Clinical Approach T o Neurodevelopmental Regression Fatima Ismail, - PowerPoint PPT Presentation

Clinical Approach T o Neurodevelopmental Regression Fatima Ismail, MBBS, FAAP , FAAN Assistant Professor of Neurology and Developmental Medicine, UAE University Adjunct Assistant Professor of Neurology, Johns Hopkins School Of Medicine Fatima.Ismail@uaeu.ac.ae 29/01/2020 FYISMAIL 2020 1

DISCLOSURES ¡ Dr. Ismail has no financial disclosure or conflict of interest pertaining to this lecture FYISMAIL 2020 29/01/2020 2

BY THE END OF THIS LECTURE, ATTENDEES WILL BE ABLE TO: ¡ Define and interpret the patterns of neurodevelopmental regression ¡ Understand the neuroscience behind neurodevelopmental regression ¡ Adopt a framework when evaluating a child with neurodevelopmental regression FYISMAIL 2020 29/01/2020 3

BRAIN DEVELOPMENT ¡ A sequenced and ordered process of brain maturation, neural circuits formation, integration and specialization leading to gain and/or loss of function ¡ Is a continuum in time Language Higher cognitive function Vision and Hearing Motor Birth Infancy Preschool School age Adulthood FYISMAIL 2020 29/01/2020 4 Bystron et al. Nature Reviews Neuroscience 2008

The Five Phases Of Brain Development Neurulation (neural tube formation) (3 rd week) 1. Neurogenesis + cell differentiation (End by 3 rd trimester) 2. Cell migration + proliferation (completed by 6 months) 3. 4. Synaptogenesis (late gestation and early postnatal period) Myelination 5. § Specific order: Motor roots 1. 2. Sensory roots Secondary association areas (1 st postnatal months) 3. Classic association areas, higher cortical functions 4. FYISMAIL 2020 1/26/20 (postnatal to adolescence) 5

Domains Of Brain Development Motor Gross motor Developmental Milestones are specific functional skills attained at specific time Fine motor Oral motor Be aware of inter-individual variability Cognition (or central processing) Language Receptive Expressive Isolated or Global developmental regression ? Problem-solving/non-language cognition Neurobehavioral Social behavior Adaptive emotional behavior, self-regulation, FYISMAIL 2020 29/01/2020 6 mental status

Can We Quantify Brain Development? 10 Developmental Quotient = Mental Age x 100 8 Chronologic Age Function 6 General or domain specific: Δ F Motor DQ 4 Language DQ 2 Δ T Visuo-spatial DQ 0 1 2 3 4 5 6 7 8 TIME Diagnosis Prognosis Courtesy of Dr. Bruce Shapiro. Counselling The Kennedy Krieger Institute, Johns Hopkins FYISMAIL 2020 Therapeutic monitoring 29/01/2020 7

Important Definitions ¡ Delay: Failure to meet age-appropriate expectations A child who is not walking by 18 months – brings child to attention ¡ ¡ Dissociation: Asynchronous development among domains (>15% variation) A two year old child who walks but does not talk – allows early diagnosis ¡ ¡ Deviance: Violation of developmental rate and/or sequence A child with autism can have language delay (slow rate) and/or echolalia (deviance) ¡ FYISMAIL 2020 29/01/2020 8

Important Definitions (2) ¡ Regression: Loss of previously acquired skills No consensus on how to ¡ Persistent and unyielding decline in developmental skills operationalize it ¡ Can also be seen in a child that has a persistent decrease rate in No standard measurements attaining milestones or who has a prolonged plateau to capture regression at its onset ¡ Not caused by trauma or brain injury ¡ Encephalopathy (acute, transient) vs. regression (slower, progressive) FYISMAIL 2020 29/01/2020 9

Important Definitions (3) ¡ Pseudo-regression: Loss of skills that have not been firmly established or failure to progress ¡ Usually confined to one stream (e.g., language) ¡ Natural history of the disorder (e.g., cerebral palsy ) ¡ Other factors (e.g., weight gain in motor disorders, depression) FYISMAIL 2020 29/01/2020 10

PATTERNS OF ABNORMAL BRAIN DEVELOPMENT OVER TIME Brain Development Plateau e.g.: Cognitive function in a child with intellectual disability Time FYISMAIL 2020 29/01/2020 11

PATTERNS OF ABNORMAL BRAIN DEVELOPMENT OVER TIME e.g.: A child admitted to the ICU à Brain Development critical illness myopathy à recovers Transient “Recovery Pattern” Time http://bronsonbeckman.com/wp-content/uploads/2013/02/ICU-days-001.jpg FYISMAIL 2020 29/01/2020 12

PATTERNS OF ABNORMAL BRAIN DEVELOPMENT OVER TIME Brain Development e.g.: A child with metabolic disorder with energy failure crisis Episodic “Decline and partial reset” Time FYISMAIL 2020 29/01/2020 13

PATTERNS OF ABNORMAL BRAIN DEVELOPMENT OVER TIME Brain Development e.g.: A child with Deterioration of neurodegenerative disorder function Time FYISMAIL 2020 29/01/2020 14

Brain Development Episodic Transient Deterioration “Decline and Plateau “Recovery partial reset” of function Pattern” Time Clinical and research challenges: 1. How do we define the onset and severity of regression? 2. How accurate is the reporting of the premorbid functional baseline? 3. Do the behavioral manifestations of regression reflect neurobiological substrates? 4. Are there overlapping mechanisms between different patterns of regression? FYISMAIL 2020 29/01/2020 15

Where does developmental regression arise from? ¡ Regression = Significant brain dysfunction at cellular, molecular, synaptic and/or network level The mechanism underlying regression can be disease-specific: • Neurodegenerative disorders (Leukodystrophies) • Neurometabolic disorders (IEMs, severe nutritional deficiencies) • Structural brain lesions (progressive hydrocephalus) • Epileptic encephalopathy syndromes (Lennox-Gastaut syndrome) • Infectious (subacute sclerosing panencephalitis) • Toxins (lead exposure) • Neoplastic FYISMAIL 2020 29/01/2020 16

Clinical Approach History ¡ General physical examination ¡ Neurological Examination ¡ Developmental Evaluation ¡ Vision and Hearing testing ¡ Obtain old documentation (photos, films, videos, etc) that documents previous baseline function ¡ Identify reversible causes of developmental regression! FYISMAIL 2020 29/01/2020 17

REVERSIBLE CAUSES OF NEURODEVELOPMENTAL REGRESSION Examples Biotinidase deficiency Wilson disease Niemann-Pick type C Neurotransmitter disorders (e.g. Segawa, tyrosine hydroxylase deficiency) Cerebral folate disorder Glucose transporter disorder Pyruvate dehydrogenase deficiency FYISMAIL 2020 29/01/2020 18

A Framework For Evaluating A Child With Regression • Acute (increased ICP) • Neonatal/early infancy • Subacute • Infantile/late infantile • Chronic Age at • Middle childhood Onset onset • Older child/adolescent Somatic/systemic Language: Autism or LKS Domains Somatic manifestations • Motor: SCA, FA • With or without epilepsy • Generalized: • Vision and hearing impairment Neurodegenerative, neurometabolic FYISMAIL 2020 29/01/2020 19

Investigations T o Be Considered Imaging: Urine ¡ ¡ MRI brain / spine MRS (lactate/creatine) Organic acids ¡ ¡ Amino acids Blood ¡ ¡ Glycosaminoglycan and oligosaccharides ¡ Ammonia ¡ CSF Lactate ¡ ¡ Plasma amino acids Lactate, pyruvate ¡ ¡ VLCFA e Very Long Chain Fatty Acids Amino acids with glycine ¡ ¡ Carnitine, acylcarnitine Glucose ¡ ¡ Copper and ceruloplasmin Neurotransmitters and folate ¡ ¡ Biotinidase Visual evoked potentials and electroretinogram ¡ ¡ White cell enzymes for GM1/2, Krabbe, MLD etc ¡ Skin/muscle biopsy ¡ Sulphocysteine and uric acid ¡ Liver biopsy ¡ FYISMAIL 2020 29/01/2020 20

NEURODEGENERATIVE DISEASES Grey matter Disease White Matter Disease Early signs Early signs ¡ ¡ -Behavior change -Spasticity/Babinski -Cognitive decline -Peripheral neuropathy -Seizures -Vision decline: optic nerve atrophy -Vision decline: retinal degeneration -Ataxia Late signs Late signs ¡ ¡ -Spasticity -Seizures -Cognitive decline FYISMAIL 2020 29/01/2020 21

AGE AT ONSET Neonatal-infancy Infancy Late infantile Middle childhood Older child – (encephalopathy) adolescent Hypothyroidism GM1 gangliosidosis Rett syndrome Sanfilippo disease Juvenile neuronal PKU GM2 gangliosidosis Late infantile Adrenoleukodystrophy ceroid Creatine synthesis Tay-Sachs neuronal Neiman Pick type C lipofuscinosis disorders Infantile Sandhoff lipofuscinosis PKAN Huntington disease disease Metachromatic SSPE Wilson disease Krabbe disease leukodystrophy Menkes disease Infantile neuroaxonal Canavan disease dystrophy Infantile neuronal FYISMAIL 2020 29/01/2020 22 ceroid lipofuscinosis

MANAGEMENT Multidisciplinary team Goals of management: 1. Identify reversible causes and treat them in a timely manner 2. Provide symptomatic treatment (dystonia, spasticity, epilepsy) 3. Involve palliative care and family counselling services at an early stage 4. Address comorbidities including swallowing problems, irritability, self-injurious behaviors 5. Family support 6. Genetic counselling for family planning purposes FYISMAIL 2020 29/01/2020 23

SUMMARY ¡ Developmental regression at any age and in any domain is a red flag ¡ Follow a systematic approach to evaluation of developmental regression ¡ Early diagnosis improves outcomes in some disorders with developmental regression FYISMAIL 2020 29/01/2020 24