFETY INFORMATION

Contraindications: • Patients who in the last 6 months, experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization,

or Class III/IV heart failure or have a presence of Mobitz type II second or third-degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial, unless the patient has a functioning pacemaker • Patients with severe untreated sleep apnea • Patients taking a monoamine oxidase (MAO) inhibitor

Please see Important Safety Information throughout and Brief Summary of full Prescribing Information.

A relapse was defined as the occurrence of new or worsening neurological symptoms persisting for more than 24 hours attributable to MS and immediately preceded by a relatively stable or improving neurological state of at least 30 days.2,3

Start at ZEPOSIAhcp.com

Before initiating treatment with ZEPOSIA, all patients require a recent CBC including lymphocyte count (within 6 months or after discontinuation of prior MS therapy), an ECG to check for preexisting conduction abnormalities, a recent liver function test (within 6 months), and consideration of current and prior medications, including vaccinations.1 Patients without a confirmed history of varicella (chickenpox) or without documented VZV vaccination should be tested for antibodies. If VZV or other live attenuated immunizations are required, administer at least 1 month prior to initiation.1 For patients with a history of uveitis or macular edema, an ophthalmic assessment is required.1 An up-titration scheme should be used to reach the maintenance dosage of ZEPOSIA, as a transient decrease in heart rate and atrioventricular conduction delays may occur.1

Diabetes mellitus and uveitis increase the risk of macular edema; patients with a history of these conditions should have an ophthalmic evaluation of the fundus, including the macula, prior to treatment initiation. A prompt ophthalmic evaluation is recommended if there is any change in vision while taking ZEPOSIA.1

ARR=annualized relapse rate; CBC=complete blood count; ECG=electrocardiogram; GdE=gadolinium enhancing; RMS=relapsing multiple sclerosis; S1P=sphingosine-1-phosphate; VZV=varicella-zoster virus.

IMPORTANT SAFETY INFORMATION (CONTINUED) Infections: ZEPOSIA may increase the susceptibility to infections. Life-threatening and rare fatal infections have occurred in patients receiving ZEPOSIA. Obtain a recent (i.e., within 6 months or after discontinuation of prior MS therapy) complete blood count (CBC) including lymphocyte count before initiation of ZEPOSIA. Delay initiation of ZEPOSIA in patients with an active infection until the infection is resolved. Consider interruption of treatment with ZEPOSIA if a patient develops a serious infection. Continue monitoring for infections up to 3 months after discontinuing ZEPOSIA • Herpes zoster was reported as an adverse reaction in ZEPOSIA-treated patients. Herpes simplex encephalitis and varicella zoster meningitis have been reported with sphingosine 1-phosphate (S1P) receptor modulators. Patients without a healthcare professional-confirmed history of varicella (chickenpox), or without documentation of a full course of vaccination against varicella zoster virus (VZV), should be tested for antibodies to VZV before initiating ZEPOSIA. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with ZEPOSIA • Cases of fatal cryptococcal meningitis (CM) were reported in patients treated with another S1P receptor modulator. If CM is suspected, ZEPOSIA should be suspended until cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.

• Progressive Multifocal Leukoencephalopathy (PML) is an opportunistic viral infection of the brain that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability. No cases of PML were identified in active-controlled MS clinical trials with ZEPOSIA. PML has been reported in patients treated with S1P receptor modulators and other MS therapies and has been associated with some risk factors. If PML is suspected, withhold ZEPOSIA and perform an appropriate diagnostic evaluation. If confirmed, treatment with ZEPOSIA should be discontinued • In clinical studies, patients who received ZEPOSIA were not to receive concomitant treatment with antineoplastic, non-corticosteroid immunosuppressive, or immunemodulating therapies used for treatment of MS. Concomitant use of ZEPOSIA with any of these therapies would be expected to increase the risk of immunosuppression. When switching to ZEPOSIA from immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects • Use of live attenuated vaccines should be avoided during and for 3 months after treatment with ZEPOSIA. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA

Discover an oral therapy for your patients with relapsing forms of multiple sclerosis (MS)1…

ZEPOSIA—FOCUSED ON WHAT COUNTS IMPORTANT SAFETY INFORMATION (CONTINUED)

Start at ZEPOSIAhcp.com

Bradyarrhythmia and Atrioventricular Conduction Delays: Since initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction delays, dose titration is recommended to help reduce cardiac effects. Initiation of ZEPOSIA without dose escalation may result in greater decreases in heart rate. If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals: • with significant QT prolongation • with arrhythmias requiring treatment with Class 1a or III anti-arrhythmic drugs • with ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension • with a history of Mobitz type II second-degree or higher AV block, sick-sinus syndrome, or sinoatrial heart block Liver Injury: Elevations of aminotransferases may occur in patients receiving ZEPOSIA. Obtain liver function tests, if not recently available (i.e., within 6 months), before initiation of ZEPOSIA. Patients who develop symptoms suggestive of hepatic dysfunction should have hepatic enzymes checked and ZEPOSIA should be discontinued if significant liver injury is confirmed. Caution should be exercised when using ZEPOSIA in patients with history of significant liver disease Fetal Risk: There are no adequate and well-controlled studies in pregnant women. Based on animal studies, ZEPOSIA may cause fetal harm. Women of childbearing potential should use effective contraception to avoid pregnancy during treatment and for 3 months after stopping ZEPOSIA Increased Blood Pressure: Increase in systolic pressure was observed after about 3 months of treatment and persisted throughout treatment. Blood pressure should be monitored during treatment and managed appropriately. Certain foods that may contain very high amounts of tyramine could cause severe hypertension in patients taking ZEPOSIA. Patients should be advised to avoid foods containing a very large amount of tyramine while taking ZEPOSIA Respiratory Effects: ZEPOSIA may cause a decline in pulmonary function. Spirometric evaluation of respiratory function should be performed during therapy, if clinically indicated Macular edema: S1P modulators have been associated with an increased risk of macular edema. Patients with a history of uveitis or diabetes mellitus are at increased risk. Patients with a history of these conditions should have an ophthalmic evaluation of the fundus, including the macula, prior to treatment initiation and regular follow-up examinations. An ophthalmic evaluation is recommended in all patients at any time if there is a change in vision. Continued use of ZEPOSIA in patients with macular edema has not been evaluated; potential benefits and risks for the individual patient should be considered if deciding whether ZEPOSIA should be discontinued Posterior Reversible Encephalopathy Syndrome (PRES): Rare cases of PRES have been reported in patients receiving a S1P receptor modulator. If a ZEPOSIA-treated patient develops unexpected neurological or psychiatric symptoms or any symptom/sign suggestive of an increase in intracranial pressure, a complete physical and neurological examination should be conducted. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, treatment with ZEPOSIA should be discontinued Unintended Additive Immunosuppressive Effects From Prior Immunosuppressive or Immune-Modulating Drugs: When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk of disease reactivation. Initiating treatment with ZEPOSIA after treatment with alemtuzumab is not recommended Severe Increase in Disability After Stopping ZEPOSIA: Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of a S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping ZEPOSIA treatment so patients should be monitored upon discontinuation Immune System Effects After Stopping ZEPOSIA: After discontinuing ZEPOSIA, the median time for lymphocyte counts to return to the normal range was 30 days with approximately 90% of patients in the normal range within 3 months. Use of immunosuppressants within this period may lead to an additive effect on the immune system, therefore caution should be applied when initiating other drugs 4 weeks after the last dose of ZEPOSIA Most common Adverse Reactions (≥ 4%): upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension.

Please see Important Safety Information throughout and Brief Summary of full Prescribing Information. References: 1. ZEPOSIA. Prescribing information. Bristol Myers Squibb; 2020. 2. Comi G, Kappos L, Selmaj KW, et al; SUNBEAM Study Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. 2019;18(11):1009-1020 and Suppl 1-26. doi:10.1016/S1474-4422(19)30239-X 3. Cohen JA, Comi G, Selmaj KW, et al; RADIANCE Trial Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019;18(11):1021-1033 and Suppl 1-31. doi:10.1016/S1474-4422(19)30238-8 4. Gilenya. Prescribing information. Novartis Pharmaceuticals Corporation; 2019. 5. Mayzent. Prescribing information. Novartis Pharmaceuticals Corporation; 2019. 6. Marrie RA. Comorbidity in multiple sclerosis: implications for patient care. Nat Rev Neurol. 2017;13(6):375-382. doi:10.1038/ nrneurol.2017.33

ZEPOSIA® is a registered trademark of Celgene Corporation, a Bristol-Myers Squibb Company. All other trademarks are the property of their respective owners. © 2020 Bristol-Myers Squibb Company. All rights reserved. Printed in the USA. 08/20 US-ZEP-19-0074

ZEPOSIA® (ozanimod) capsules, for oral use The following is a Brief Summary; refer to full Prescribing Information for complete product information. 1

• Have the presence of Mobitz type II second-degree or third degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker [see Warnings and Precautions (5.2)]

INDICATIONS AND USAGE

ZEPOSIA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. 2

DOSAGE AND ADMINISTRATION

2.1 Assessments Prior to First Dose of ZEPOSIA Before initiation of treatment with ZEPOSIA, assess the following: Complete Blood Count Obtain a recent (i.e., within the last 6 months or after discontinuation of prior MS therapy) complete blood count (CBC), including lymphocyte count [see Warnings and Precautions (5.1)]. Cardiac Evaluation Obtain an electrocardiogram (ECG) to determine whether preexisting conduction abnormalities are present. In patients with certain preexisting conditions, advice from a cardiologist should be sought [see Warnings and Precautions (5.2)]. Liver Function Tests Obtain recent (i.e., within the last 6 months) transaminase and bilirubin levels [see Warnings and Precautions (5.3)]. Ophthalmic Assessment In patients with a history of uveitis or macular edema, obtain an evaluation of the fundus, including the macula [see Warnings and Precautions (5.7)]. Current or Prior Medications • If patients are taking anti-neoplastic, immunosuppressive, or immune-modulating therapies, or if there is a history of prior use of these drugs, consider possible unintended additive immunosuppressive effects before initiating treatment with ZEPOSIA [see Warnings and Precautions (5.1) and Drug Interactions (7.1)]. • Determine if patients are taking drugs that could slow heart rate or atrioventricular conduction [see Warnings and Precautions (5.2) and Drug Interactions (7.2)]. Vaccinations Test patients for antibodies to varicella zoster virus (VZV) before initiating ZEPOSIA; VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with ZEPOSIA [see Warnings and Precautions (5.1) and Drug Interactions (7.3)]. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA. 2.2 Dosing Information Maintenance Dosage After initial titration (see Treatment Initiation), the recommended maintenance dosage of ZEPOSIA is 0.92 mg taken orally once daily starting on Day 8. ZEPOSIA capsules should be swallowed whole and can be administered with or without food. Treatment Initiation Initiate ZEPOSIA with a 7-day titration, as shown in Table 1 [see Warnings and Precautions (5.2)]. Table 1: Dose Titration Regimen Days 1-4

0.23 mg once daily

Days 5-7

0.46 mg once daily

Day 8 and thereafter

0.92 mg once daily

2.3 Reinitiation of ZEPOSIA After Treatment Interruption If a dose of ZEPOSIA is missed during the first 2 weeks of treatment, reinitiate treatment using the titration regimen [see Dosage and Administration (2.2)]. If a dose of ZEPOSIA is missed after the first 2 weeks of treatment, continue with the treatment as planned. 4

CONTRAINDICATIONS

ZEPOSIA is contraindicated in patients who: • In the last 6 months, have experienced a myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III or IV heart failure [see Warnings and Precautions (5.2)]

• Have severe untreated sleep apnea [see Warnings and Precautions (5.2)] • Are taking a monoamine oxidase (MAO) Inhibitor [see Drug Interactions (7.7)] 5

WARNINGS AND PRECAUTIONS

5.1 Infections Risk of Infections ZEPOSIA causes a mean reduction in peripheral blood lymphocyte count to 45% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues [see Clinical Pharmacology (12.2)]. ZEPOSIA may therefore increase the susceptibility to infections, some serious in nature. Life-threatening and rare fatal infections have occurred in patients receiving ZEPOSIA. Obtain a recent (i.e., within 6 months or after discontinuation of prior MS therapy) complete blood count (CBC) including lymphocyte count before initiation of ZEPOSIA. Delay initiation of ZEPOSIA in patients with an active infection until the infection is resolved. In Study 1 and Study 2, the overall rate of infections and rate of serious infections in patients treated with ZEPOSIA was similar to that in patients who received interferon (IFN) beta-1a (35% vs 34% and 1% vs 0.8%, respectively). ZEPOSIA increased the risk of viral upper respiratory tract infections, urinary tract infections, and herpes zoster [see Adverse Reactions (6.1)]. The proportion of patients who experienced lymphocyte counts less than 0.2 x 109/L was 3.3%. These values generally returned to greater than 0.2 x 109/L while patients remained on treatment with ZEPOSIA. After discontinuing ZEPOSIA 0.92 mg, the median time for peripheral blood lymphocytes to return to the normal range was 30 days, with approximately 90% of patients in the normal range within 3 months [see Clinical Pharmacology (12.2)]. Consider interruption of treatment with ZEPOSIA if a patient develops a serious infection. Because the elimination of ZEPOSIA after discontinuation may take up to 3 months, continue monitoring for infections throughout this period.

Herpes Viral Infection In Study 1 and Study 2, herpes zoster was reported as an adverse reaction in 0.6% of patients treated with ZEPOSIA 0.92 mg and in 0.2% of patients who received IFN beta-1a. Herpes simplex encephalitis and varicella zoster meningitis have been reported with sphingosine 1-phosphate (S1P) receptor modulators. Patients without a healthcare professional-confirmed history of varicella (chickenpox), or without documentation of a full course of vaccination against varicella zoster virus (VZV), should be tested for antibodies to VZV before initiating ZEPOSIA (see Vaccinations below). Cryptococcal Infection Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with S1P receptor modulators. Physicians should be vigilant for clinical symptoms or signs of CM. Patients with symptoms or signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment. ZEPOSIA treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. PML has been reported in patients treated with S1P receptor modulators and other multiple sclerosis (MS) therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). Physicians should be vigilant for clinical symptoms or MRI findings that may be suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. If PML is suspected, treatment with ZEPOSIA should be suspended until PML has been excluded by an appropriate diagnostic evaluation. If PML is confirmed, treatment with ZEPOSIA should be discontinued.

ZEPOSIA® (ozanimod) capsules, for oral use Prior and Concomitant Treatment with Anti-neoplastic, Immunosuppressive, or Immune-modulating Therapies In clinical studies, patients who received ZEPOSIA were not to receive concomitant treatment with anti-neoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies used for the treatment of MS. Concomitant use of ZEPOSIA with any of these therapies would be expected to increase the risk of immunosuppression. Antineoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids) should be co-administered with caution because of the risk of additive immune system effects during such therapy. When switching to ZEPOSIA from immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects. Vaccinations Patients without a healthcare professional-confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating ZEPOSIA. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with ZEPOSIA, following which initiation of treatment with ZEPOSIA should be postponed for 4 weeks to allow the full effect of vaccination to occur. No clinical data are available on the efficacy and safety of vaccinations in patients taking ZEPOSIA. Vaccinations may be less effective if administered during ZEPOSIA treatment. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA. Avoid the use of live attenuated vaccines during and for 3 months after treatment with ZEPOSIA. 5.2 Bradyarrhythmia and Atrioventricular Conduction Delays Since initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction delays, an up-titration scheme should be used to reach the maintenance dosage of ZEPOSIA [see Dosage and Administration (2.2) and Clinical Pharmacology (12.2)]. ZEPOSIA was not studied in patients who had: • A myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization within the last 6 months • New York Heart Association Class III / IV heart failure • Cardiac conduction or rhythm disorders, including sick sinus syndrome, significant QT prolongation (QTcF > 450 msec in males, > 470 msec in females), risk factors for QT prolongation, or other conduction abnormalities or cardiac condition that in the opinion of the treating investigator could jeopardize the patient’s health • Other pre-existing stable cardiac conditions without clearance from a cardiologist • Severe untreated sleep apnea • A resting heart rate less than 55 beats per minute (bpm) at baseline Reduction in Heart Rate Initiation of ZEPOSIA may result in a transient decrease in heart rate. In Study 1 and Study 2, after the initial dose of ZEPOSIA 0.23 mg, the greatest mean decrease from baseline in heart rate of 1.2 bpm occurred at Hour 5 on Day 1, returning to near baseline at Hour 6. With continued up-titration, the maximal heart rate effect of ozanimod occurred on Day 8. The utility of performing first-dose cardiac monitoring when initiating ZEPOSIA in patients with characteristics similar to those studied in the clinical trials of ZEPOSIA is unclear. Heart rates below 40 bpm were not observed. Initiation of ZEPOSIA without titration may result in greater decreases in heart rate [see Dosage and Administration (2.2)]. In Study 1 and Study 2, bradycardia was reported on the day of treatment initiation in 0.6% of patients treated with ZEPOSIA compared to no patients who received IFN beta-1a. After Day 1, the incidence of bradycardia was 0.8% in patients treated with ZEPOSIA compared to 0.7% of patients who received IFN beta-1a. Atrioventricular Conduction Delays Initiation of ZEPOSIA may result in transient atrioventricular conduction delays. At ZEPOSIA exposures higher than the recommended dosage without dose titration, first- and second-degree type 1 atrioventricular blocks were observed in healthy volunteers; however, in Study 1 and Study 2 with dose titration, second- or third-degree atrioventricular blocks were not reported in patients treated with ZEPOSIA. If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals: • With significant QT prolongation (QTcF > 450 msec in males, > 470 msec in females) • With arrhythmias requiring treatment with Class 1a or Class III anti-arrhythmic drugs

• With ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension • With a history of with second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sinoatrial heart block [see Contraindications (4)] 5.3 Liver Injury Elevations of aminotransferases may occur in patients receiving ZEPOSIA. Obtain transaminase and bilirubin levels, if not recently available (i.e., within 6 months), before initiation of ZEPOSIA. In Study 1 and Study 2, elevations of ALT to 5-fold the upper limit of normal (ULN) or greater occurred in 1.6% of patients treated with ZEPOSIA 0.92 mg and 1.3% of patients who received IFN beta-1a. Elevations of 3-fold the ULN or greater occurred in 5.5% of patients treated with ZEPOSIA and 3.1% of patients who received IFN beta-1a. The median time to an elevation of 3-fold the ULN was 6 months. The majority (79%) of patients continued treatment with ZEPOSIA with values returning to less than 3 times the ULN within approximately 2-4 weeks. In clinical trials, ZEPOSIA was discontinued for a confirmed elevation greater than 5-fold the ULN. Overall, the discontinuation rate because of elevations in hepatic enzymes was 1.1% of patients treated with ZEPOSIA 0.92 mg and 0.8% of patients who received IFN beta-1a. Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, should have hepatic enzymes checked, and ZEPOSIA should be discontinued if significant liver injury is confirmed. Individuals with an AST or ALT greater than 1.5 times ULN were excluded from Study 1 and Study 2. Although there are no data to establish that patients with preexisting liver disease are at increased risk to develop elevated liver function test values when taking ZEPOSIA, caution should be exercised when using ZEPOSIA in patients with a history of significant liver disease. 5.4 Fetal Risk There are no adequate and well-controlled studies in pregnant women. Based on animal studies, ZEPOSIA may cause fetal harm [see Use in Specific Populations (8.1)]. Because it takes approximately 3 months to eliminate ZEPOSIA from the body, women of childbearing potential should use effective contraception to avoid pregnancy during treatment and for 3 months after stopping ZEPOSIA [see Use in Specific Populations (8.1)]. 5.5 Increased Blood Pressure In Study 1 and Study 2, patients treated with ZEPOSIA had an average increase of approximately 1 to 2 mm Hg in systolic pressure over patients who received IFN beta-1a, and no effect on diastolic pressure. The increase in systolic pressure was first detected after approximately 3 months of treatment and persisted throughout treatment. Hypertension was reported as an adverse reaction in 3.9% of patients treated with ZEPOSIA 0.92 mg and in 2.1% of patients who received IFN beta-1a. Two patients treated with ZEPOSIA in Study 1 and one patient treated with interferon (IFN) beta-1a in Study 2 experienced a hypertensive crisis that was not clearly influenced by a concomitant medication. Blood pressure should be monitored during treatment with ZEPOSIA and managed appropriately. Certain foods that may contain very high amounts (i.e., more than 150 mg) of tyramine could cause severe hypertension because of potential tyramine interaction in patients taking ZEPOSIA, even at the recommended doses. Because of an increased sensitivity to tyramine, patients should be advised to avoid foods containing a very large amount of tyramine while taking ZEPOSIA. 5.6 Respiratory Effects Dose-dependent reductions in absolute forced expiratory volume over 1 second (FEV1) were observed in patients treated with ZEPOSIA as early as 3 months after treatment initiation. In pooled analyses of Study 1 and Study 2, the decline in absolute FEV1 from baseline in patients treated with ZEPOSIA compared to patients who received IFN beta-1a was 60 mL (95% CI: -100, -20) at 12 months. The mean difference in percent predicted FEV1 at 12 months between patients treated with ZEPOSIA and patients who received IFN beta-1a was 1.9% (95% CI: -2.9, -0.8). Dose-dependent reductions in forced vital capacity (FVC) (absolute value and %-predicted) were also seen at Month 3 in pooled analyses comparing patients treated with ZEPOSIA to patients who received IFN beta-1a (60 mL, 95% CI (-110, -10); 1.4%, 95% CI: (-2.6, -0.2)), though significant reductions were not seen at other timepoints. There is insufficient information to determine the reversibility of the decrease in FEV1 or FVC after drug discontinuation. One patient discontinued ZEPOSIA because of dyspnea. Spirometric evaluation of respiratory function should be performed during therapy with ZEPOSIA, if clinically indicated.

ZEPOSIA® (ozanimod) capsules, for oral use 5.7 Macular Edema S1P modulators, including ZEPOSIA, have been associated with an increased risk of macular edema. In Study 1 and Study 2, macular edema was observed in 0.3% of patients treated with ZEPOSIA and in 0.3% of patients who received IFN beta-1a. An ophthalmic evaluation of the fundus, including the macula, is recommended in all patients at any time if there is any change in vision while taking ZEPOSIA. Continuation of ZEPOSIA therapy in patients with macular edema has not been evaluated. A decision on whether or not ZEPOSIA should be discontinued needs to take into account the potential benefits and risks for the individual patient.

B:11.125" T:10.875" S:9.875"

Macular Edema in Patients with a History of Uveitis or Diabetes Mellitus Patients with a history of uveitis and patients with a history of diabetes mellitus are at increased risk of macular edema during ZEPOSIA therapy. The incidence of macular edema is also increased in MS patients with a history of uveitis. In addition to the examination of the fundus, including the macula, prior to treatment, MS patients with diabetes mellitus or a history of uveitis should have regular follow-up examinations. 5.8 Posterior Reversible Encephalopathy Syndrome Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving a S1P receptor modulator. In controlled clinical trials with ZEPOSIA, one case of PRES was reported. Should a ZEPOSIA-treated patient develop any unexpected neurological or psychiatric symptoms/signs (e.g., cognitive deficits, behavioral changes, cortical visual disturbances, or any other neurological cortical symptoms/signs), any symptom/sign suggestive of an increase of intracranial pressure, or accelerated neurological deterioration, the physician should promptly schedule a complete physical and neurological examination and should consider an MRI. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, treatment with ZEPOSIA should be discontinued. 5.9 Unintended Additive Immunosuppressive Effects From Prior Treatment with Immunosuppressive or Immune-Modulating Drugs When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk of disease reactivation, when initiating ZEPOSIA. Initiating treatment with ZEPOSIA after treatment with alemtuzumab is not recommended [see Drug Interactions (7.1)]. 5.10 Severe Increase in Disability After Stopping ZEPOSIA Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of a S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping ZEPOSIA treatment. Patients should be observed for a severe increase in disability upon ZEPOSIA discontinuation and appropriate treatment should be instituted, as required. 5.11 Immune System Effects After Stopping ZEPOSIA After discontinuing ZEPOSIA, the median time for peripheral blood lymphocytes to return to the normal range was 30 days, with approximately 90% of patients in the normal range within 3 months [see Clinical Pharmacology (12.2)]. Use of immunosuppressants within this period may lead to an additive effect on the immune system, and therefore caution should be applied when initiating other drugs 4 weeks after the last dose of ZEPOSIA [see Drug Interactions (7.1)]. 6

ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling: • Infections [see Warnings and Precautions (5.1)] • Bradyarrhythmia and Atrioventricular Conduction Delays [see Warnings and Precautions (5.2)] • Liver Injury [see Warnings and Precautions (5.3)] • Fetal Risk [see Warnings and Precautions (5.4)] • Increased Blood Pressure [see Warnings and Precautions (5.5)] • Respiratory Effects [see Warnings and Precautions (5.6)] • Macular Edema [see Warnings and Precautions (5.7)] • Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.8)] • Unintended Additive Immunosuppressive Effects From Prior Treatment With Immunosuppressive or Immune-Modulating Drugs [see Warnings and Precautions (5.9)] • Severe Increase in Disability After Stopping ZEPOSIA [see Warnings and Precautions (5.10)] • Immune System Effects After Stopping ZEPOSIA [see Warnings and Precautions (5.11)]

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of ZEPOSIA was evaluated in two randomized, double-blind, active comparator-controlled clinical studies in which 882 patients received ZEPOSIA 0.92 mg [see Clinical Studies (14)]. Table 2 lists adverse reactions that occurred in at least 2% of ZEPOSIA-treated patients and greater than comparator. The most common adverse reactions that occurred in at least 4% of ZEPOSIA-treated patients and greater than in patients who received IFN beta-1a were upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension. Table 2: Adverse Reactions with an Incidence of at Least 2% in ZEPOSIA-Treated Patients and at Least 1% Greater than IFN beta-1aa (Pooled Study 1 and Study 2)

Adverse Reactions

Studies 1 and 2 ZEPOSIA IFN beta-1a 0.92 mg 30 mcg (n=882) Intramuscularly % Once Weekly (n=885) %

Upper respiratory infectionb

Hepatic transaminase elevationc

Orthostatic hypotension

Urinary tract infection

Back pain

Hypertensiond

Abdominal pain upper

Data are not an adequate basis for comparison of rates between ZEPOSIA and the active control. b Includes the following terms: nasopharyngitis, upper respiratory tract infection, pharyngitis, respiratory tract infection, bronchitis, rhinitis, respiratory tract infection viral, viral upper respiratory tract infection, rhinorrhea, tracheitis, and laryngitis. c Includes the following terms: alanine aminotransferase increased, gammaglutamyl transferase increased, aspartate aminotransferase increased, hepatic enzyme increased, liver function test abnormal, and transaminases increased. d Includes hypertension, essential hypertension, and orthostatic hypertension. Reduction in Heart Rate Initiation of ZEPOSIA may result in transient decrease in heart rate [see Warnings and Precautions (5.2)]. Respiratory Effects Dose-dependent reductions in absolute FEV1 and FVC were observed in patients treated with ZEPOSIA [see Warnings and Precautions (5.6)]. Malignancies Malignancies, such as melanoma, basal cell carcinoma, breast cancer, and seminoma, were reported with ZEPOSIA in the active-controlled trials for ZEPOSIA. An increased risk of cutaneous malignancies has been reported with another S1P receptor modulator. Hypersensitivity Hypersensitivity, including rash and urticaria, has been reported with ZEPOSIA in active-controlled MS clinical trials. 7

DRUG INTERACTIONS

7.1 Anti-Neoplastic, Immune-Modulating, or Immunosuppressive Therapies ZEPOSIA has not been studied in combination with anti-neoplastic, immunemodulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during such therapy and in the weeks following administration [see Warnings and Precautions (5.1)]. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects [see Warnings and Precautions (5.9)].

ZEPOSIA® (ozanimod) capsules, for oral use Because of the characteristics and duration of alemtuzumab immune suppressive effects, initiating treatment with ZEPOSIA after alemtuzumab is not recommended. ZEPOSIA can generally be started immediately after discontinuation of beta interferon or glatiramer acetate. 7.2 Anti-Arrhythmic Drugs, QT Prolonging Drugs, Drugs That may Decrease Heart Rate ZEPOSIA has not been studied in patients taking QT prolonging drugs. Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) anti-arrhythmic drugs have been associated with cases of Torsades de Pointes in patients with bradycardia. If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought. Because of the potential additive effects on heart rate, treatment with ZEPOSIA should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties [see Warnings and Precautions (5.2)]. If treatment initiation with ZEPOSIA is considered in patients on QT prolonging drugs, advice from a cardiologist should be sought. 7.3 Vaccination During, and for up to three months after, discontinuation of treatment with ZEPOSIA, vaccinations may be less effective. The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during ZEPOSIA treatment and for up to 3 months after discontinuation of treatment with ZEPOSIA [see Warnings and Precautions (5.1)]. 7.4 Strong CYP2C8 Inhibitors Co-administration of ZEPOSIA with strong CYP2C8 inhibitors increases the exposure of the active metabolites of ozanimod [see Clinical Pharmacology (12.3)], which may increase the risk of ZEPOSIA adverse reactions. Therefore, co-administration of ZEPOSIA with strong CYP2C8 inhibitors (e.g., gemfibrozil) is not recommended. 7.5 Breast Cancer Resistance Protein (BCRP) Inhibitors Co-administration of ZEPOSIA with BCRP inhibitors increases the exposure of the active metabolites of ozanimod [see Clinical Pharmacology (12.3)], which may increase the risk of ZEPOSIA adverse reactions. Therefore, co-administration of ZEPOSIA with inhibitors of BCRP (e.g., cyclosporine, eltrombopag) is not recommended. 7.6 Strong CYP2C8 Inducers Co-administration of ZEPOSIA with strong CYP2C8 inducers (e.g., rifampin) reduces the exposure of the major active metabolites of ozanimod [see Clinical Pharmacology (12.3)], which may decrease the efficacy of ZEPOSIA. Therefore, co-administration of ZEPOSIA with strong CYP2C8 inducers should be avoided. 7.7 Monoamine Oxidase (MAO) Inhibitors Co-administration of ZEPOSIA with MAO-B inhibitors may decrease exposure of the active metabolites of ozanimod. In addition, metabolites of ozanimod may inhibit MAO [see Clinical Pharmacology (12.3)]. The potential for a clinical interaction with MAO inhibitors has not been studied; however, the increased risk of nonselective MAO inhibition may lead to a hypertensive crisis. Therefore, co-administration of ZEPOSIA with MAO inhibitors (e.g., selegiline, phenelzine, linezolid) is contraindicated. At least 14 days should elapse between discontinuation of ZEPOSIA and initiation of treatment with MAO inhibitors. 7.8 Adrenergic and Serotonergic Drugs Because an active metabolite of ozanimod inhibits MAO-B in vitro, there is a potential for serious adverse reactions, including hypertensive crisis. Therefore, co-administration of ZEPOSIA with drugs or over-the-counter medications that can increase norepinephrine or serotonin [e.g., opioid drugs, selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), tricyclics, tyramine] is not recommended. Monitor patients for hypertension with concomitant use. Opioid Drugs Serious, sometimes fatal reactions have been precipitated with concomitant use of opioid drugs (e.g., meperidine and its derivatives, methadone, or tramadol) and MAOIs, including selective MAO-B inhibitors. Although a small number of patients treated with ZEPOSIA were concomitantly exposed to opioids, this exposure was not adequate to rule out the possibility of an adverse reaction from co-administration. Serotonergic Drugs Although a small number of patients treated with ZEPOSIA were concomitantly exposed to serotonergic medications, this exposure was not adequate to rule out the possibility of an adverse reaction from co-administration.

Sympathomimetic Medications Concomitant use of ZEPOSIA with pseudoephedrine did not potentiate the effects on blood pressure [see Clinical Pharmacology (12.3)]. However, hypertensive crisis has occurred with administration of ZEPOSIA alone [see Warnings and Precautions (5.5)] and hypertensive crisis has been reported with co-administration of other selective and nonselective MAO inhibitors (e.g., rasagiline) with sympathomimetic medications. 7.9 Tyramine MAO in the gastrointestinal tract and liver (primarily type A) provides protection from exogenous amines (e.g., tyramine). If tyramine were absorbed intact, it could lead to severe hypertension, including hypertensive crisis. Aged, fermented, cured, smoked, and pickled foods containing large amounts of exogenous amines (e.g., aged cheese, pickled herring) may cause release of norepinephrine resulting in a rise in blood pressure (tyramine reaction). Patients should be advised to avoid foods containing a large amount of tyramine while taking recommended doses of ZEPOSIA [see Warnings and Precautions (5.5)]. 8

USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of ZEPOSIA in pregnant women. In animal studies, administration of ozanimod during pregnancy produced adverse effects on development, including embryolethality, an increase in fetal malformations, and neurobehavioral changes, in the absence of maternal toxicity. In rabbits, fetal blood vessel malformations occurred at clinically relevant maternal ozanimod and metabolite exposures (see Data). The receptor affected by ozanimod (sphingosine-1-phosphate) has been demonstrated to have an important role in embryogenesis, including vascular and neural development. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Oral administration of ozanimod (0, 0.2, 1, or 5 mg/kg/day) to female rats during organogenesis resulted in a marked increase in embryofetal mortality, increased fetal malformations and skeletal variations (abnormal/delayed ossification), and reduced fetal body weight at the highest dose tested. No maternal toxicity was observed. At the no-effect dose (1 mg/kg/day) for adverse effects on embryofetal development, plasma ozanimod exposure (AUC) for ozanimod was approximately 60 times that in humans at the maximum recommended human dose (MRHD) of 0.92 mg/day. Plasma AUCs for major human metabolites, CC112273 and CC1084037, were similar to and less than, respectively, those in humans at the MRHD. Oral administration of ozanimod (0, 0.2, 0.6, or 2.0 mg/kg/day) to female rabbits during organogenesis resulted in a marked increase in embryofetal mortality at the highest dose tested and increased fetal malformations (malformed blood vessels) and skeletal variations at the mid and high doses. Maternal toxicity was not observed. At the no-effect dose (0.2 mg/kg/day) for adverse effects on embryofetal development in rabbit, plasma ozanimod exposure (AUC) was approximately 2 times that in humans at the MRHD; plasma AUCs for major human metabolites, CC112273 and CC1084037, were less than those in humans at the MRHD. Oral administration of ozanimod (0, 0.2, 0.7, or 2 mg/kg/day) to female rats throughout gestation and lactation resulted in persistent body weight reductions and long-term effects on reproductive (prolonged estrus cycle) and neurobehavioral (increased motor activity) function in offspring at the highest dose tested, which was not associated with maternal toxicity. At the no-effect dose (0.7 mg/kg/day) for adverse effects on pre- and postnatal development, plasma ozanimod exposure (AUC) was 30 times that in humans at the MRHD; plasma AUCs for major human metabolites, CC112273 and CC1084037, were less than those in humans at the MRHD. 8.2 Lactation Risk Summary There are no data on the presence of ozanimod in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Following oral administration of ozanimod, ozanimod and/or metabolites were detected in the milk of lactating rat at levels higher than those in maternal plasma. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZEPOSIA and any potential adverse effects on the breastfed infant from ZEPOSIA or from the underlying maternal condition.

ZEPOSIA® (ozanimod) capsules, for oral use 8.3 Females and Males of Reproductive Potential Contraception Before initiation of ZEPOSIA treatment, women of childbearing potential should be counseled on the potential for a serious risk to the fetus and the need for contraception during treatment with ZEPOSIA [see Use in Specific Populations (8.1)]. Because of the time it takes to eliminate the drug from the body after stopping treatment, the potential risk to the fetus may persist and women of childbearing age should also use effective contraception for 3 months after stopping ZEPOSIA. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of ZEPOSIA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of the ozanimod major active metabolites is unknown [see Clinical Pharmacology (12.3)]. Use of ZEPOSIA in patients with hepatic impairment is not recommended. 13

NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Oral administration of ozanimod (0, 8, 25, or 80 mg/kg/day) to Tg.rasH2 mice for 26-weeks resulted in an increase in hemangioma and hemangiosarcoma (combined) in males and females at the mid and high doses tested. Oral administration of ozanimod (0, 0.2, 0.7, or 2 mg/kg/day) to rats for 2 years resulted in no increase in tumors. At the highest dose tested (2 mg/kg/day), plasma exposure (AUC) for ozanimod was approximately 100 times that in humans at the maximum recommended human dose (MRHD) of 0.92 mg/day. Plasma AUCs for major human metabolites, CC112273 and CC1084037, were similar to and less than, respectively, those in humans at the MRHD. Mutagenesis Ozanimod was negative in a battery of in vitro (Ames, mouse lymphoma tk) and in vivo (rat micronucleus) assays. Metabolite CC1122273 was negative in in vitro (Ames, chromosomal aberration in mammalian cell) assays. Metabolite CC1084037 was negative in an Ames assay, and positive in an in vitro chromosomal aberration assay in human (TK6) cells but negative in an in vivo rat micronucleus/comet assay. Impairment of Fertility Oral administration of ozanimod (0, 0.2, 2, or 30 mg/kg/day) to male and female rats prior to and during mating and continuing through gestation day 7 resulted in no adverse effects on fertility. At the highest dose tested (30 mg/kg/day), plasma ozanimod exposure (AUC) was approximately 1600 times that in humans at the maximum recommended human dose (MRHD) (0.92 mg/day); plasma AUCs for metabolites, CC112273 and CC1084037, at 30 mg/kg/day were 13 and 3 times, respectively, those in humans at the MRHD. 17

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Risk of Infections Inform patients that they may be more likely to get infections, some of which could be life-threatening, when taking ZEPOSIA and for 3 months after stopping it, and that they should contact their healthcare provider if they develop symptoms of infection [see Warnings and Precautions (5.1)].

Inform patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection. Advise patients that some vaccines containing live virus (live attenuated vaccines) should be avoided during treatment with ZEPOSIA. If immunizations are planned, administer at least 1 month prior to initiation of ZEPOSIA. Avoid the use of live attenuated vaccines during and for 3 months after treatment with ZEPOSIA. Patients without a healthcare professional-confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating ZEPOSIA. Cardiac Effects Advise patients that initiation of ZEPOSIA treatment may result in a transient decrease in heart rate. Inform patients that to reduce this effect, dose titration is required. Advise patients that the dose titration is also required if a dose is missed for 1 day or more during the first 14 days of treatment [see Dosage and Administration (2.2, 2.3) and Warnings and Precautions (5.2)]. Liver Injury Inform patients that ZEPOSIA may increase liver enzymes. Advise patients that they should contact their healthcare provider if they have any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine [see Warnings and Precautions (5.3)]. Pregnancy and Fetal Risk Inform patients that, based on animal studies, ZEPOSIA may cause fetal harm. Discuss with women of childbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant. Advise women of childbearing potential of the need for effective contraception during treatment with ZEPOSIA and for 3 months after stopping ZEPOSIA. Advise a female patient to immediately inform her healthcare provider if she is pregnant or planning to become pregnant [see Warnings and Precautions (5.4)]. Respiratory Effects Advise patients that they should contact their healthcare provider if they experience new onset or worsening dyspnea [see Warnings and Precautions (5.6)]. Macular Edema Advise patients that ZEPOSIA may cause macular edema, and that they should contact their healthcare provider if they experience any changes in their vision. Inform patient with diabetes mellitus or a history of uveitis that their risk of macular edema maybe increased [see Warnings and Precautions (5.7)]. Posterior Reversible Encephalopathy Syndrome Advise patients to immediately report to their healthcare provide any symptoms involving sudden onset of severe headache, altered mental status, visual disturbances, or seizure. Inform patients that delayed treatment could lead to permanent neurological consequences [see Warnings and Precautions (5.8)]. Severe Increase in Disability After Stopping ZEPOSIA Inform patients that severe increase in disability has been reported after discontinuation of a S1P receptor modulator like ZEPOSIA. Advise patients to contact their physician if they develop worsening symptoms of MS following discontinuation of ZEPOSIA [see Warnings and Precautions (5.10)]. Immune System Effects After Stopping ZEPOSIA Advise patients that ZEPOSIA continues to have effects, such as lowering effects on peripheral lymphocyte count, for up to 3 months after the last dose [see Warnings and Precautions (5.11)]. Manufactured for: Celgene Corporation Summit, NJ 07901 Patent: www.celgene.com/therapies ZEPOSIA® is a trademark of Celgene, a Bristol-Myers Squibb Company. © 2020 Bristol-Myers Squibb Company. All rights reserved. ZEP_HCP_BSv.001.05 03/2020

AANnews · May 2021

May Highlights The Mission of the AAN is to promote the highest quality patient-centered neurologic care and enhance member career satisfaction. The Vision of the AAN is to be indispensable to our members. Contact Information American Academy of Neurology 201 Chicago Avenue Minneapolis, MN 55415 Phone: (800) 879-1960 (toll free) (612) 928-6000 (international) Email:

memberservices@aan.com

Website: AAN.com For advertising rates, contact: Eileen R. Henry Wolters Kluwer Health | Medical Research Lippincott, Williams & Wilkins Phone: (732) 778-2261 Email: Eileen.Henry@wolterskluwer.com

AAN Chief Executive Officer: Mary E. Post, MBA, CAE

2021 QI Innovation Awards Honor Quality Improvement and Patient Safety Efforts

Emerging Leaders Graduate Finds Success in Uniting Music, Medicine, and Leadership

The Quality Improvement Innovation Award debuted in 2020 to recognize individuals and teams who implement and successfully advance quality improvement and patient safety in practice. This year, Dara V.F. Albert, DO, MEd, and Mahjabin Islam, MBBS, MRCP (UK), have been selected to receive this award.

“Music is what I would be doing professionally, were it not for neurology,” began 2015 Emerging Leaders Program graduate Alexander Pantelyat, MD. Luckily for Pantelyat—and his patients—he has been able to combine both passions to great success, and in no small part due to the skills he gained through his experience with the AAN’s Emerging Leaders Program.

AAN Member Provides Generous Endowment for Alma Mater SIGN Chapter

AAN member Barney J. Stern, MD, FAAN, has provided a generous lead gift to support Student Interest Group in Neurology (SIGN) chapter at his residency medical school and alma mater at the University of Rochester, NY.

News Briefs Editor-in-Chief: Melissa W. Ko, MD, FAAN, CPE Managing Editor: Angela M. Babb, MS, CAE, APR Editor: Tim Streeter Writers: Ryan Knoke and Sarah Parsons Designer: Siu Lee Email: aannews@aan.com AANnews® is published monthly by the American Academy of Neurology for its 36,000 members worldwide. Access this magazine and other AAN publications online at AAN.com. The American Academy of Neurology ’ s registered trademarks and service marks are registered in the United States and various other countries around the world. “American Brain Foundation” is a registered service mark of the American Brain Foundation and is registered in the United States. The inclusion of advertisements and/or promotions of Sponsors and other Internet sites or resources that offer content, goods, or services on the Website does not imply endorsement of the advertised/promoted products or services by AAN.

Guillain-Barré Syndrome and Vaccine Trial Report

AAN Members Champion National Wellness Activities

Two people participating in a COVID-19 vaccine trial, one who received the vaccine and one who received a placebo of saline solution, developed GuillainBarré syndrome according to a new case report published in the April 6, 2021, online issue of Neurology ®. Researchers emphasized that just because a vaccinated person later developed Guillain-Barré syndrome does not prove the vaccine was the cause, as supported by how the person who received the placebo in the trial also developed the syndrome. Both people were enrolled in the Johnson & Johnson vaccine trial.

Several AAN members who have been instrumental in AAN wellness initiatives have taken on additional national leadership roles in this area. Neil A. Busis, MD, FAAN, is serving as co-leader of the National Academy of Medicine Clinician Well-being Collaborative COVID-19 Working Group. Jeffrey Dewey, MD, is chair of the Back to Bedside Work and Advisory Group for the Accreditation Council for Graduate Medical Education (ACGME), which is a grant program that funds resident- and fellow-run projects around the country focused on giving residents more meaningful contact with their patients. Mark Milstein, MD, FAAN, has served as an AAN liaison for wellness activities supported by the American Medical Association (AMA) through his role as chair of the AAN delegation to the AMA. 

President’s Column

Preparing for Our Renaissance

continued from cover

For the first time, we held virtual meetings, and they broke records for attendance. Our 2021 Annual Meeting drew thousands of registrants and presented a platform that surpassed any other we had heretofore seen. We discovered that we could hold committee meetings virtually, as nearly 800 volunteer members doubled down on their commitment to the AAN and devoted long hours on Zoom to help redefine how we deliver education, science, advocacy, and more. Bolstered by the talent of our indefatigable and diligent staff, the AAN has raised the bar for programs and services through innovation, ingenuity, and determination, with nearly four percent membership growth for 2020 vs 2019.

After the emergence of SARS-CoV-2, our editorial teams met more frequently—both independently and together—to ensure that our members, trainees, patients, caregivers, press, policymakers, and regulatory agencies received unbiased information about the neurologic sequelae of COVID-19 and the transformations to the practice of neurology. Due to these efforts, our publications’ online traffic skyrocketed. The AAN COVID-19 Neurology Resource Center reached peak traffic numbers and was accessed by members across the globe. This organization’s role as the leader in brain health was never clearer, and the value of our member expertise and experience never better demonstrated.

While preparing for this presidency I have added several new committees to address changes borne of the pandemic. Recognizing the accelerated adoption of telehealth by almost every neurologist in the nation, the AAN will be introducing the Telehealth Subcommittee to the Medical Economics and Practice Committee; it will ensure quality of care and advocate for services beyond the public health emergency. Speaking with hundreds of neurologists, many during interviews for Neurology Today ® about how COVID-19 has impacted their lives, I became increasingly concerned about the emotional toll the pandemic has extracted on front-line workers and other members. The threat to our workforce, as well as to our pipeline, is considerable. To address those repercussions, I established a Wellness Subcommittee of the Membership Engagement Committee and have charged it with focusing on the well-being of our members and creating strategies to help advocate for systemic and enduring changes that will support healing.

As we launch these new committees and reconvene existing ones, we will be focusing on inclusion. Each of our committees will be convened in a hybrid manner, so that in addition to in-person attendance, there will be members joining virtually. That will allow more diverse segments of our constituency to join us—private practitioners who had previously been unable to leave their offices; parents of small children or those caring for elder parents; and international members who are unable to travel. The new committee structure will benefit from their contributions and provide us with a diversity of thought which better reflects our membership.

The Board of Directors has recently approved an Academic Neurology Committee which will address business and organizational issues of academic neurology departments including leadership, mentorship, financial, equity, diversity, inclusion, and gender issues, and share best practices. It will promote the work of department chairs, academic business administrators, diversity officers, and division chiefs. For the past few years, former AAN President Ralph L. Sacco, MD, MS, FAHA, FAAN, has piloted successful chair summits and a webinar series which addressed topics of mutual interest including department finances and strategic planning. I am also excited about the addition of a Patient and Public Initiatives Committee which will bring together all our organization’s public-facing endeavors and be charged to stake a claim to the field of brain health. Under the Brain & Life® brand, this organization will work toward raising public awareness of the value of neurology and promoting the critical role neurologists play in the delivery of care.

Of course, this organization would not exist if not for our members, and as such, many of my future president’s columns will be devoted to your remarkable stories. As we return to seeing each other face-to-face, I look forward to meeting many of you, reconnecting with those of you I have gotten to know through interviews for the past 20 years, and seeing colleagues and old friends. What I have missed most—and what I am hearing you have as well—is getting together in person, exchanging warm greetings, and hearing laughter and animated conversation fill the air. I soon anticipate a surge of interest in getting together, and as with the original Renaissance, sharing our knowledge with a rebirth of creativity and discovery. We will emerge stronger than ever! 

Orly Avitzur, MD, MBA, FAAN President, AAN oavitzur@aan.com @OrlyA on Twitter

AANnews • May 2021 11

Tools & Resources

New Quality Measures for MS Added to Axon Registry The Axon Registry® continues to develop and incorporate new quality measures for neurology clinicians and practices caring for patients with multiple sclerosis (MS). In 2021, two new MS measures have been added to the registry: Axon 65: Fatigue Screening and Follow-Up for Patients with Multiple Sclerosis (MS) Axon 66: Bladder, Bowel, and Sexual Dysfunction Screening and Follow-Up for Patients with Multiple Sclerosis (MS) In addition, the Axon Registry has existing measures addressing MS patients: Axon 17: Documentation of Current Medications in the Medical Record Axon 18: Advanced Care Plan Axon 23: Exercise and Appropriate Physical Activity Counseling for Patients with MS Axon 64: Patient Reported Falls and Plan of Care

According to the National Multiple Sclerosis Society, there are approximately 1 million people in the United States and 2.3 million people worldwide living with MS. Each year, there are nearly 12,000 new cases of MS in the United States. MS is around two to three times more common in women than in men. As MS cases continue to grow each year, the financial impact is

felt by many patients. The total health care cost for MS patients in the United States ranges from $8,528 to $52,244 annually (Dilokthornsakul et al., 2016). For a complete list of all the quality measures in the Axon Registry, visit AAN.com/axon. For any inquiries about joining the Axon Registry, contact registry@aan.com. 

References Dilokthornsakul, P., Valuck, R. J., Nair, K. V., Corboy, J. R., Allen, R. R., & Campbell, J. D. (2016). Multiple sclerosis prevalence in the United States commercially insured population. Neurology, 86(11), 1014–1021. https://doi.org/10.1212/WNL.0000000000002469. “Multiple Sclerosis FAQs.” National Multiple Sclerosis Society, www.nationalmssociety.org/What-is-MS/MS-FAQ-s#question-Who-gets-MS.

Paper Examines Pricing for Neurologist-prescribed Drugs A paper written by the Health Services Research Subcommittee, “Five-Year Trends in Payments for Neurologist-Prescribed Drugs in Medicare Part D,” was published in the March 10, 2021, online issue of Neurology ®. The objective of the paper was to determine whether there was an increase in payments for neurologist-prescribed drugs evident in prescription claims in the Medicare Part D Prescriber Public Use Files from 2013–2017. The authors

performed a retrospective analysis that included 520 drugs, of which 322 were generic, 61 brand name only, and 137 brand name prescribed even though a generic equivalent is available. These represented 90,716,536 claims and generated payments of $26,654,750,720. The authors found that while the number of claims from 2013 to 2017 only increased 7.6 percent, the total payment increased 50.4 percent. Claim payments for the generic drugs increased less than one percent, while the other two categories increased more than 40 percent. Neuroimmunology/multiple sclerosis drugs represented over 50 percent of the total payments despite being only 4.3 percent of claims. The paper concludes, “Payments for neurologist-prescribed brand name, but not generic, drugs in Medicare Part D increased consistently and well above inflation from 2013–2017. Unless the overall trend stabilizes or is reversed, or high cost-to-claim drugs are addressed, this trend will place an increasing burden on the neurologic Medicare budget.” To read the paper, visit n.Neurology.org. 

AANnews • May 2021

Academy Delivers Answers to practice @aan.com Emails The practice@aan.com email inbox is an efficient way to reach staff and member expertise on practice related topics such as payers, MIPS/MACRA, coding, and practice management. Staff experts respond within one business day and can seek the assistance of the Practice Support Network, a group of 29 practicing neurologists and graduates of the AAN’s Practice Leadership Program for real-world expertise. Below are some common questions that have come into the inbox recently.

PRACTICE MANAGEMENT Q: How do I manage consistent patient flow in my practice? A: Managing patient flow into your practice is a complex issue but reviewing two key components can help. First, if you have a steady, but high, no-show rate, consider strategically overbooking by that same rate. Alternatively, if you do not want to overbook your schedule, consider adjusting your template to shorten visits to allow for more patients on your schedule. Lastly, consider increasing appointment reminders by using integrated EHR tools or third parties to text, email, or call your patients. Additionally, there are several ways to increase referrals into your practice. First, consider participating in community events such as patient support groups for neurologic diseases so potential patients get more familiar with you. Second, know your “competition” and highlight your strengths to differentiate yourself and your practice. Third, strengthen your relationships with referring providers by meeting with them personally, reserving spots to get referrals in quickly, and following up with referring providers promptly. Learn more about building your referral network by visiting AAN.com/Top5/#referral.

CODING Q. Under the revised guidelines for outpatient E/M coding, what activities can I count toward my time for the visit if basing my code selection on time?

Performing medical appropriate exam Ordering medications, tests, or procedures Documenting clinical information in the EHR Referring and communicating with other health care professionals (when not separately reported) Stay current on E/M coding and documentation guidelines at AAN.com/EM.

QUALITY PAYMENT PROGRAM Q: I’m a solo practitioner who applied to waive MIPS reporting due to COVID-19 in 2020. Do I have to report MIPS in 2021? A: The Centers for Medicare & Medicaid Services (CMS) will continue to offer relief to Merit-based Incentive Payment System (MIPS) eligible clinicians, groups, and APM entities related to COVID-19. CMS has indicated that the Extreme and Uncontrollable Circumstances policy will be available for the 2021 MIPS performance year, as it was in 2020. This means that MIPS-eligible clinicians and groups may submit an application requesting reweighting of one or more MIPS performance categories due to the COVID-19 public health emergency. CMS has indicated the 2021 application will be made available in the spring. The AAN will share the announcement via AAN channels when the application is released. You can learn more about MIPS and regulatory relief at AAN.com/QPP. 

A. This is a common question! First, remember both non-faceto-face activities in addition to the actual face-to-face time spent with the patient during the visit can be counted towards the total time used for code selection. The activities must be related to the billed encounter and have occurred within the window of midnight to midnight on the actual date of service. Some examples of appropriate activities include: Preparing to see the patient (e.g., review of tests) Obtaining and/or reviewing a separately obtained history

This Exclusive $500 AAN Member Benefit Closes May 14 View benchmarking for advanced practice providers See how the COVID-19 pandemic affected practices across the country Find out average on-call rates and duties

continued from cover

later. As in previous years, the AAN is committed to protecting your anonymity and collected data is de-identified and reported only in aggregate.

We have made enhancements to the 2021 survey to save you time and help you get the most out of the data. These include the ability to download the question set before you start, to skip questions that aren’t relevant, and to save your work and come back to it

For more information and to begin the survey, visit AAN.com/Benchmark. 

AANnews • May 2021 13

Tools & Resources

2021 QI Innovation Awards Honor Quality Improvement and Patient Safety Efforts The Quality Improvement Innovation Award debuted in 2020 to recognize individuals and teams who implement and successfully advance quality improvement and patient safety in practice. This year, Dara V.F. Albert, DO, MEd, at Nationwide Children’s Hospital in Columbus, OH, and Mahjabin Islam, MBBS, MRCP (UK), of Royal Hallamshire Hospital in Sheffield, South Yorkshire, UK, have been selected to receive this award because of their dedication and success implementing quality improvement initiatives. These awardees exemplified innovation in their respective fields of epilepsy and motor neuron disease. “We know that neurologists all over the world are engaged in systematic clinical innovations, and many of their successes go unrecognized,” said Lyell K. Jones, Jr., MD, FAAN, chair of the Quality Committee. “So, it is really a pleasure to recognize two outstanding quality improvement projects this year from Drs. Albert and Islam. These projects not only led to improved care for their patients but are a model for the rest of us to improve care in our own practices.” Albert and Islam’s award-winning efforts are described below. The AAN is interested in hearing your success stories. To learn more, contact quality@aan.com. Using Quality Improvement Methodology to Increase Provider Use of Seizure Action Plans for Pediatric Patients with Seizures / Dara V.F. Albert, DO, MEd A Seizure Action Plan (SAP) is a useful patient and caregiver educational tool that provides important information about Albert seizure care including acute emergency care and may help caregivers feel more comfortable and confident in managing epilepsy at home. We designed an SAP within our electronic health record that can be customized to the patients’ specific seizure care and can be updated easily when changes are needed. We then employed quality improvement (QI) methodology to identify key barriers to completion of the SAP in clinic and opportunities for interventions to improve utilization with the aim of increasing the percentage of families of children with seizures who received an SAP as part of their outpatient neurology clinic visit. Through multiple Plan-Do-Study-Act (PDSA) cycles implementing incremental changes, we were able to achieve an overall improvement of 149 percent from baseline (from 39 percent to an average of 77 percent) and sustain high utilization over time. Some key interventions with high impact were the redesign of the SAP by streamlining options, reducing the number of needed clicks, and providing a button that when checked automatically prints the SAP along with the After Visit Summary for the visit, adding Best Practice Alerts to remind providers when an SAP needs completion or updating, and empowering our clinic nursing staff to provide and review the SAP with the families at the time of discharge from clinic.

Quality Improvement Innovation Award

Pick, Tick, and Click: How We Improved the Quality of Management of Our Motor Neuron Disease (MND) Patients in Sheffield / Mahjabin Islam, MBBS, MRCP (UK) Sheffield Motor Neurone Disease (MND) Centre is one of the leading MND centers Islam in the UK and at the forefront of research advances in motor neuron disease. Our team aims to provide exemplary care for our MND patients. We have done two PDSA cycles evaluating 13 domains of MND care with an aim to improving our services. We identified the problem areas with a robust data collection process and a systematic approach was adopted to individually address the issues. The domains that required improvement in the first cycle were respiratory and NIV support, cough effectiveness, end-oflife planning, and psychological support. We adopted a unique approach to address the problem areas which we labelled as “Pick, tick, and click” method. We identified that the patients required specialist's input for cognitive assessment, psychosocial support, and respiratory therapy needs, therefore, we appointed skilled and trained neuropsychologists and MND respiratory therapist (Pick). To address respiratory problems and derived complications, we designed a checklist for patients who will eventually require advanced respiratory therapy (Tick). Patients and carers were engaged in palliative and end-of-life discussions and they were educated about the available online resources which could be easily accessed with a “Click.” We re-evaluated our service in two years' time. As the data suggested, significant improvement was noted in respiratory services and end-of-life care. In the second cycle, cognitive assessment and saliva management were the main areas requiring service development. Although the neuropsychologist's input improved the quality of service, a clear documentation and incorporation of cognitive strategies to patient management was required. Therefore, neuropsychology assessments were transferred to easy access online portal and a checklist was generated after every assessment (Tick). We developed MND thick and thin salivary secretion guideline for the hospital setting to provide better symptomatic secretion management (Click). MND patients develop complex care needs as time progresses. This reproducible strategy addressed multi-disciplinary care needs and ensured best utilization of our resources. We hope that ongoing promising MND research is on its way to a curative therapy for MND, till then we aim to provide comprehensive care to compassionately address our patient needs. 

Conferences & Community

May 10 Is Deadline to Submit Abstracts for 2021 Sports Concussion Conference The AAN is seeking abstract submissions no later than May 10 on topics related to sports concussion for presentation during the 2021 AAN Sports Concussion Conference, which will be held virtually this July 30 through 31. Submission of previously presented or published work is encouraged if it is of interest to the field, and the cost to submit is $25. Submission is free for residents and students.

MAY 10, 2021

The Sports Concussion Conference is a leading voice in shaping the sport-related concussion conversation for all clinicians and scientists involved in the prevention, diagnosis, and management of sport-related concussion at the youth, high school, collegiate, and professional levels. Attendees can expect to find top experts presenting the latest scientific information and best practices through a variety of programming. Registration for the Sports Concussion Conference will open in June. Learn more and submit your concussion research at AAN.com/SCC. 

May 23 Is Last Chance to Submit Online Evaluations for Annual Meeting CME With 2021 Annual Meeting content available on demand for 30 days after the live event took place last month, don’t forget to submit your evaluation forms no later than May 23 to receive your Annual Meeting CME. Forms may be completed online at AAN.com/evals21. Annual Meeting attendees who upgraded to Gold Registration—with its access to Annual Meeting On Demand—will have additional opportunities to claim CME through Annual Meeting On Demand until March 31, 2022. 

April 17– April 22

Are You Getting Your AANe-news? Don’t miss the latest news headlines from your Academy! As an exclusive member benefit, you should be receiving AANe-news™ the second and fourth Wednesday of each month if your email address is on file. If not, be sure to set your email filter to accept mailer@aan.com as a friendly address. Or update your email address at AAN.com/MemberProfile.

It’s Not Spam... It’s AANe-news!

AANnews • May 2021 15

Conferences & Community

Emerging Leaders Graduate Finds Success in Uniting Music, Medicine, and Leadership “Music is what I would be doing professionally, were it not for neurology,” began 2015 Emerging Leaders Program graduate Alexander Pantelyat, MD. He grew up playing the violin since the age of seven while simultaneously being exposed to neurology via his mother, who completed her neurology residency training and established her practice during his teens. “By the 11th grade I had decided to pursue medical training, but music has remained my main avocation: my stress relief, my solace, and the joy I am able to share with others.” Luckily for Pantelyat—and his patients—he has been able to combine both passions to great success, and in no small part due to the skills he gained through his experience with the AAN’s Emerging Leaders Program. “I came to Johns Hopkins for a neurology faculty position in 2014, after completing fellowship training,” said Pantelyat. “During my job interview, the Chair of Neurology, Dr. Justin McArthur, asked me what my ideal position would look like. I answered that I would like to try and combine my passion for neurology with my love of music and a growing appreciation of the powerful effects that music-based interventions can exert on health.” Pantelyat was pleased to find McArthur both open and extremely supportive of the idea, and he advised Pantelyat to reach out to several people across the department and the university to see if it could gain traction. “At this same time, I was thrilled to learn that the AAN accepted me into the Emerging Leaders Program for the 2014–2015 season,” said Pantelyat. “It is often said that timing is everything. In my case, it could not have been more true: I was working to develop the Johns Hopkins Center for Music and Medicine initiative and was simultaneously honing my leadership skills!” During his time in the leadership program, Pantelyat learned about the key differences between executive (traditional topdown) and legislative (collaborative) leadership and how to approach different types of leaders. “From personality testing during the program, I learned about my own leadership style preferences and about the importance of communicating with

Alexander Pantelyat, MD, and his unique neurologic tool.

team members effectively about leadership and learning styles,” he said. “A crucial non-intuitive insight was that the best teams are made up of people who have different ways of integrating information. In addition, our leadership training reinforced the importance of adjusting the way we deliver a message based on a team member’s personality, thereby ensuring understanding, and greatly increasing the likelihood of success.” These new insights greatly informed Pantelyat’s approach in establishing and co-directing the Center for Music and Medicine. “This initiative is, by its nature, interdisciplinary—involving the Peabody Conservatory, multiple School of Medicine departments, and the undergraduate campus—and the work has required collaboration and negotiation with many people of different backgrounds and personality preferences.” Pantelyat credits his AAN leadership training with enhancing his ability to recruit team members, navigate conflict, and effectively collaborate with peers and mentors at Hopkins and beyond. “During training, we received a quick reference guide card to personality types and communication preferences based on Jungian archetypes. This card has been in my work bag since 2014 and I have productively used it in countless interviews and work interactions. And I continue to use the skills I learned every day for management, collaborations, and conflict resolution.” Pantelyat believes strongly that the skills he gained from his AAN leadership program experience—namely his understanding of legislative leadership and ability to identify complementary personality traits for successfully team building—have been instrumental in the success of the Center for Music and Medicine. “To date, our center has engaged faculty and students across Johns Hopkins and beyond, secured more than $300,000 in funding for several projects, and is featured on the US News and World Report’s website description for Johns Hopkins Hospital. In addition to developing, implementing, and disseminating research studies of music and rhythm-based interventions for Parkinson's and Alzheimer's disease, and other disorders, we collaborate with the Peabody Conservatory to provide treatment for musicians’ illnesses. Importantly, we engage with the greater Baltimore community to support programs such as the ParkinSonics choir for individuals with

parkinsonism and a new virtual drumming class for people with Parkinson’s and their care partners. During the pandemic, we have partnered with the Baltimore Symphony Orchestra to provide biweekly virtual mini concerts for our department of neurology, worked with medical students and faculty volunteers to provide virtual performances for hospitalized patients and staff, and supported the establishment of a new Racial Justice

Concert Series in Baltimore.” Added Pantelyat, “Armed with the knowledge and leadership skills I gained through the AAN’s Emerging Leaders Program, I feel confident that our Center will continue to grow and fulfill our dual vision: Music as Medicine. Medicine for Musicians.” 

Applications Now Open for Three Leadership Programs Applications are currently open for three prestigious AAN leadership development programs: Diversity Leadership, Emerging Leaders, and Practice Leadership. Learn more and apply at AAN.com/Lead. The AAN thanks the organizations supporting this program in part:

Education & Research

Review, Self-assess, and Prepare for the Boards with Convenient NeuroReady Whether you’re looking to prepare for the American Board of Psychiatry and Neurology (ABPN) initial certification exam in neurology, preparing for recertification, or seeking a comprehensive review and update in neurology, the AAN’s NeuroReady is poised to get you ready for whatever lies ahead. No matter which you choose, the convenient online format includes a full 12 months of access and the opportunity to download course materials for offline studying.

NeuroReady: Board Prep Edition Designed to help neurologists prepare for initial board certification with: Syllabi on the 21 most heavily weighted categories from the ABPN content outline for the initial certification exam in neurology Audio interviews from syllabi authors A practice exam made up of 250 multiple-choice questions with feedback by subspecialty area and suggestions for further reading

NeuroReady: Advanced Practice Provider Edition

Designed for advanced practice providers one to three years out of graduation and looking for a solid foundational knowledge in neurology. This course helps participants self-assess their knowledge, identify areas of neurology that require more focused study and review, and demonstrate improved competency and performance in clinical neurology with:

Audio interviews with syllabi authors and experts in the field More than 160 multiple-choice question self-assessment exam with feedback by subspecialty areas, suggestions for further reading, and comparative peer performance results Up to eight self-assessment CME credits

NeuroReady: Continuing Certification (Second Edition) Designed to help neurologists prepare for recertification or get a comprehensive review and update in neurology with: Syllabi on the 14 most heavily weighted categories from the ABPN content, which cover new and updated science and therapies to bring you up-to-date Up to 15 self-assessment CME Audio interviews from syllabi authors Self-assessment exam with more than 130 multiple-choice questions, feedback by subspecialty areas, suggestions for further reading, and comparative peer performance results Get started by visiting AAN.com/NeuroReady today. 

Syllabi on eight categories in clinical neurology

AANnews • May 2021 17

Education & Research

In First Year, Neurology Question of the Day App Sees Impressive Engagement resource for all neurologists”; “quick, digestible, and covers a wide variety of topics”; “a very useful tool for a busy practitioner”; and “innovative—love it.”

Since launching in April of 2020, the AAN’s fun and educational Neurology Question of the Day mobile app has seen an impressive response and engagement with more than 7,000 members downloading and using the free member resource. Developed to meet the need for shorter, succinct, “micro-learning” opportunities in neurology, the app follows a monthly

curriculum, serving up one new multiple-choice question with discussion each day on various topics and provides suggested resources for further study. A separate track of questions is available for medical students. Just some of the many accolades expressed in the app evaluation comments include: “easy, quick, fun”; “brief but spectacular”; “an excellent

Over the last year, Neurology Question of the Day has enhanced its functionality by adding features such as question ratings; a mentor chat; and, most recently, a Teams function in which users can form a team of up to five colleagues for friendly competition between other teams and the chance to earn virtual achievements. Learn more and start engaging with the app at AAN.com/QODAPP. 

Your Monthly IDEAS Update: AAN Diversity Officer Work Group Makes Progress on Goals Inclusion is the reason the AAN was founded. To be an organization that is the home for all neurologists. It is what makes us stronger. In 2020, the AAN Board of Directors adopted a new goal to be a full inclusive, deliberately diverse, and anti-racist organization. We also expanded our core values of Diversity and Equity to now include Inclusion, Diversity, Equity, Anti-racism, and Social Justice, otherwise known as IDEAS. We are working hard to achieve this new goal and demonstrate these expanded values through an actionable roadmap approved by the Board. Members should look for these monthly updates in AANnews to follow our progress. The AAN Diversity Officers Work Group was established in 2018 as part of the academic initiative that is led by former AAN President Ralph L. Sacco, MD, MS, FAHA, FAAN. Its purpose is to promote the development of diversity officers in academic neurology departments; assess the needs of diversity officers and provide resources to support their roles; strengthen inclusion, diversity, equity, anti-racism, and social justice (IDEAS) in the culture and structures of academic neurology departments; and engage the AAN in creating a “home” for neurology diversity officers. The group is co-chaired by Roy H. Hamilton, MD, MS, FAAN, and Nimish A. Mohile, MD, MS. Last March, the AAN Diversity Officers Work Group hosted its first webinar, “The Diversity Officer: An Indispensable Leadership Role in Academic Neurology.” More than 140

AANnews • May 2021

Hamilton

Mohile

attendees tuned in live to learn why neurology departments should consider having their own diversity officer, how they might affect change, and what skills and resources they leverage to be effective in their positions. To view a recording of the webinar, visit https://bit.ly/3wY34Bi. Since it was launched, the work group has connected with department chairs to identify diversity officers and gather insights into the role of diversity officers. In 2020, a paper— "Developing the Neurology Diversity Officer: A Roadmap for Academic Neurology Departments”—examined these survey results and was published in the Neurology ® journal. The work group also planned and implemented the Health Care Disparities Poster Walk at the 2019 Annual Meeting. 

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Education & Research

AAN Member Provides Generous Endowment for Alma Mater SIGN Chapter AAN member Barney J. Stern, MD, FAAN, has provided a generous lead gift to support Student Interest Group in Neurology (SIGN) chapter at his residency medical school and alma mater at the University of Rochester, NY. The first of its kind gift to a SIGN chapter—the Barney J. Stern, MD, Student Interest Group in Neurology Support Fund—will provide support for activities beyond what the AAN already supports, including partial support of faculty time to oversee the program, social events for engagement of medical students, medical student travel to annual neurology society meetings, and hosting an annual SIGN lectureship. “Protecting neurology faculty time for this endeavor will ensure medical students reap the benefits of mentorship and professional development opportunities,” said U of R Chair of Neurology Robert Holloway, MD, MPH. “The SIGN program provides a framework for medical students to follow their hearts into our field; private philanthropic support such as Dr. Stern’s will bolster those efforts. This important gift demonstrates not only the lasting impact alumni can have on our field, but also to the institutions that have mattered so much in their lives and careers.” Stern

Indeed, Stern is quick to praise his experience at the university with shaping his interests and career. “The U of R offered me a wonderful education but also, most importantly, exposure to supportive mentors such as Dr. David Goldblatt, Dr. Robert Joynt, and Dr. Robert Griggs,” said Stern, who is a professor of neurology at Johns Hopkins University in Baltimore, MD. “As my interest in neurology grew, they offered guidance and advice and, ultimately, I was accepted to the Department of Neurology’s residency program. Years after residency, I was a member of the AAN’s Education Committee when the SIGN program was initiated. I thought that support of the U of R

Department of Neurology’s SIGN program was a perfect way to ‘give back’ to both my medical school and residency program.” “On behalf of the University of Rochester SIGN chapter, we are thankful and thrilled about Dr. Stern's generous donation and look forward to seeing the impact for years to come,” said Anna Gershteyn, MD candidate and leader of the U of R SIGN chapter, who credits her early involvement with SIGN during her first year of medical school with solidifying her decision to pursue neurology as a career. “Dr. Stern's endowment will make it possible for more students who are interested in neurology to experience the AAN Annual Meeting by helping offset some of the financial burden, and it will help expand U of R SIGN programming and perhaps allow for more collaboration with other surrounding SIGN programs at other institutions.” Traditionally, a career in neurology attracts a small proportion of graduating medical students. Stern cites the exciting scientific advances in neuroscience and the aging of the population as key factors in why there is a strong need for more neurologists— and it is his hope that the endowment will provide support for SIGN faculty mentors and student activities that will generate excitement for neurology as a career and help recruit the “best and the brightest” to enter the specialty. “Importantly, the endowment is agnostic to the student’s career path or to any one disease entity; how students decide on a career path will change over time as the specialty evolves,” he explained. Stern strongly encourages other AAN members to consider similar gifts of their own for SIGN chapters at institutions that are meaningful to them. “Hopefully, we all will enter a stage of our careers, and lives, when we can look back at our own professional experiences and define key moments that impacted our journey,” he said. “By giving back, we are acknowledging these opportunities and enhancing the experiences of those coming behind us. In many ways, we are also helping to create a new, and perhaps better, work force to help those burdened by neurological illnesses. In my view, it affirms the excitement we all felt when we decided to become neurologists and acknowledges the professional experience that is integral to our personal identity many years later.” Added Gershteyn, “Investing in SIGN is investing in future generations of neurologists who may become your mentees, colleagues, or even providers for you or your loved ones.” Learn more about SIGN at AAN.com/SIGN. 

AANnews • May 2021

June 1 Is Application Deadline for Subspecialty Fellowship Program Accreditation Applications for subspecialty fellowship programs seeking United Council for Neurologic Subspecialties (UCNS) accreditation are due by June 1. Accreditation is a measure of training program excellence and UCNS-accredited programs demonstrate that they meet the standards of graduate medical education excellence set by both the UCNS and the subspecialty experts of each of the UCNS-recognized subspecialties. The peer-reviewed accreditation process is overseen by the Accreditation Council, a standing committee reporting to the UCNS Board of Directors. Visit UCNS.org/Accreditation to learn more and to apply to join the 210 programs already accredited. 

UCNS Certifies New Diplomates in Neuroimaging The United Council for Neurologic Subspecialties (UCNS) has certified six physicians in the neurologic subspecialty of Neuroimaging. The physicians passed the 2021 Neuroimaging certification examination, demonstrating their expert knowledge in the subspecialty. There are now 222 diplomates in Neuroimaging. To see the list of diplomates, visit “News” at UCNS.org. 

NEURO-OTOLOGY APRIL 2021, VOL 27, NO 2

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AANnews • May 2021 21

Policy & Guidelines

Capitol Hill Report Capitol Hill Report presents regular updates on legislative and regulatory actions and how the Academy ensures that the voice of neurology is heard on Capitol Hill. It is emailed to US members twice monthly and is posted at AAN.com/view/HillReport. Below are some recent highlights. Arizona Neurological Society Is Back! The Arizona Neurological Society (ANS) held its first meeting on March 27 since its relaunch. The meeting, “Bringing Arizona Brains Back Together,” was hosted virtually by the Barrow Neurological Institute. The meeting featured topics such as neurological manifestations Knievel of COVID-19, cluster seizures, and multiple sclerosis updates. It received high marks from the 43 attendees who tuned in for the one-day event. What made this meeting so special was that it was the first time the ANS has met in a few years. It was led by Kerry Knievel, DO, who has been instrumental in rebooting the society in recent years. Assisting her with bringing the society back together has been Jennifer Robblee, MD; Glynnis Zieman, MD; and Nikesh Bajaj, DO.

Robblee

Ziemen

Bajaj

The ANS is excited to meet again in person, not virtually, to be able to network and truly bring Arizona Brains Back Together. For more information on the Arizona Neurological Society, check out the arizonaneurologicalsociety.org website.

As COVID Crisis Continues, So Does AAN Advocacy While vaccines offer a light at the end of tunnel, the COVID-19 public health emergency still weighs heavily on the US. The AAN continues to advocate for the needs of neurologists, neurology practices, and neurology patients as proposals are developed in response to the ongoing pandemic. Relief for the effects of COVID-19 will continue to be a top policy priority for the AAN in 2021. The AAN continues to emphasize the need to maintain flexibilities for telehealth, support for practices, regulatory relief, workforce continuity, and maintaining neuroscience research. Over the past year, the AAN authored 10 letters to policymakers outlining neurology’s specific needs during the public health emergency and joined more than 35 sign-on letters related to COVID-19. The latest COVID-19 relief package, the $1.9 trillion American Rescue Plan Act of 2021, was signed into law in March and includes public health measures such as funding to support vaccine distribution and $8 billion for rural hospitals. Learn more about AAN COVID-19 advocacy activities and resources by visiting AAN.com/Covid19 and opening the Advocacy in Action section.

AANnews • May 2021

The AAN’s advocacy staff continues to meet virtually with key members of Congress, including freshman representatives and senators, to educate them on the needs of neurologists during this critical time, including topics such as drug pricing, research funding, cognitive reimbursement, and reducing regulatory burdens. Learn more at AAN.com/policy-andguidelines/policy. 

Follow Your Colleagues During Neurology on the Hill On May 19, 150+ neurologists will meet virtually with their congressional representatives to advocate on behalf of neurology. Follow the conversation on social media at #NOH21 and #AANadvocacy.

Cerebral Palsy Advocate Gives First Congressional Briefing continued from cover

This was Aravamuthan’s debut at a congressional briefing, which is a tool to provide members of Congress and their staff background and information to understand the context of current legislative topics. The Congressional Neuroscience Caucus (CNC) is one of the many caucuses in Congress that are formal or informal groups of congresspeople who meet to pursue common legislative objectives. The CNC is co-chaired by Reps. Earl Blumenauer (D-OR) and Cathy McMorris Rodgers (R-WA), two representatives with whom the AAN has strong relationships. Aravamuthan believes it is vitally important to make the case to Congress for more research in this area. “Intellectual and developmental disabilities (IDDs) are common in our neurologic patient population. These disorders are functionally limiting throughout life: from childhood through adulthood. Therefore, the cumulative medical and economic costs of IDDs are high. However, research on IDDs is lacking and answers to the most basic clinical research questions remain unknown. We need to recruit more clinical researchers interested in studying IDDs across the lifespan and we need dedicated funding to support their research.”

the program has emphasized the importance of aligning people with your vision before describing how they can help achieve this vision. I hope I was able to convince those attending the congressional briefing that our shared vision should be to improve the lives of people with cerebral palsy and other neurodevelopmental disorders and that a way Congress can help do this is to support research on these disorders.”

people affected by CP and their caregivers through talks given via the American Academy of Cerebral Palsy and Developmental Medicine and the Cerebral Palsy Research Network. This was my first time giving a congressional briefing. I am grateful that the AAN allowed me to share my research and passion for helping people with cerebral palsy on a national stage.” As to applying her experience as a participant in the Academy’s Emerging Leaders Program to her advocacy mission, Aravamuthan said, “This has been a transformative experience for me. Amongst many other things,

To view a recording of Aravamuthan and others speaking during the congressional briefing, visit americanbraincoalition.org/page/ CongrNeurosciCaucus. 

Aravamuthan's passion for this topic makes her a natural spokesperson on behalf of this community. “I am an ardent advocate for people affected by cerebral palsy, a neurodevelopmental disorder that is the most common cause of motor disability in childhood. I have been fortunate to help educate

AANnews • May 2021 23

American Brain Foundation

Living with Glioblastoma: A Story of Laughter and Advocacy In October 2018, Kelly Rodenberg left a massage appointment thinking she’d pinched a nerve in her neck. But later that night, Rodenberg awoke from a deep sleep thanks to lightning bolts running through her left hand. She looked down to see her hand involuntarily shaking.

A Critical Diagnosis

Over the next few days, she noticed subtle changes. She had trouble getting her left arm in her sleeve. She cut her thumb while slicing an apple and didn’t feel a thing. But when Rodenberg, who worked as an admin for 35 years, saw a trail of Rs on her computer screen that she couldn’t explain, she knew it was time to call her local clinic. She realized that she could no longer feel her left hand connecting with the keyboard.

Rodenberg

When she called, she was told it was a three-week wait to get an appointment. A few hours later, she got a call from a nurse who read the transcript of her call and urged her to see a neurologist. Within just a few days, Rodenberg would get a life-changing diagnosis of glioblastoma, undergo major brain surgery, and begin a lifelong journey.

When Rodenberg saw the neurologist, he asked her to do some simple things. This included flexing her hand, smiling really big, and walking in a straight line. The neurologist noticed her mouth drooping a little bit on the left side, and she was walking a bit crooked. “And I had no idea,” she says. “That’s how subtle it was.”

An MRI confirmed a golf-ball-sized tumor above Rodenberg’s right ear, which was affecting the left side of her body. The tumor was a glioblastoma, a rare and aggressive type of cancer occurring in the brain or spinal cord. “You sit up in your chair a little bit straighter when the neurologist starts talking about your lifetime in months versus years,” she says. The neurologist wanted to do surgery as soon as possible. Rodenberg and her husband opted to get a second opinion at Mayo Clinic because Rodenberg’s husband got treatment

“YOU LEARN TO APPRECIATE EVERY LITTLE MOMENT.”

The American Brain Foundation promotes and invests in research across the whole spectrum of brain disease, so one day people like Kelly don’t need to live life against the odds. We believe that when we cure one of these diseases, we will cure many. Make a gift today to give someone like Kelly a chance to plan for their future. Donate at AmericanBrainFoundation.org/Kelly.

there. The surgeon there told her he didn’t think waiting a few days would make a difference. “From a patient standpoint, we were placed at ease,” she says. The neurologist told Rodenberg that even with surgery, there was only a 50-50 chance she would regain movement in her left hand. While he didn’t think the impairment would get any worse, he also didn’t think it would get any better. The surgery itself was successful. She was able to go home less than 48 hours later, which is not always the case after brain surgery. The next month was a brain resting period, and then Rodenberg started chemo and radiation.

Finding the Light and Love Rodenberg says her darkest days during the whole ordeal were during radiation, which lasted five days a week for six weeks. Rodenberg began to feel depressed. Even the thought of getting out of bed to brush her teeth felt overwhelming. So, she searched for an outlet. “I ended up just sitting down at the computer and writing a book,” she says. For Rodenberg, it was about finding the good in a tragedy, finding the light and love in a heavy diagnosis such as glioblastoma. But it was also about processing her experience with her signature good humor. The book, titled “There’s Something Going On Upstairs: Learning to Laugh My Way through a Cancerous Brain Tumor, One Chemo Cycle at a Time,” is part memoir, part patient roadmap, and part comedy. Writing her book gave her reason to wake up and allowed her to process all that had happened. It also gave her a chance to write the humorous, insightful book she wished she could have read while navigating glioblastoma. The positive response to her book showed Rodenberg that she had filled a need. She had helped people like she set out to do.

Life as a Survivor Just like the doctor at the Mayo Clinic predicted, the movement in Rodenberg’s left hand didn’t get any better. “It’s not any worse, but I still have zero use of it,” she says. It makes day-today activities, like driving, more difficult. Even folding a load of

clothes takes three times longer than it ever did. More than two years removed from her surgery, Rodenberg still feels uncertainty about the future. “I still feel that life is lived MRI to MRI, in eight-week chunks,” she says. “Until you get that validation or check of approval that, OK, your MRI was good, you don’t plan all that far out.” But Rodenberg has come to accept and even embrace her new life. “You learn to appreciate every day, every moment. You burn the candles, you use the good dishes, all that kind of stuff that I didn’t honestly think that much about before October 2018.” Rodenberg’s struggle with an invisible disease such as glioblastoma also fostered more empathy. “Nobody can see it. It’s not a cast, it’s not a crutch, it’s not a wheelchair,” she says. “People walking down the street would never guess that I had a brain tumor. It’s just opening up your heart a little bit more and trying to see what people go through, even though it’s not visible to the human eye necessarily, and everybody needs a lesson in that.” Rodenberg has taken that increased empathy and turned it into a passion for patient advocacy. She’s active in online patient communities and before COVID-19 she was doing free speaking engagements at long-term care facilities to educate residents on strokes and brain tumors. She urges patients to give themselves time and grace. “The biggest thing that I could encourage other glioblastoma patients is just to be patient with yourself because it is a very life-changing disease,” she says. “Once you wrap your brain around that it’s something that’ll never go away, I think you give yourself more grace because it will be with you for life.” As part of her advocacy, Rodenberg regularly sends copies of her book to people she’s met either in person or in online patient communities. She always inserts the same bookmark with a quote: We can’t always choose the music life plays for us, but we can choose how we dance to it. For Rodenberg, that means turning a life-changing diagnosis into a way to connect with other individuals living with a brain tumor and help them navigate the path a little bit easier. 

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AANnews • May 2021 25

Dates & Deadlines

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Applications Open: UCNS Neurocritical Care Certification UCNS.org/NCCcertification

JUNE 6

Application Deadline: Diversity Leadership Program AAN.com/DLP

JUNE 6

Application Deadline: Emerging Leaders Program AAN.com/ELP

JULY 22

Early Registration Deadline: Sports Concussion Conference AAN.com/SCC

JULY 30–31

Sports Concussion Conference AAN.com/SCC

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Application Deadline: Practice Leadership Program AAN.com/PLP

MAY 14

Deadline: Neurology Compensation and Productivity Survey AAN.com/Benchmark

MAY 19

Neurology on the Hill Virtual Event AAN.com/NOH

MAY 23

Submission Deadline: Annual Meeting CME AAN.com/CME

Careers.aan.com

Visit the AAN’s Neurology Career Center to view hundreds of additional jobs and sign up for customized, confidential notifications when positions of interest are added. Pediatric Neuroimmunology Developmental Neuroscience Research Faculty: Pacific Northwest Merritt Hawkins—Portland, Oregon The Papé Family Pediatric Research Institute and Department of Pediatrics at Oregon Health & Science University (OHSU) are seeking applications for a full-

time Pediatric Developmental Neuroscience research faculty. The successful candidate will work on the basic or translational aspects of neuroimmunology, developmental neuroscience, and/or childhood brain diseases (including brain cancer). Ideal candidates should have highly interactive research programs with the potential to synergize or enhance those of the department and the institution, which includes neuroinflammation, learning and memory, cognitive neuroscience, pediatric brain cancer, neuronal development, and neurobiology of childhood-onset diseases. Investigators focused on inflammation and metabolism in other organs, particularly the gut, are also encouraged to reply. An endowed-professorship is also available for a cancer researche—this individual will already be at the Full Professor rank and will have a long, sustained track record of grant funding and high impact publications. Functions effectively and respectfully within the context of varying cultural beliefs, behaviors, and backgrounds. For immediate consideration please inquire with an updated copy of your CV so we can discuss the position by phone. Also, inform me of your best available times

to speak. I look forward to your reply and thank you for your review. Please do not delay as we anticipate a significant response. Please contact Kendra Thompson at medcareers@merritthawkins.com or at (866) 406-0269 and reference NEUR-105733 AANnews® Classified Advertising The AAN offers a complete package of print, online, and in-person recruitment advertising opportunities. Visit careers.AAN.com for all AAN options, rates, and deadlines. Ad copy for the July 2021 print edition of AANnews must be submitted by June 1, 2021. The same deadline applies to changes/cancellations. The American Academy of Neurology reserves the right to decline, withdraw, or edit advertisements at its discretion. Every care is taken to avoid mistakes, but the responsibility for clerical or printer errors does not exceed the cost of the ad. 

GOCOVRI® (amantadine) extended release capsules Brief Summary of full Prescribing Information. See full Prescribing Information. Rx Only. INDICATIONS AND USAGE: GOCOVRI® (amantadine) extended release capsules is indicated: • For the treatment of dyskinesia in patients with Parkinson’s disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications • As adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes CONTRAINDICATIONS: Contraindicated in patients with creatinine clearance below 15 mL/min/1.73 m2 WARNINGS AND PRECAUTIONS: Falling Asleep During Activities of Daily Living and Somnolence: Patients treated with Parkinson’s disease medications have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes has resulted in accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. In controlled clinical trials, somnolence and fatigue were reported in 4% vs 1% of patients treated with GOCOVRI or placebo, respectively. Before initiating treatment with GOCOVRI, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with GOCOVRI, such as concomitant sedating medications or the presence of a sleep disorder. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require full attention (eg, driving a motor vehicle, conversations, eating), GOCOVRI should ordinarily be discontinued. If a decision is made to continue GOCOVRI, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living or daytime somnolence. Suicidality and Depression: In controlled clinical trials, suicidal ideation or suicide attempt was reported in 2% vs 0%; depression or depressed mood 6% vs 1%; confusional state 3% vs 2%; apathy 2% vs 0%, of patients treated with GOCOVRI or placebo, respectively. Monitor patients for depression, including suicidal ideation or behavior. Prescribers should consider whether the benefits outweigh the risks of treatment with GOCOVRI in patients with a history of suicidality or depression. Hallucinations/Psychotic Behavior: Patients with a major psychotic disorder should ordinarily not be treated with GOCOVRI because of the risk of exacerbating psychosis. In controlled trials, the incidence of patients who experienced visual hallucination, auditory hallucination, delusions, illusions, or paranoia was 25% vs 3%; hallucinations caused discontinuation of treatment in 8% vs 0%; of patients treated with GOCOVRI or placebo, respectively. Observe patients for the occurrence of hallucinations throughout treatment, especially at initiation and after dose increases. Dizziness and Orthostatic Hypotension: In controlled clinical trials, 29% vs 2% experienced dizziness, syncope, orthostatic hypotension, presyncope, postural dizziness or hypotension; and 3% vs 0% discontinued study treatment because of dizziness, postural dizziness, or syncope; of patients receiving GOCOVRI or placebo, respectively. Monitor patients for dizziness and orthostatic hypotension, especially after starting GOCOVRI or increasing the dose. Concomitant use of alcohol with GOCOVRI is not recommended. Withdrawal-Emergent Hyperpyrexia and Confusion: A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone. Abrupt discontinuation of GOCOVRI may cause an increase in the symptoms of Parkinson’s disease or cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech. If possible, avoid sudden discontinuation of GOCOVRI. Impulse Control/Compulsive Behaviors: Patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including GOCOVRI, that increase central dopaminergic tone. In some cases, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of such urges, and to consider dose reduction or stopping GOCOVRI treatment. ADVERSE REACTIONS: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. GOCOVRI was evaluated in 2 double-blind, placebo-controlled efficacy trials of similar design and population: Study 1 (123 patients) and Study 2 (75 patients). The study population was approximately 56% male and 94% white, with a mean age of 65 years (age range from 34 years to 82 years). The mean duration of levodopa-induced dyskinesia was 4 years (range 0.1 to 14 years). Active treatment started at 137 mg once daily for 1 week, followed by a dose increase to 274 mg once daily. The treatment duration was 25 weeks for Study 1 and 13 weeks for Study 2. Study 1 was stopped prematurely unrelated to safety, with 39/100 patients (safety population) treated with GOCOVRI for 24 weeks. The most common adverse reactions reported in >10% of GOCOVRI-treated patients and more frequently than on placebo were: hallucination, dizziness, dry mouth, peripheral edema, constipation, falls, and orthostatic hypotension. The overall rate of discontinuation because of adverse reactions was 20% vs 8% for patients treated with GOCOVRI or placebo, respectively. Adverse reactions that led to treatment discontinuation in at least 2% of patients were hallucination (8% GOCOVRI vs 0% placebo), dry mouth (3% GOCOVRI vs 0% placebo), peripheral edema (3% GOCOVRI vs 0% placebo), blurred vision (3% GOCOVRI vs 0% placebo), postural dizziness and syncope (2% GOCOVRI vs 0% placebo), abnormal dreams (2% GOCOVRI vs 1% placebo), dysphagia (2% GOCOVRI vs 0% placebo), and gait disturbance (2% GOCOVRI vs 0% placebo). Pooled Analysis of Adverse Reactions Reported for ≥3% of Patients Treated With GOCOVRI 274 mg (n=100) or placebo (n=98), respectively: Psychiatric disorders: visual and/or auditory hallucination (21%, 3%); anxiety and/or generalized anxiety (7%, 3%); insomnia (7%, 2%); depression/depressed mood (6%, 1%); abnormal dreams (4%, 2%); confusional state (3%, 2%) Nervous system disorders: dizziness (16%, 1%); headache (6%, 4%); dystonia (3%, 1%) Gastrointestinal disorders: dry mouth (16%, 1%); constipation (13%, 3%); nausea (8%, 3%); vomiting (3%, 0%) General disorders and administration-site conditions: peripheral edema (16%, 1%); gait disturbance (3%, 0%) Injury, poisoning, and procedural complications: fall (13%, 7%); contusion (6%, 1%) Infections and infestations: urinary tract infection (10%, 5%) Skin and subcutaneous tissue disorders: livedo reticularis (6%, 0%); pigmentation disorder (3%, 0%) Metabolism and nutrition disorders: decreased appetite (6%, 1%) Vascular disorders: orthostatic hypotension, including postural dizziness, syncope, presyncope,

and hypotension (13%, 1%) Eye disorders: blurred vision (4%, 1%); cataract (3%, 1%); dry eye (3%, 0%) Musculoskeletal and connective tissue disorders: joint swelling (3%, 0%), muscle spasm (3%, 0%) Reproductive system and breast disorders: benign prostatic hyperplasia—all male (6%, 2%) Respiratory, thoracic, and mediastinal disorders: cough (3%, 0%). Other clinically relevant adverse reactions observed at <3% included somnolence, fatigue, suicide ideation or attempt, apathy, delusions, illusions, and paranoia. Difference in the Frequency of Adverse Reactions by Gender in Patients Treated With GOCOVRI Adverse reactions reported more frequently in women (n=46) vs men (n=54) were: dry mouth (22% vs 11%), nausea (13% vs 4%), livedo reticularis (13% vs 0%), abnormal dreams (9% vs 0%), and cataracts (7% vs 0%), respectively. Men vs women reported the following adverse reactions more frequently: dizziness (20% vs 11%), peripheral edema (19% vs 11%), anxiety (11% vs 2%), orthostatic hypotension (7% vs 2%), and gait disturbance (6% vs 0%), respectively. Difference in the Frequency of Adverse Reactions by Age in Patients Treated With GOCOVRI Hallucinations (visual or auditory) were reported in 31% of patients age 65 years and over (n=52) vs 10 % in patients below the age of 65 years (n=48). Falls were reported in 17% of patients age 65 and over vs 8% of patients below age 65. Orthostatic hypotension was reported in 8% of patients age 65 and over compared with 2% of patients below age 65. DRUG INTERACTIONS: Other Anticholinergic Drugs: Products with anticholinergic properties may potentiate the anticholinergic-like side effects of amantadine. The dose of anticholinergic drugs or of GOCOVRI should be reduced if atropine-like effects appear when these drugs are used concurrently. Drugs Affecting Urinary pH: The pH of the urine has been reported to influence the excretion rate of amantadine. Urine pH is altered by diet, drugs (eg, carbonic anhydrase inhibitors, sodium bicarbonate), and clinical state of the patient (eg, renal tubular acidosis or severe infections of the urinary tract). Since the excretion rate of amantadine increases rapidly when the urine is acidic, the administration of urine acidifying drugs may increase the elimination of the drug from the body. Alterations of urine pH towards the alkaline condition may lead to an accumulation of the drug with a possible increase in adverse reactions. Monitor for efficacy or adverse reactions under conditions that alter the urine pH to more acidic or alkaline, respectively. Live Attenuated Influenza Vaccines: Due to its antiviral properties, amantadine may interfere with the efficacy of live attenuated influenza vaccines. Therefore, live vaccines are not recommended during treatment with GOCOVRI. Inactivated influenza vaccines may be used, as appropriate. Alcohol: Concomitant use with alcohol is not recommended, as it may increase the potential for CNS effects such as dizziness, confusion, lightheadedness, and orthostatic hypotension, and may result in dose-dumping. USE IN SPECIFIC POPULATIONS: Pregnancy: There are no adequate data on the developmental risk associated with use of amantadine in pregnant women. Based on animal data, it may cause fetal harm. Lactation: Amantadine is excreted into human milk, but amounts have not been quantified. There is no information on the risk to a breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for GOCOVRI and any potential adverse effects on the breastfed infant from GOCOVRI or from the underlying maternal condition. Pediatric Use: Safety and effectiveness of GOCOVRI in pediatric patients have not been established. Geriatric Use: In Phase 3 clinical trials, the mean age of patients at study entry was 65 years. Of the total number of patients in clinical studies of GOCOVRI, 46% were less than 65 years of age, 39% were 65-74 years of age, and 15% were 75 years of age or older. Hallucinations and falls occurred more frequently in patients 65 years of age or older, compared with those less than 65 years of age. No dose adjustment is recommended on the basis of age. GOCOVRI is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Renal Impairment: GOCOVRI is contraindicated for use in patients with end-stage renal disease (creatinine clearance values lower than 15 mL/min/1.73 m2). A 50% dose reduction of GOCOVRI to a starting daily dose of 68.5 mg daily for a week, followed by a daily maintenance dose of 137 mg is recommended in patients with moderate renal impairment (creatinine clearance between 30 and 59 mL/min/1.73 m2). For patients with severe renal impairment (creatinine clearance between 15 and 29 mL/min/1.73 m2), a daily dose of 68.5 mg is recommended. Overdosage: Deaths have been reported from overdose with amantadine immediaterelease. The lowest reported acute lethal dose was 1 g of amantadine hydrochloride (equivalent to 0.8 g amantadine). Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has resulted in cardiac, respiratory, renal, or central nervous system toxicity. Pulmonary edema and respiratory distress (including adult respiratory distress syndrome, ARDS) have been reported with amantadine; renal dysfunction, including increased BUN and decreased creatinine clearance, can occur. Central nervous system effects that have been reported with overdose include agitation, aggressive behavior, hypertonia, hyperkinesia, ataxia, tremor, disorientation, depersonalization, fear, delirium, psychotic reactions, lethargy, and coma. Seizures may be exacerbated in patients with prior history of seizure disorders. Hyperthermia has occurred with amantadine overdose. For acute overdosing, general supportive measures should be employed along with immediate gastric decontamination if appropriate. Give intravenous fluids if necessary. The excretion rate of amantadine increases with acidification of urine, which may increase the elimination of the drug. Monitor patients for arrhythmias and hypotension. Electrocardiographic monitoring may be needed after ingestion because arrhythmias have been reported after overdose, including arrhythmias with fatal outcomes. Adrenergic agents, such as isoproterenol, in patients with an amantadine overdose has been reported to induce arrhythmias. Monitor blood electrolytes, urine pH, and urinary output. Although amantadine is not efficiently removed by hemodialysis, this procedure may be useful in the treatment of amantadine toxicity in patients with renal failure. References: 1. GOCOVRI® (amantadine) [Prescribing Information]. Emeryville, CA: Adamas Pharma LLC; 2021. 2. Hauser RA, Pahwa R, Wargin WA, et al. Pharmacokinetics of ADS-5102 (amantadine) extended release capsules administered once daily at bedtime for the treatment of dyskinesia. Clin Pharmacokinet. 2018;58(1):77-88. 3. Elmer LW, Juncos JL, Singer C, et al. Pooled analyses of phase III studies of ADS- 5102 (amantadine) extended-release capsules for dyskinesia in Parkinson disease. CNS Drugs. 2018;32(4): 387-398. 4. Data on file. Adamas Pharma LLC, Emeryville, CA.

Adamas and Gocovri are registered trademarks of Adamas Pharmaceuticals, Inc. or its related companies. © 2021 Adamas Pharmaceuticals, Inc. or its related companies. All rights reserved. GOC-0728 v3 02/21

NIGHTTIME NIGHTTIMEDOSING DOSING

DAYTIME DAYTIMECOVERAGE COVERAGE

For Parkinson's disease patients with motor complications,1,2

New Additional Indication GOCOVRI® is now FDA approved to also treat OFF episodes in patients taking levodopa1

GOCOVRI® COULD MEAN THE DIFFERENCE

BETWEEN GETTING UP

AND GETTING OUT GOCOVRI® is ready when your Parkinson’s disease (PD) patients with dyskinesia or OFF episodes need it.1,2 With a single bedtime dose, high levels of GOCOVRI® are reached by morning before the ﬁrst levodopa dose, providing all-day coverage with levels slowly decreasing in the hours before bedtime.2 In clinical trials, GOCOVRI® reduced PD dyskinesia (primary endpoint) and OFF time and increased GOOD ON time (secondary endpoints).1 *

Not an actual patient.

27% DECREASE IN DYSKINESIA 36% DECREASE IN OFF TIME 29% INCREASE IN GOOD ON TIME

10.1-point reduction in UDysRS score (-17.7 GOCOVRI® vs -7.6 placebo) 3†

1-hour decrease (-0.6 GOCOVRI® vs 0.4 placebo) 3,4†

2.4-hour increase (3.8 GOCOVRI® vs 1.4 placebo) 3,4†

GOOD ON time, ON time without troublesome dyskinesia; UDysRS, Uniﬁed Dyskinesia Rating Scale.

Visit GocovriHCP.com to learn more.

*As seen in pooled results of 2 independently positive, pivotal, Phase 3, randomized, placebo-controlled trials (Study 1 and Study 2) in PD patients on levodopa. Study 1, a 24-week study, was conducted in 121 PD patients with dyskinesia (GOCOVRI® [n = 63], placebo [n = 58]). Study 2, a 12-week study, was conducted in 75 PD patients with dyskinesia (GOCOVRI® [n = 37], placebo [n = 38]).1,3 † In Study 1, GOCOVRI® reduced the UDysRS total score by 15.9 points (vs 8.0 with placebo) (P = 0.0009), decreased OFF time by 0.6 hours (vs an increase of 0.3 hours with placebo) (P = 0.0171), and increased GOOD ON time by 3.6 hours (vs 0.8 hours with placebo) (P < 0.0001) from baseline. In Study 2, GOCOVRI® reduced the UDysRS total score by 20.7 points (vs 6.3 with placebo) (P < 0.0001), decreased OFF time by 0.5 hours (vs an increase of 0.6 hours with placebo) (P = 0.0199), and increased GOOD ON time by 4.0 hours (vs 2.1 hours with placebo) (P = 0.0168) from baseline.1

INDICATION GOCOVRI® (amantadine) extended release capsules is indicated: • For the treatment of dyskinesia in patients with Parkinson’s disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications • As adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes It is not known if GOCOVRI is safe and effective in children. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS GOCOVRI is contraindicated in patients with creatinine clearance below 15 mL/min/1.73 m2. WARNINGS AND PRECAUTIONS Falling Asleep During Activities of Daily Living and Somnolence: Patients treated with Parkinson’s disease medications have reported falling asleep during activities of daily living. If a patient develops daytime sleepiness during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), GOCOVRI should ordinarily be discontinued or the patient should be advised to avoid potentially dangerous activities. Suicidality and Depression: Monitor patients for depression, including suicidal ideation or behavior. Prescribers should consider whether the beneﬁts

outweigh the risks of treatment with GOCOVRI in patients with a history of suicidality or depression. Hallucinations/Psychotic Behavior: Patients with a major psychotic disorder should ordinarily not be treated with GOCOVRI because of the risk of exacerbating psychosis. Observe patients for the occurrence of hallucinations throughout treatment, especially at initiation and after dose increases. Dizziness and Orthostatic Hypotension: Monitor patients for dizziness and orthostatic hypotension, especially after starting GOCOVRI or increasing the dose. Withdrawal-Emergent Hyperpyrexia and Confusion: Rapid dose reduction or abrupt discontinuation of GOCOVRI, may cause an increase in the symptoms of Parkinson’s disease or cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech. Avoid sudden discontinuation of GOCOVRI. Impulse Control/Compulsive Behaviors: Patients may experience urges (e.g. gambling, sexual, money spending, binge eating) and the inability to control them. It is important for prescribers to ask patients or their caregivers about the development of new or increased urges. Consider dose reduction or stopping medications. ADVERSE REACTIONS The most common adverse reactions (>10%) were hallucination, dizziness, dry mouth, peripheral edema, constipation, fall, and orthostatic hypotension.

Please see Brief Summary of full Prescribing Information on the adjacent page.