Microcephaly

1. Microcephaly Sonya Mary Palathumpat, MD

2. Microcephaly • Occipitofrontal circumference (OFC) more than 2 standard deviations (SD) below the mean for a given age, sex, and gestation (<3rd percentile) • Mild microcephaly: OFC between 2 and 3 SD below the mean • Severe microcephaly: OFC > 3 SD below the mean

3. Measurement • Occipitofrontal circumference (OFC) • Should be measured at health maintenance visits between birth and 3yo and in any children with neurologic symptoms • Measuring tape should encircle head and include an area 1-2 cm above the glabella and the most prominent portion of the occiput

4. Measurement • OFC measurements may be inaccurate until the 3-4th day of life due to: • Caput succedaneum • Cephalohematoma • Molding

5. Monitoring • OFC measurements are most informative when plottted overtime • CDC has head circumference charts for 0 – 36 mo for boys and girls; and Pt’s with certain syndromes

6. Classification • Time of Onset • Congenital (Primary microcephaly) • Present at birth • Postnatal (Secondary microcephaly) • Normal HC at birth • Etiology • Genetic • Environmental • Relation to Other Growth Parameters • Symmetric • Asymmetric • Association with other Anomalies • Isolated (Pure): not associated with other anolalies • Syndromal (Complex): associated with one or more anomalies

7. Pathogenesis • Primary Microcephaly: • Lack of brain development or abnormal brain development • Reduction in the number of neurons generated during neurogenesis • Secondary Microcephaly: • Injury or insult to a previously normal brain • Reduction in the number of dendritic processes and synaptic connections

8. Etiology I. Isolated Microcephaly II. Syndromic Microcephaly III. Neuroanatomic abnormalities IV. Metabolic disorders V. Environmental Factors

9. I. Isolated Microcephaly • Primary Microcephaly • Present at birth • Uncomplicated by other anomalies • Brain with normal architecture but is small

10. II. Syndromic Microcephaly

11. III. Neuroanatomic Abnormalities 1. Neural Tube Defects 2. Holoprosencephaly -Incomplete development and septation of CNS structures 3. Atelencephaly -No telencephalon derived brain structures(cerebrum) 4. Lissencephaly -The six cortical layers do not form normally due to impaired migration of neurons from the germinal matrix lining the ventricles -The surface of the brain appears completely or partially smooth with loss or reduction of sulci 5. Schizencephaly -Asymmetric infolding of cortical gray matter along primary brain cleft 6. Polymicrogyria -Developmental malformation characterized by excessive gyri on brain surface 7. Pachygyria - Developmental malformation characterized by reduction in number of sulci of the cerebrum (often seen in lissencephaly) 8. Fetal Brain Disruption Sequence -Severe microcephaly of prenatal onset(of about 5.8 SD below the mean) -Pt with overlapping cranial sutures, prominence of occipital bone, and scalp rugae. 9. Hydranencephaly -Fluid-filled cavities replace the cerebral hemispheres with preservation of cerebellum, midbrain, thalami, and basal ganglia

12. IV. Metabolic Disorders • Aminoacidurias (PKU) • Organic Acidurias (Methylmalonic aciduria) • Urea Cycle Disorders (Citrullinemia) • Storage Diseases (Neuronal Ceroid Lipofuscinosis) • Maternal Diabetes Mellitus

13. V. Enviornmental Causes • Congenital Infection • CMV, HSV, Rubella, Varicella, Toxoplasmosis, HIV, Syphilis, Enterovirus • Meningitis • In-utero Drug or Toxin Exposure • Alcohol, Tobacco, Marijuana, Cocaine, Heroin • Antineoplastic agents, Antiepileptic agents, Radiation, Toluene • Perinatal Insult • Hypoglycemia, Hypothyroidism, Hypopituitarism, Hypoadrenocorticism • Anoxia/Ischemia

14. Evalutation • If single OFC measurement is 2-3 SD below the mean • If serial measurements reveal progressive decrease in head size • Evalutation: • Re-measurement of HC • Thorough history and physical • Labs/Imaging • Consults

15. Evaluation • History • Prenatal history • Maternal medications, infections, tobacco, alcohol, substance use, radiation exposure, findings of antenatal US • Birth history • Perinatal complications, infections, metabolic issues • Weight, length, and OFC • Determine if microcephaly is proportionate to weight and length • Family History • Consanguinity, any microcephaly in family

16. Evaluation • Physical Examination • General Appearance • Dysmorphic features • Suggesting a particular syndrome • OFC (Patient and Parents) • Weight and length • Head • Assess frontanelles • Palpate cranial sutures • Eyes • May provide clues in regards to intrauterine infections • Chorioretinitis(Toxoplasma, CMV); Cataracts (Rubella)

17. Evaluation • Physical Examination: • Oropharynx • Midline defects (cleft lip or palate, bifid uvula) • Skin • Look for petechiae, jaundice (infection); eczematous rash (PKU) • Abdomen • Hepatomegaly or splenomegaly (congenital infection) • Neurologic Assessment • Tone, reflexes, developmental ability

18. Evaluation • Neuroimaging: • Head U/S • CT Head • Intracranial calcification • MRI Brain • Delineate abnormalities in CNS architecture

19. Evaluation • Genetic Studies/ Genetics Consult • If Pt with dysmorphic features • Infectious Diseases Consult • If evaluation for congenital infection is indicated • Evaluation for metabolic disease or storage disorder • Testing for amino- and organic acidurias, lactate • Testing for very-long-chain fatty acids • if Pt hypotonic • Testing for plasma 7-dehydrocholesterol • Pt with features suggestive of Smith-Lemli-Opitz syndrome

20. Prognosis • Depends upon underlying cause • Worse for Pt’s with a wider pattern of malformation and Pt’s with intrauterine infection • Severity of cognitive impairment related to the severity of the microcephaly

21. Sources • Etiology and evaluation of microcephaly in infants and children; UptoDate; Boom, Julie, MD • Microcephaly Syndromes; Pediatric Neurology; Abuela, Dianne, MD