COGNITIVE FUNCTION CHANGES IN COGNITIVE FUNCTION CHANGES IN CONGENITAL HYPOTHYROIDISM CONGENITAL HYPOTHYROIDISM

ELIMINATED THROUGH NEONATAL ELIMINATED THROUGH NEONATAL SCREENINGSCREENING

DOINA TEODORESCU , MD, Ph.D.Assistant Professor

Arad, Romania,,Vasile Goldis,, Western University of Arad

Szeged, 13 december, 2011

MOTTO: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

Historic: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.

The cerebral and socio-economic impact of CH The cerebral and socio-economic impact of CH is enormous.is enormous.

Evolution with thyroid dwarfism, oligophrenia III-rd degree

C.B., an old patient with permanent sporadic CH tardily diagnosed

Untreated patient with irreversible changes in CNS development. Similar clinical aspect to myxedemic cretinism.

Cognitive functionsCognitive functionsThey are defined as the most highly specialized brain functions with cognitive brain substrate

Areas of the brain affected by the HT Areas of the brain affected by the HT concentrations (1)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

(2)(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

(3)(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.

(4)(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.

The role of HT in brain The role of HT in brain neurogenesisneurogenesisTemporary coordinates brain

development eventsRegulates 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).

Chronology of brain neurogenesis and the Chronology of brain neurogenesis and the role of HTrole of HT

Ontogenia of thyroid function and regulation during fetal and early postnatal life in relation to brain growth speed

Delange si Fischer, 2001

Chronology of major CNS impairment in Chronology of major CNS impairment in congenital myxedem vs. endemic congenital myxedem vs. endemic cretinism 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

The neuropathological basis of the clinical The neuropathological basis of the clinical changes of HC 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

Physiopathology of cognitive and Physiopathology of cognitive and behavioral functions in hypothyroidismbehavioral 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

Brain electrophysiology in CHBrain 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.

Brain imaging in CHBrain 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

Etiology of congenital Etiology of congenital hypothyroidismhypothyroidism

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 deficitIodine excessMaternal treatment with anti-thyroid drugsBlocked maternal antibodies of TSH receptorIdiopathicTrisomy 21

Psychomotor development in CHPsychomotor 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.

Comparative study of endemic cretinism Comparative study of endemic cretinism cognitive changes and congenital cognitive changes and congenital hypothyroidismhypothyroidism

Brain damage from EC due to iodine deficiency which occurs in the first trimester of pregnancy through maternal and subsequently fetal hypothyroxinemia is 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.

Transient congenital Transient congenital hypothyroidismhypothyroidism

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

Congenital hypothyroidism Congenital hypothyroidism screeningscreeningCH 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

ConclusionsConclusionsThe 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