Cost Effective Evaluation of a Child With Neurodevelopmental Disabilities (NDD)

Kenton R. Holden, M.D. Professor of Neurosciences (Neurology) & Pediatrics Medical University of South Carolina Charleston, South Carolina Senior Clinical Research Neurologist Greenwood Genetic Center Greenwood, South Carolina

Tegucigalpa, Honduras January 31, 2014

Neurodevelopmental Disabilities (NDD)

Disclosures:
1. NIH Funding R01s re: ID Etiologies 2010-15, and Neuronal Gene Regulatory Elements with Epilepsy 2012-2016. 2. Smile Foundation: Co-PI for Pilot Funding 2013-2014; Assessment of Brain Structures and Tracts in X-Linked MCT8 Gene Abnormalities Using MRI. 3. Pediatric Neurology Consultant at the Greenwood Genetic Center, Greenwood, SC. 4. My favorite canvas briefcase was given to me at AES 2000 by Abbott Labs (Depakote / Depakene).
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Neurodevelopmental Disabilities (NDD)

I. Characteristics:
A. Common problem: About 100,000 born/yr; 2 to 3% of all children < 6-yrs-old B. Etiologies heterogeneous, but childrens delays similar - many of whom have intellectual disabilities (ID) C. Chronic disorder without prolonged plateau or regression in skills D. Frequent referral to Pediatrics, Neurology, & Genetics
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Neurodevelopmental Disabilities (NDD)

I. Graphic Representation of Childhood Development
5 4
Developmental
Skills (Years)

(A)

3
(B)

2
1

(C) (D) (E)

5
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Chronological Age (Years)

Neurodevelopmental Disabilities (NDD)

I. Characteristics: (continued)
A. Cognition

NOTE: Many reports use IQ [or developmental quotient (DQ)] of 50-69 as mild impairment, and IQ or DQ <50 as moderate to severe impairment.

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Neurodevelopmental Disabilities (NDD)

I. Characteristics: (continued)
A. Significant documented disturbance in two or more developmental domains ( 2 std. dev. below the mean for age)
Cognitive (intellect) Motor (gross and/or fine) Speech/language Behavioral/Social Activities of daily living
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Neurodevelopmental Disabilities (NDD)

I. Characteristics Summary:
A. DOMAINS: Single: Cognitive / intellectual disability (ID)... formerly mental retardation (MR); gross motor delay / cerebral palsy (CP)
Multiple: Neurodevelopmental disabilities (NDD) B. FINAL DIAGNOSIS relies on a careful and detailed history (pedigree), observational and direct examination (OFC, fundi, etc.), appropriate psychological testing, and laboratory investigations.

C. SECOND VISIT is an integral part of the diagnostic

assessment.
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Neurodevelopmental Disabilities (NDD)

II. Why Evaluate? (mostly Class III evidence,
lack of therapies, low yield, availability, invasiveness, costs, etc.)
A. Treatments are evolving B. Prognosis is evolving

C. Management of related disorders

D. Risk of reoccurrence (screening) E. Limits additional unnecessary testing F. Empowers family to plan, network, etc.
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Summary: Neurodevelopmental Disabilities (NDD)

1. Obtain a detailed history and examination (...includes birth/neonatal OFC & current OFC) 2. Refer for auditory and ophthalmologic screening 3. Consider metabolic studies/T4 if universal newborn screening not done. 4. If history of suspected seizures or epilepsy syndrome, obtain EEG 5. Consider screening for a language disorder or autism

6. Is there a close family member with NDD (e.g., sibling, aunt/uncle, first cousin, etc.):

A. Due to a known metabolic, genetic, or structural nervous system disorder?

B. Unexplained NDD? (A.)/(B.)---- Yes (A.) Obtain specific test(s) for that disorder (B.) Obtain microarray and Fragile X If tests are (-) (A.)/(B.) ---- No 7. Are there features suggesting a specific diagnosis? C. Are there historical or physical findings (e.g. dysmorphic features) to suggest Down, Fragile X, Rett syndrome, other neurogenetic disorders, or hypothyroidism? D. Are there historical (intrapartum asphyxia, neurobehavioral, etc.), or physical findings (microcephaly, cerebral palsy, focal findings), or seizures (infantile spasms (IS); partial) to suggest CNS injury or malformation? E. Does the child have any identifiable risk factors for excessive environmental/lead/other exposure as per established current guidelines? Yes (C.) Specific test(s) for that disorder (D.) Brain MRI preferred to CT scan (E.) Blood Lead level, etc. No (F.) but plateau and/or regression in milestones evident (F.) Stepwise evaluations for Neurodegenerative Disease. Holden K 01/31/14

Neurodevelopmental Disabilities (NDD)

III. Evaluation
1. Obtain a detailed history & exam; however, not all NDD genetic d/o have syndromic FHx or exam. 2. Auditory and ophthalmologic screening

3. Metabolic studies, T4/TSH if universal newborn screening not done

4. EEG only if history of suspected seizures or an epileptic syndrome 5. Screen for autism prn
NOTE: No single set of laboratory tests is indicated in all cases.
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Neurodevelopmental Disabilities (NDD)

Electroencephalography:

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Neurodevelopmental Disabilities (NDD)

III. Evaluation: (continued)
A. If close family relative with NDD due to known cause, obtain specific test (plasma amino acids, lactate / pyruvate, ammonia, ceruloplasmin, transferrin, urine organic acids, Fragile X) B. If close family relative with NDD due to unexplained cause, obtain a microarray and Fragile X.
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Neurodevelopmental Disabilities (NDD)

III. Evaluation: (continued)
C. Are there features suggesting a specific diagnosis?
Are there significant historical or physical findings, e.g. Down, Fragile X, Rett, Angelman, other neurogenetic d/o, hypothyroidism, etc.?...then obtain specific test.
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Neurodevelopmental Disabilities (NDD)

Dx: ??

Dx: ??

Dx: ??

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Neurodevelopmental Disabilities (NDD)

Dxs: Down Syndrome

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Neurodevelopmental Disabilities (NDD)

Dx: ??

Dx: ??

Dx: ??
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Neurodevelopmental Disabilities (NDD)

Dxs: Fragile X
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Neurodevelopmental Disabilities (NDD)

III. Evaluation: (continued)
D. Are there features suggesting a specific diagnosis? Are there historical (intrapartum, neurobehavioral, etc.) or physical findings (microcephaly*, CP, focal findings) or epilepsy [Infantile Spasms (IS); partial sz] to suggest brain injury or malformation?...then obtain brain MRI (preferred to CT).
*Reference #8: Rollins, JD et al., J Peds 2010;156:907
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Neurodevelopmental Disabilities (NDD)

2 mo old HM with NDD and IS Dx: ??

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Neurodevelopmental Disabilities (NDD)

Dx: MSUD

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Neurodevelopmental Disabilities (NDD)

2 yo WF with NDD & partial epilepsy

Request MRIs: ?? DX: ??

5 yo WM with NDD & partial epilepsy

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Neurodevelopmental Disabilities (NDD)

T1-sagittal

T1-axial

Dx: ??

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Neurodevelopmental Disabilities (NDD)

2 yo WF NDD & partial epilepsy

5 yo WM NDD & partial epilepsy

T1-sagittal

T1-axial
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Dx: Epidermal Nevus syndrome

Neurodevelopmental Disabilities (NDD)

III. Evaluation: (continued)
E. Does the child have any identifiable risk factors for excessive environmental exposures, infections, etc., per established guidelines?
If identifiable, obtain iron, lead, HIV testing, etc., prn.

Holden K 01/31/14

Summary: Neurodevelopmental Disabilities (NDD)

1. Obtain a detailed history and examination (...includes birth/neonatal OFC & current OFC) 2. Refer for auditory and ophthalmologic screening 3. Consider metabolic studies/T4 if universal newborn screening not done. 4. If history of suspected seizures or epilepsy syndrome, obtain EEG 5. Consider screening for a language disorder or autism

6. Is there a close family member with NDD (e.g., sibling, aunt/uncle, first cousin, etc.):

A. Due to a known metabolic, genetic, or structural nervous system disorder?

B. Unexplained NDD? (A.)/(B.)---- Yes (A.) Obtain specific test(s) for that disorder (B.) Obtain microarray and Fragile X If tests are (-) (A.)/(B.) ---- No 7. Are there features suggesting a specific diagnosis? C. Are there historical or physical findings (e.g. dysmorphic features) to suggest Down, Fragile X, Rett syndrome, other neurogenetic disorders, or hypothyroidism? D. Are there historical (intrapartum asphyxia, neurobehavioral, etc.), or physical findings (microcephaly, cerebral palsy, focal findings), or seizures (infantile spasms (IS); partial) to suggest CNS injury or malformation? E. Does the child have any identifiable risk factors for excessive environmental/lead/other exposure as per established current guidelines? Yes (C.) Specific test(s) for that disorder (D.) Brain MRI preferred to CT scan (E.) Blood Lead level, etc. No (F.) but plateau and/or regression in milestones evident (F.) Stepwise evaluations for Neurodegenerative Disease. Holden K 01/31/14

III. Evaluation : F. Evaluation of Neurodegenerative Disorders of Childhood with Cognitive Decline (Dementia)

(1) Screen for disorders that are potentially treatable or have genetic implications - Rule out: (A) Systemic Illness or Intoxicant (C) Hypothyroidism (B) Increased Intracranial Pressure (D) Metabolic Disease No Yes

Visceromegaly? Yes

Abnormalities of Skin and / or Hair No

(12) (13) (14) (15) (16) (17) No

Menke Disease Fabry Disease Biotinidase Deficiency Cockayne Syndrome Type I Cerebrotendinous Xanthomatosis Glycosylation Disorders Brain MRI with Symmetrical Lesions in Basal Ganglia / Thalamus / Brainstem No Ophthalmology Consult No Pathology Pathology

Dysmorphic ? No

Yes

Elements of Hurler Phenotype No Yes

Brain MRI with Demyelination or Dysmyelination? Yes Macrocephaly? Urine Screen for Mucopolysaccharides Negative Urine Screen for Oligosaccharides No Yes

No

Brain MRI with Eye of the Tiger Sign? Yes (28) Pantothenate Kinase-Associated Neurodegeneration

Urine Screen for Reducing Substances Positive (2) Galactosemia (3) Fructose Intolerance

(7) Disorders of Peroxisomal Biogenesis Zellweger Syndrome Neonatal Adrenoleukodystrophy Negative Infantile Refsum Disease

Yes

(18) Alexander Disease (19) Canavan Disease (1) Organic / Amino Acid Disorders (14) Biotinidase Deficiency (23) Mitochondrial Disorders (Leigh Syndrome, etc.) (29) Huntington Disease (30) Wilson Disease

Bone Marrow Aspirate For Gaucher Cells Positive (4) Gaucher Disease

Positive

Microcephaly? Yes Negative

See Table 2

(8) Mucopolysaccharidosis MPS I - Hurler MPS II - Hunter Negative Positive MPS III - Sanfilippo MPS VII - Sly Multiple Sulfatase Deficiency

No (20) Acquired Immunodeficiency Syndrome (11) Mucolipidosis II Seizures as Yes Prominent Symptom? (17) Glycosylation Disorders (21) Krabbe Disease (22) Subacute Sclerosing Panencephalitis (SSPE) (23) Mitochondrial Disorders No (23) (24) (25) (26) (27)

Seizures as Prominent Symptom? No Yes

(5) Sandhoff Disease (6) Niemann-Pick Disease

(9) Oligosaccharidosis Mannosidosis I Fucosidosis I Sialidosis II Galactosialidosis (10) GM1Gangliosidosis Type I

(23) Mitochondrial Disorders (31) Lesch-Nyhan Syndrome (17) (23) (29) (32) (33) Glycosylation Disorders Mitochondrial Disorders Huntington Disease Rett Syndrome GM1 Gangliosidosis Type II

Mitochondrial Disorders Pelizaeus-Merzbacher Disease Metachromatic Leukodystrophy Adrenoleukodystrophy Leukoencephalopathy with Vanishing White Matter

See Reference #7: Goldstein EM, Holden KR, Chapter 51 in Maria BLs text book, 2009.

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Neurodevelopmental Disabilities (NDD)

References:
1. Shevell M, et al: Practice parameter: evaluation of the child with global developmental delay. Neurology 2003; 60:367-380. 2. Shaffer LG: American College of Medical Genetics guideline on the cytogenetic evaluation of the individual with developmental delay or mental retardation. Genetics in Medicine 2005; 7:650-654. 3. Moeschler JB, Shevell M, and the Committee on Genetics: Clinical Genetic Evaluation of the Child With Mental Retardation or Developmental Delays. Pediatrics 2006; 117:2304-2316. 4. Paciorkowski AR and Fang M: Chromosomal microarray interpretation: What is a child neurologist to do? Pediatr Neurol 2009; 41:391-398. 5. Ashwal S, et al: Practice Parameter: Evaluation of the child with microcephaly (an evidence-based review). Neurology 2009; 73:887-897. 6. Holden KR and Lyons MJ: Chapter 62, Microcephaly-Acquired. In: Maria BL, ed. Current Management in Child Neurology. 4th Edition. Shelton, CT: PMPH/BC Decker, Inc, 2009:421-428. 7. Goldstein EM and Holden KR: Chapter 51, Neurodegenerative Disorders. In: Maria BL, ed. Current Management in Child Neurology. 4th Edition. Shelton, CT: PMPH/BC Decker, Inc, 2009:322-336. 8. Rollins JD, Collins JS, and Holden KR: US head circumference growth reference charts: Birth to 21 years. Jour Pediatr 2010; 156:907-913. 9. Michelson DJ, et al: Evidence Report: Genetic and metabolic testing on children with global developmental delay. Neurology 2011; 77:1629-1635.
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Neurodevelopmental Disabilities (NDD)

Acknowledgements:
1) Patti Broome & Suzan White, Admin Assts. at GGC. 2) All my patients, their parents, and my instructors for teaching me the ever evolving subject of childhood NDD.

Thank you!
Questions???
Holden K 01/31/14