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

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

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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

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Clinical Approach T

  • 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

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DISCLOSURES

¡ Dr. Ismail has no financial disclosure or conflict of interest pertaining to this lecture

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¡ Define and interpret the patterns of neurodevelopmental regression ¡ Understand the neuroscience behind neurodevelopmental regression ¡ Adopt a framework when evaluating a child with neurodevelopmental regression

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BY THE END OF THIS LECTURE, ATTENDEES WILL BE ABLE TO:

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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

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Bystron et al. Nature Reviews Neuroscience 2008

Birth Preschool School age Infancy Adulthood Higher cognitive function Vision and Hearing Motor Language

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The Five Phases Of Brain Development

1.

Neurulation (neural tube formation) (3rd week)

2.

Neurogenesis + cell differentiation (End by 3rd trimester)

3.

Cell migration + proliferation (completed by 6 months)

4.

Synaptogenesis (late gestation and early postnatal period)

5.

Myelination

§

Specific order:

1.

Motor roots

2.

Sensory roots

3.

Secondary association areas (1st postnatal months)

4.

Classic association areas, higher cortical functions (postnatal to adolescence)

5

1/26/20 FYISMAIL 2020

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Domains Of Brain Development

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Isolated or Global developmental regression ?

Motor Gross motor Fine motor Oral motor Cognition (or central processing) Language Receptive Expressive Problem-solving/non-language cognition Neurobehavioral Social behavior Adaptive emotional behavior, self-regulation, mental status

Be aware of inter-individual variability Developmental Milestones are specific functional skills attained at specific time

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Can We Quantify Brain Development?

2 4 6 8 10 1 2 3 4 5 6 7 8 TIME Function

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ΔF ΔT

General or domain specific: Motor DQ Language DQ Visuo-spatial DQ Diagnosis Prognosis Counselling Therapeutic monitoring

Courtesy of Dr. Bruce Shapiro. The Kennedy Krieger Institute, Johns Hopkins

Developmental Quotient =

Mental Age Chronologic Age

x 100

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¡ 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)

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Important Definitions

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¡ Regression: Loss of previously acquired skills ¡ Persistent and unyielding decline in developmental skills ¡ Can also be seen in a child that has a persistent decrease rate in

attaining milestones or who has a prolonged plateau

¡ Not caused by trauma or brain injury ¡ Encephalopathy (acute, transient) vs. regression (slower, progressive)

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Important Definitions (2)

No consensus on how to

  • perationalize it

No standard measurements to capture regression at its

  • nset
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¡ 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)

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Important Definitions (3)

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PATTERNS OF ABNORMAL BRAIN DEVELOPMENT OVER TIME

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Brain Development Time

Plateau

e.g.: Cognitive function in a child with intellectual disability

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e.g.: A child admitted to the ICU à critical illness myopathy à recovers

Transient “Recovery Pattern”

Time Brain Development

http://bronsonbeckman.com/wp-content/uploads/2013/02/ICU-days-001.jpg

PATTERNS OF ABNORMAL BRAIN DEVELOPMENT OVER TIME

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e.g.: A child with metabolic disorder with energy failure crisis

Episodic “Decline and partial reset”

Brain Development Time

PATTERNS OF ABNORMAL BRAIN DEVELOPMENT OVER TIME

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e.g.: A child with neurodegenerative disorder

Deterioration of function

Brain Development Time

PATTERNS OF ABNORMAL BRAIN DEVELOPMENT OVER TIME

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Brain Development

Time

Plateau

Transient “Recovery Pattern” Episodic “Decline and partial reset”

Deterioration

  • f function

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?
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Where does developmental regression arise from?

¡ Regression = Significant brain dysfunction at cellular, molecular, synaptic and/or network level

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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
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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

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Identify reversible causes of developmental regression!

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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

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Somatic/systemic manifestations

  • With or without epilepsy
  • Vision and hearing impairment

Language: Autism or LKS

  • Motor: SCA, FA
  • Generalized:

Neurodegenerative, neurometabolic

  • Neonatal/early infancy
  • Infantile/late infantile
  • Middle childhood
  • Older child/adolescent
  • Acute (increased ICP)
  • Subacute
  • Chronic

Onset Age at

  • nset

Somatic Domains

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A Framework For Evaluating A Child With Regression

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Investigations T

  • Be Considered

¡

Imaging:

¡

MRI brain / spine MRS (lactate/creatine)

¡

Blood

¡

Ammonia

¡

Lactate

¡

Plasma amino acids

¡

VLCFA e Very Long Chain Fatty Acids

¡

Carnitine, acylcarnitine

¡

Copper and ceruloplasmin

¡

Biotinidase

¡

White cell enzymes for GM1/2, Krabbe, MLD etc

¡

Sulphocysteine and uric acid

¡

Urine

¡

Organic acids

¡

Amino acids

¡

Glycosaminoglycan and oligosaccharides

¡

CSF

¡

Lactate, pyruvate

¡

Amino acids with glycine

¡

Glucose

¡

Neurotransmitters and folate

¡

Visual evoked potentials and electroretinogram

¡

Skin/muscle biopsy

¡

Liver biopsy

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NEURODEGENERATIVE DISEASES

Grey matter Disease

¡

Early signs

  • Behavior change
  • Cognitive decline
  • Seizures
  • Vision decline: retinal degeneration

¡

Late signs

  • Spasticity

White Matter Disease

¡

Early signs

  • Spasticity/Babinski
  • Peripheral neuropathy
  • Vision decline: optic nerve atrophy
  • Ataxia

¡

Late signs

  • Seizures
  • Cognitive decline

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

AGE AT ONSET

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MANAGEMENT

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

Multidisciplinary team

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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

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REFERENCES

¡

Bystron, I., Blakemore, C. & Rakic, P ., 2008. Development of the human cerebral cortex: Boulder Committee revisited. Nature Reviews Neuroscience, 9, p.110. Available at: https://doi.org/10.1038/nrn2252.

¡

Tan, A.P ., 2017. Pediatric MRI Brain : Normal or abnormal, that is the question. Radiology and Diagnostic Imaging, 1(2), pp.1–10.

¡

King M and Stephenson J. A handbook of neurological investigations in children. Mac Keith Press. 2009

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CASE STUDY: 20 MONTH OLD WITH GLOBAL REGRESSION

¡

He was born at term without difficulty after an uncomplicated pregnancy

¡

He met his early developmental milestones on time

¡

GM:

¡

Walked around 12 months of age

¡

Around 15 months he began preferring to crawl rather than walk

¡

For past 3 months, has not walked at all

¡

Fine motor:

¡

Began to feed himself at 15 months of age

¡

Now requires spoon feeding, sometimes chokes on food, and drools frequently.

¡

Language:

¡

He no longer says any words, but has returned to babbling.

¡

There is no history of developmental problems in primary relatives

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https://learning.aan.com/diweb/catalog/launch/package/4/sid/59310315

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¡ Examination:

¡

His forehead is prominent – something which his mother reports have been increasingly notable over the past several months.

¡

HC: 50th %ile at birth, now > the 98th %ile for age

¡

He is awake but not very attentive or interactive

¡

He has symmetric hyperreflexia of all four limbs with increased tone and upgoing toes bilaterally.

¡

He has dysmetria when reaching for objects.

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WHAT WOULD YOU DO NEXT?

¡ Chronic progressive regression in more than one developmental domain ¡ Associated neurological deficits (White matter + Grey matter) ¡ Macrocephaly

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BRAIN MRI

¡

Increased T2 signal in the subcortical white matter

¡

Frontal predominance (*)

¡

Symmetric and confluent

¡

Involvement of subcortical U-fibers in frontal lobe

¡

T1 post contrast rim enhancement within the caudate (à)

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Tan, Radiology and Diagnostic Imaging 2017

DDx: Metachromatic Leukodystrophy Canavan Disease Alexander Disease

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GFAP (Glial Fibrillary Acidic Protein) AD Aspartoacylase AR

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Arylsulfatase A AR Adrenoleukodystrophy protein (ALDP) X-linked

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EXAMINATION

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Macrocephaly

Fragile X syndrome, Alexander’s disease, Canavan’s disease, Progressive hydrocephalus, Metachromatic leukodystrophy

Microcephaly

Angelman’s syndrome, Craniosynostosis, CNS malformation, Rett’s syndrome

Coarse facial features

Mucopolysaccharidoses

Hepatomegaly

Inborn Error of Metabolism, Wilson’s disease

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Abnormal Skin

Adrenoleukodystrophy, NF1, Sturge-Weber, Tuberous sclerosis, PKU

Abnormal Hair

Menkes’, PKU, Homocystinuria, Hypothyroidism, mucopolysaccharidoses

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CLUES FROM EXAMINATION

Abnormal Hearing

CHARGE Syndrome, Down Syndrome, Pfeiffer’s Syndrome, Canavan’s leukodystrophy, Smith-Magenis, Velocardiofacial and DiGeorge Syndrome

Ocular abnormalities

Tay-Sachs, Congenital Syphilis, CHARGE syndrome

Genital abnormalities

Noonan’s, Fragile X syndrome