The Brigham Department of Neurology Martin A. Samuels, Chairman Director, Brigham and Women’s Institute for the Neurosciences Miriam Sydney Joseph Professor of Neurology Harvard Medical School

Miriam Sydney Joseph Samuels Conflict of Interest Disclosure

NONE Update in Neurology ACP 2017

Martin A. Samuels, MD, MACP Chairman, Department of Neurology Brigham and Women’s Hospital Miriam Sydney Joseph Professor of Neurology Harvard Medical School Update in Neurology 2017

• Stroke and Cerebrovascular Diseases • Neuromuscular Diseases • Movement Disorders • Traumatic Brain Injury • Nociception, Pain, Suffering and Opioids • Autoimmune Neurology • Neurocardiology Stroke and Cerebrovascular Diseases • Since 2015 endovacular Rx is an option • Some trials terminated early; small sample size • Meta-analysis of five trials – 1287 participants – Primary outcome: disability at 3 months – Mean age 67 year; 47% female – Median time to trial entry = 196 minutes – Median time to arterial puncture = 238 minutes – Median time to reperfusion = 286 minutes – 71% proximal MCA; 22% distal internal carotid – Results • Disability increased with Rx delay • 3 hours: OR = 2.79; risk difference = 39.2% • 6 hours: OR = 1.98; risk difference = 30.2% • 8 hours: OR = 1.58; risk difference = 0 • Risk reduction persisted through 7 hours, 18 minutes • Conclusions: benefit for about 6-7 hours post stroke

Badhiwala JH et al. Endovascular thrombectomy for acute ischemic stroke: a meta-analysis. JAMA 2015; 314: 1832. Neuromuscular Diseases

• Acquired myasthenia gravis (MG) is caused by binding of autoantibodies to acetylcholine receptors • Thymectomy in non-thymomatous cases was controversial • Randomized trial of 126 patients with generalized non- thymomatous MG of less than 5 years duration • All were class II-IV (generalized) with anti-receptor Abs • Results: Thymecomy patients – had lower MG score compared to prednisone alone – Had lower average requirements for alternate-day prednisone – Required less immunosupprsssion with azathioprine – Were less likely to be admitted for exacerbations • Conclusion: Thymectomy improves outcome in acquired generalized MG, but is not a cure

Wolfe GI et al. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med 2016; 375: 511. Movement Disorders • Braak hypothesis: abnormally folded protein (α- synuclein) carried from the gut by nerves to CNS; vagus a major pathway • Swedish and Danish National Patient Registries queried and results were similar • Results: Up to 20 years post truncal vagotomy, there is a lower risk of Parkinson disease; not true for selective (gastric) vagotomy • Conclusions: Data support the Braak hypothesis of the pathogenesis of PD, but vagotomy is not recommended as a treatement for PD Svensson E et al. Vagotomy and subsequent risk of Parkinson disease. Ann Neurol 2015; 78: 522-529

Movement Disorders • Braak hypothesis: abnormally folded protein (α- synuclein) carried from the gut by nerves to CNS; vagus a major pathway • Swedish and Danish National Patient Registries queried and results were similar • Results: Up to 20 years post truncal vagotomy, there is a lower risk of Parkinson disease; not true for selective (gastric) vagotomy • Conclusions: Data support the Braak hypothesis of the pathogenesis of PD, but vagotomy is not recommended as a treatement for PD Svensson E et al. Vagotomy and subsequent risk of Parkinson disease. Ann Neurol 2015; 78: 522-529 Mild Traumatic Brain Injury (Concussion)

• Concussion: a neurological deficit caused by head injury (formerly loss of consciousness from trauma). • Chronic traumatic encephalopathy (CTE) – Dementia pugilistica – Tau (tangle) pathology – ? Prion-like pathophysiology

McKee A et al. The neuropathology of chronic traumatic encephalopathy. Brain Pathology 2015; 25: 350. Can A Folded Protein Released By Head Injury Spread Like A Prion? Frank L. Wiley Junior High School Football Team 1959 Frank L. Wiley Junior High School Football Team 1959 Frank L. Wiley Junior High School Football Team 1959 Frank L. Wiley Junior High School Football Team 1959 Tom Mack in High School Marty Samuels in High School Marty Samuels in High School Tom Mack, University of Michigan

Tom Mack NFL Hall of Fame 184 Straight Games Marty Samuels, Neurologist 40 Straight Years as a Doctor A Balanced View

• Protein aggregation may, in fact, be an important mechanism in neurodegeneration (e.g. amyloid, tau, prion, ubiquitin, synuclein) • Genetics are probably the main determinant of protein self-aggregation, but other factors (e.g. infection, trauma, environmental exposures) are possibly also important • As in all of medicine (and in life) one must weigh the relative benefits and risks of any activity (e.g. sports, foods, sex) Nociception, Pain and Suffering

• Nociception: potentially tissue damaging stimuli • Pain: the unpleasant effects of nociception • Suffering: A psychological state of dysphoria. Causes include Pain, poverty, war and numerous other social factors • Opiods (endogenous and exogenous) are useful for pain due to nociception • Treating suffering with opioids can lead to complications Nociception Transmission System Descending Nociception Modulation System Consequenses of Nociception • Neurogenic inflammation is caused by innervation of vessels and other structures by neurons that mediate nociception (the inflammatory reflex), a process that can be inhibited by serotonin Ib and Id receptor activity • The inflammatory reflex may result in a CSF pleocytosis • A slowly migrating negative wave may arise in the cortex (spreading depression), which is probably the cause of the aura of some migraines • Pain only results when the afferent limb of the reflex reaches the thalamus • Chronic pain is one cause of suffering • Opioids used to treat chronic pain causes suffering rather than relieve it Autoimmune Neurology

• Paraneoplastic and now “benign” diseases

• Intracellular antigens – Hu – Ro – Etc

• Cell surface antigens – VGKC • LGI1 • Caspr 2 – NMDA Neurocardiology

• Takotsubo-like cardiomyopathy • Catecholamine toxicity • Balance of autonomic innervation protects Patient Case History (courtesy of Leonard Lilly, M.D.) • 62 year old woman, previously healthy, presented to hospital with chest discomfort • Symptoms began 6 hours earlier, described as a diffuse anterior heaviness with shortness of breath; started minutes after being told that her son was seriously injured in an automobile accident Laboratory Studies

Echocardiogram LAD Coronary Angiogram Right Coronary Angiogram Left Ventriculogram

Clinical Course

• Remained clinically stable: chest discomfort resolved; no heart failure or arrhythmias • Maintained on aspirin, beta-blocker, ACE inhibitor; No diuretic requirement • Discharged on hospital day 3 • Returned for repeat echocardiogram Repeat Echocardiogram Two weeks later Schematic Diagram of the Innervation of the Heart (after Truax) Two Sisters

A woman in her 70’s collapses and is brought to the emergency department by her sister, who is told the the problem is a lethal intracerebral hemorrhage. Upon hearing the news the second sister also collapses. Sister 1

Sister 2

Debby Reynolds and Carrie Fisher Update in Neurology 2017

• Stroke and Cerebrovascular Diseases • Neuromuscular Diseases • Movement Disorders • Traumatic Brain Injury • Nociception, Pain, Suffering and Opioids • Autoimmune Neurology • Neurocardiology Martin A. Samuels Chairman, Department of Neurology Brigham and Women’s Hospital Miriam Sydney Joseph Professor of Neurology Harvard Medical School

Miriam Sydney Joseph Samuels

1940 1980 2017 The Brigham Department of Neurology Martin A. Samuels, Chairman Director, Brigham and Women’s Institute for the Neurosciences Miriam Sydney Joseph Professor of Neurology Harvard Medical School

Miriam Sydney Joseph Samuels