COGNITIVE FUNCTION CHANGES IN CONGENITAL HYPOTHYROIDISM ELIMINATED THROUGH NEONATAL SCREENING

1. COGNITIVE FUNCTION CHANGES IN CONGENITAL HYPOTHYROIDISM ELIMINATED THROUGH NEONATAL SCREENING DOINA TEODORESCU , MD, Ph.D. Assistant Professor Arad, Romania ,,Vasile Goldis,, Western University of Arad Szeged, 13 december, 2011

2. MOTTO: Every child has the right to an adequate iodine intake for a normal development. A particular importance in this context is the right of the unborn child. Each mother has the right to an adequate intake of iodine, which would ensure normal mental development of the unborn child. Declaration on the Child’s Rights, New York, UN,1989

3. Historic: • In South America were discovered sculptures dating from 400 BC representing dwarfs with goiter. • The clinical course of the intellect in the primary hypothyroidism was described in 1888 by the Clinical Society of London.

4. The cerebral and socio-economic impact of CH is enormous. Evolution with thyroid dwarfism, oligophrenia III-rd degree Untreated patient with irreversible changes in CNS development. Similar clinical aspect to myxedemic cretinism. C.B., an old patient with permanent sporadic CH tardily diagnosed

5. Cognitive functions They are defined as the most highly specialized brain functions with cognitive brain substrate

6. Areas of the brain affected by the HT concentrations (1) Broca's area, "the headquarters of articulate language" of the dominant hemisphere of each individual. Wernicke-area – short-term memory, understanding written or spoken language Auditory cortex – role in recognizing and receiving sound waves

7. (2) Corpus callosum – connects the hemispheres Frontal lobe – role in cognition, memory, concentration, attention, thought processes and inhibition, language Parietal lobe – processing sensory information, recognition of the body scheme, space orientation

8. (3) Occipital lobe - primary area of visual perception and association. Temporal lobe - the receptive area for hearing, associative area with a role in understanding spoken language and evoked memory.

9. (4) hippocampus - role in learning and spatial memory hypothalamus - central relay in the collection and integration of signals from different brain sources with a role in hormonal integration.

10. The role of HT in brain neurogenesis • Temporary coordinates brain development events • Regulates gene expression by inducing transcription of specific mRNA through action on its nuclear receptors • Initiation and regulation of protein synthesis • Adjusting the biochemical maturation of the HT brain acts via growth factors (NGF, EGF, IGF1) and through coactivators(SRC1, TIF 2/GRIP 1) and RT corepresors(N-Cor, SMRT).

11. Chronology of brain neurogenesis and the role of HT Delange si Fischer, 2001 Ontogenia of thyroid function and regulation during fetal and early postnatal life in relation to brain growth speed

12. Chronology of major CNS impairment in congenital myxedem vs. endemic cretinism Schematic representation of the chronology of major development events in human brain overlapping changes in fetal availability and sources of T4. The table refers to the initial period of CNS development which is not known whether or not is HT dependent - after Dr. RG Long - 1997

13. The neuropathologicalbasis of the clinical changes of HC • Bad development of neocortex > mental retardation • Defects of cerebellar maturation > cerebellar ataxia • Abnormalities in the development of pyramidal cells → GM crisis • Bad-development of auditory and visual cortex → deafness, decrease in visual processing and spatial orientation

14. Physiopathology of cognitive and behavioral functions in hypothyroidism • Hypometabolic status with cognitive functions decline • Mitochondrial alteration with protein release and apoptosis during brain development • Reduced cerebral blood flow and O2 and glucose consumption • Raised cerebro-vascular resistance

15. Brain electrophysiology in CH • EEG - low voltage, predominance of theta and delta waves. Sleep stages 3 and 4 can be reduced. • The study of visual evoked potentials - short-term decrease of recognition of visual stimuli and spatial memory.

16. Brain imaging in CH • Spectroscopic magnetic resonance spectroscopic: phosphate metabolism in the frontal lobe increases after treatment with T4 • SPECT / SCAN: cerebral hypoperfusion and low metabolic activity • PET shows the relationship between thyroid status, cerebral blood flow and cerebral glucose metabolism

17. Etiology of congenital hypothyroidism Permanent HC Primary Thyroid disgenesis thyroid agenesis thyroid ectopy thyroid hypoplasia Dishormono-genesis Iatrogenic (radioiodine maternal therapy) Secondary and tertiary (hypotalamo-pituitary) Peripheral resistance to thyroid hormones Transient HC Iodine deficit Iodine excess Maternal treatment with anti-thyroid drugs Blocked maternal antibodies of TSH receptor Idiopathic Trisomy 21

18. Psychomotor development in CH • Over 90%newborns with CH have a cvasinormal psychomotor and somatic development if treatment is initiated soon after birth. • Untreated, CH leads to severe brain damage similar to that of endemic myxedemic cretinism.

19. Comparative study of endemic cretinism cognitive changes and congenital hypothyroidism • Brain damage from EC due to iodine deficiency which occurs in the first trimester of pregnancy through maternal and subsequently fetal hypothyroxinemiais irreversible. • The main difference between the EC and CH is related to thyroid status of the mother which is normal in most cases of CH.

20. Transient congenital hypothyroidism • Hypothyroidism detected through neonatal screening which subsequently disappeares spontaneously and completely • Minimum criteria for diagnosis is the initial screening TSH concentration> 40 mU/l with subsequent return to normal • Iodine deficiency, prematurity, male gender, low birth weight, TSH <100 are suggestive factors of TCH

21. Congenital hypothyroidism screening • CH screening revolutionized the prognosis of children with CH through early diagnosis and treatment of the disease • TSH screening does not identify newborns with secondary hypothyroidism (1 / 50 000), those with a delayed increase in TSH concentration (10% of NN with hypothyroidism), those with TBG deficiency

22. Conclusions • The degree of hypothyroidism in utero, the etiology and severity of CH, the age at the onset of therapy, T4 levels at diagnosis are the major factors influencing the intellectual development of CH • Children with HC monthly lose 3-5 points from the IQ score if diagnosis and treatment with T4 is inadequate • HC screening demonstrates the importance of communication between the geneticist, pediatrician, endocrinologist, family doctor and patient’s parents

23. THANK YOU !!