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

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