New Insights Into the Diagnosis and Treatment of Single-Gene Disorders Associated With Cryptogenic Ischemic Stroke A Continuing Medical Education Monograph Release date: September 30, 2010 Expiration date: September 30, 2013 Editor Contributors Katherine B. Sims, MD Mark J. Alberts, MD, FAHA Louis R. Caplan, MD Massachusetts General Hospital Northwestern University Beth Israel Deaconess Medical Center Harvard Medical School Feinberg School of Medicine Harvard Medical School Boston, Massachusetts Northwestern Memorial Hospital Boston, Massachusetts Chicago, Illinois This activity is jointly sponsored by the University of Kentucky College of Medicine and CE Health Sciences Inc. New Insights Into the Diagnosis and Treatment of Single-Gene Disorders Associated With Cryptogenic Ischemic Stroke A Continuing Medical Education Monograph Editor Katherine B. Sims, MD Director, Developmental Neurogenetics Clinic Director, Neurogenetics DNA Diagnostic Laboratory Massachusetts General Hospital Associate Professor of Neurology Harvard Medical School Boston, Massachusetts Contributors Mark J. Alberts, MD, FAHA Professor of Neurology Section Chief, Stroke and Cerebrovascular Disease Northwestern University, Feinberg School of Medicine Director, Stroke Program Northwestern Memorial Hospital Chicago, Illinois Louis R. Caplan, MD Beth Israel Deaconess Medical Center Professor of Neurology Harvard Medical School Boston, Massachusetts To receive CME credit for this activity, please review the material in full and complete the online posttest and evaluation form at www.CECentral.com/getcredit (activity code MEN09182). A printable statement of credit will be issued upon successful completion of the required forms. 3 Accreditation This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Kentucky College of Medicine and CE Health Sciences Inc. The University of Kentucky College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. The University of Kentucky College of Medicine designates this educational activity for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. The University of Kentucky College of Medicine presents this activity for educational purposes only. Participants are expected to use their own expertise and judgment while engaged in the practice of medicine. The content of this activity is provided solely by editors who have been selected for their contributions on the basis of recognized expertise in their field. The University of Kentucky is an equal opportunity employer. Release date: September 30, 2010 Expiration date: September 30, 2013 Evaluation and Posttest To obtain CME credit for this activity, please log on to www.CECentral.com/getcredit, enter activity code MEN09182, log in or register for a free account, and complete the online evaluation and posttest. A minimum score of 70% is required on the posttest to receive acknowledgment of completing the activity. A printable statement of credit will be issued upon successful completion of the required forms. This activity should take 1.5 hours to complete. Overview Conventional risk factors, including age, hypertension, smoking, and obesity, account for 40% to 50% of stroke risk. Routine diagnostic procedures can be used to identify stroke etiology in more than half of patients, but in 20% to 40% of patients, strokes are classified as cryptogenic (ie, unknown cause despite extensive workup). Cryptogenic stroke appears to be more common in young adults than in older individuals. Therefore, other factors, including genetic ones, may be involved in these cryptogenic stroke cases. Because of the unique challenges of diagnosing and managing patients with stroke due to single- gene disorders, there has been a recent increase in published literature on these disorders. Although management of some single-gene disorders, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, is limited to symptomatic management, support, and counseling, other single-gene disorders, including Fabry disease, have treatment options available that may affect the course of the disease. This activity will review the differential diagnosis for cryptogenic stroke and identify the diagnostic and treatment options for managing single-gene disorders associated with ischemic stroke. Target Audience This activity is designed for neurologists and other health care professionals who have an interest in the diagnosis and treatment of patients with cryptogenic stroke. Learning Objectives Upon completion of this activity, the participant should be able to • Recognize the incidence of cryptogenic stroke and the need for differential diagnosis • Describe the types of single-gene stroke disorders • Summarize the clinical presentation of genetic stroke disorders • Identify treatment options and prevention techniques for complications resulting from genetic stroke disorders 4 New Insights Into the Diagnosis and Treatment of Single-Gene Disorders Associated With Cryptogenic Ischemic Stroke Faculty Disclosure In accordance with policies set forth by the Accreditation Council for Continuing Medical Education (ACCME), the University of Kentucky College of Medicine Continuing Education Office requires all persons with an opportunity to affect the content of a continuing education (CE) activity to disclose any relevant financial relationship with commercial interests that produce health care goods and/or services consumed by, or used on, patients. Relationships with commercial interests and conflicts of interest resulting from those relationships must be made known to the audience and resolved prior to the activity. Faculty may not accept payment directly from commercial interests for involvement in a CE activity. Pursuant to Standard 2.1 of the ACCME’s Standards for Commercial Support, financial relationships of a spouse/significant other must be disclosed. Name Company and Relationship Katherine B. Sims, MD Research grant: Genzyme Corporation Mark J. Alberts, MD, FAHA Consultation fees: Genzyme Corporation Louis R. Caplan, MD Advisory board: Avanir Pharmaceuticals; Boehringer Ingelheim; Genentech, Inc.; LifeCycle Pharma A/S; NeuroLogica Corporation; Novovision, Inc.; ReNeuron. Consultant: AstraZeneca Pharmaceuticals; Bayer Schering Pharma; CoAxia, Inc.; Genzyme Corporation; Jones & Davis LLP; Micromedex Solutions; Millennium Pharmaceuticals, Inc.; Novo Nordisk; Takeda Pharmaceutical Company Limited. Speakers list: AstraZeneca Pharmaceuticals; Boehringer Ingelheim; Bristol-Myers Squibb; Otsuka America Pharmaceutical, Inc.; Sanofi-Aventis. This activity is supported by an unrestricted educational grant provided by Genzyme Corporation. 5 New Insights Into the Diagnosis and Treatment of Single-Gene Disorders Associated With Cryptogenic Ischemic Stroke Introduction Stroke is a leading cause of death in the United States and a common cause of serious long-term disability.1 Worldwide, strokes occur in approximately 15 million people each year.2 Among these individuals, approximately 5 million die and 5 million are permanently disabled as a result of a stroke.2 Each year in the United States, approximately 795,000 strokes occur; approximately 137,000 people died from stroke in 2006.1 Although most strokes occur in individuals over the age of 65 years, they can happen at any age, and nearly 25% of strokes occur in persons under age 65 years.1 Estimates of the incidence of new cases of stroke in individuals aged 54 years or younger range from 3 to 47 per 100,000 people, varying widely by country.2 In the United States, the incidence of new stroke cases in persons aged 20 to 44 years varies by ethnicity from 10 to 26 per 100,000 people.2 In individuals aged 55 to 84 years, the incidence of stroke is higher in men than in women. However, in those aged 85 years or older, the incidence of stroke is higher in women. In 2006, women accounted for 60.6% of deaths from stroke.3 Women are 3 times more likely to die as a result of stroke than of breast cancer.4 Ischemic strokes, which occur when blood flow to the brain is blocked, are the most commonly occurring type of stroke and represent approximately 87% of all strokes.5 The determination of stroke etiology is important to help plan treatments that will be effective in preventing another stroke. For most patients who have a stroke, an etiology (eg, atherosclerosis, cardiac embolism, arterial dissection) can be identified; however, the cause of stroke is unknown (ie, cryptogenic) in approximately 20% to 40% of cases.6-8 This figure is highly dependent on the extent of the initial and subsequent evaluations. Some research suggests that cryptogenic stroke is more common in younger patients (ie, those aged 45 years or younger) than in older patients.9,10 Conventional risk factors for stroke include increased age, diabetes mellitus, lack of exercise, dyslipidemia, obesity, hypertension, smoking, drug abuse, and metabolic syndrome.11-15 Such factors account for only approximately half of all stroke risk11-14; other elements, including geographic and genetic factors, are also involved.6,11,16 Genetic factors may contribute to stroke by influencing conventional risk factors for stroke (eg, hypertension, diabetes)13; they may predispose an individual to a specific