Mechanisms of Injury in Dyskinetic Cerebral Palsy Alec Hoon, MD Associate Professor of Pediatrics Johns Hopkins University School of Medicine Director, Phelps Center for Cerebral Palsy Kennedy Krieger Institute Neurodevelopmental Evaluation Structure‐Function Genetic, Epigenetic, Clinical Phenotype Abnormalities Environmental Risk Factors CP Diagnosis Etiologic Diagnosis Child‐Family Rehabilitative Characteristics Management Medical Surgical Measurement CAM Cell‐Based therapy Techniques Outcome Key Concepts in Cerebral Palsy • Motor control‐ tone, posture, movement • 2‐3/1000 children • Risk factors include infection, inflammation, low birth weight, prematurity, genetic • Secondary to brain dysgenesis or injury • “Non‐progressive”‐ manifestations can change • Unilateral and bilateral phenotypes • A range of associated disorders • Etiology links to phenotype links to treatment 1 Cerebral Palsy‐ Clinical Phenotypes CEREBRAL PALSY Spastic Dyskinetic Ataxic Hypotonia Bilateral Unilateral Hypertonic Hyperkinetic Spastic Diplegia Hemiplegia Dystonic Rigid Dystonic Tetraplegia Quadriplegia Athetosis Chorea Hemiballismus Cascade of events in brain injury 1. Prenatal antecedents may be suspected‐(Freud) 2. Final common pathways often involve hypoxia‐ ischemia and infection‐inflammation 3. Injury may have a protracted time course 4. Injury may lead to myelin abnormalities, reduced plasticity and decreased cell number 5. Injury changes both developmental trajectory and may sensitive brain to later injury The Evolving Nature of Injury TIME MINUTES HOURS DAYS WEEKS YEARS Nucleus INSULTS TRIGGERING Mitochondria Fleiss, Gressens. Lancet Neurology 2012;11:556‐66 2 Dyskinetic Disorders Disorder Etiology/Risk Factors Neuroimaging Acute HIE Hypoxia‐Ischemia Putamen, VL Thalamus, Perirolandic Motor Strip Kernicterus Bilriubin toxicity Globus Pallidus, Subthalamic Nucleus, Substantia Nigra, Brainstem PVL+ Hypoxia‐Ischemia Pulvinar, Periventricular White Infection‐Inflammation Matter PKAN PKAN2 Globus Pallidus (“Eye of the Tiger”) GA1 GCDH Caudate and Putamen Leigh Nuclear, Mitochondrial Basal Ganglia, Brainstem, other Syndrome genes Proprionic PCCA, PCCB Globus Pallidus Acidemia Striatal Neuroinflammatory Caudate and Putamen Necrosis Basal Ganglia Circuitry Neonatal Encephalopathy‐ Term Infant: A Cause of CP in 15‐20% of Cases • A constellation of findings including abnormal consciousness, tone, reflexes, feeding, respiration or seizures and can result from myriad conditions. • May/may not result in permanent neurologic impairment. • Pathway from intrapartum hypoxic‐ischemic injury to CP must progress through NE. ACOG Task Force on Neonatal Encephalopathy, 2003 3 Term infant with HIE: Energy Failure Impairs Glutamate Pump Glutamate pump depends on glucose Slide Courtesy of Michael Johnston, MD Slide Courtesy of Michael Johnston, MD Acute HIE: Images in Newborn Period T2 T2 T1 T2W (normal) Hyperintense signal in the thalamus DWI ADC Slide Courtesy of Doris Lin, MD, PhD 4 Asphyxia Damages Structures Connected by Excitatory Pathways Slide Courtesy of Michael Johnston, MD Involvement of GP in Kernicterus T2 FLAIR ©AP Periventricular Leukomalacia (PVL) Periventricular White Matter Injury (PVL) in premature Infants‐ the most common cause of CP Selective Vulnerability‐ Immature Oligodendroglia • Immature vascularity‐ impaired autoregulation • Oligodendroglia vulnerable to ischemia/inflammation • Free radical pathway to destruction 5 Periventricular Leukomalacia (PVL) Sagittal T1 Axial FLAIR Axial T2 Thalamic Lesions in HIE and PVL MRI: Striatal Necrosis 6.