Cognitive and White Matter Microstructure Development in Congenital Hypothyroidism and Familial Thyroid Disorders

Abstract

Context Children with congenital hypothyroidism (CH) are at risk for suboptimal neurodevelopment. Objectives To evaluate neurocognitive function and white matter microstructure in children with permanent or transient CH and to correlate these findings with disease severity. Design, participants and methods A retrospective and prospective observational study was conducted in 39 children with permanent or transient CH, and in 39 healthy children. Cognitive function was assessed by Wechsler Intelligence Scale (WISC-IV) and by other tests; the white matter microstructure was investigated by 3 Tesla magnetic resonance (MRI). Results Children with permanent CH have lower cognitive scores at a median age of 9.5 years than those with transient CH and controls. An IQ score between 71-84 was found in 28.6% of permanent CH and of <70 (p=0.06) in 10.7%. The Processing Speed Index (PSI, p=0.004), sustained visual attention (p=0.02), reading speed (p=0.0001), written calculations (p=0.002) and numerical knowledge (p=0.0001) were significantly lower than controls. Children born to mothers with Hashimoto’s thyroiditis have significantly lower IQ values (p=0.02), Working Memory Index (p=0.03) and PSI (p=0.02). Significantly lower IQ and Verbal Comprehension Index values were found in children with a family history of thyroid disorders (p=0.004; p=0.009), respectively. In children with permanent CH, significant correlations between abnormalities in white matter microstructural, clinical and cognitive measures were documented. Conclusions These findings indicate that children with CH are at risk of neurocognitive impairment and white matter abnormalities despite timely and adequate treatment. The association between offspring cognitive vulnerability and maternal thyroid disorders requires careful consideration.

Effect of initial levothyroxine dose on neurodevelopmental and growth outcomes in children with congenital hypothyroidism

“…Mean IQ was normal and comparable to controls however, there was a great variability in IQ values with a high percentage of CH patients having sub-optimal IQ (28.6%) and intellectual disability (10.7%). A significant impairment was detected in specific neurocognitive outcomes such as processing speed, visual attention, reading skills and arithmetic which correlated with white matter structure abnormalities ( 9 ). In this study the age at the beginning of treatment was quite variable (15.3 ± 7.9 days) as well as L-T4 starting dose (9.46 ± 2.28 µg/kg/day) and the mean TSH values (6.98 ± 4.68 µU/L) at the time of cognitive assessment was mildly elevated in some CH patients.…”

“…However, the finding of CH patients with subnormal IQ suggest that neurodevelopmental rescue should not be taken for granted even in the era of neonatal screening ( 27 ). Prenatal brain damage due to thyroid hormone insufficiency in utero , may not be completely prevented by trans-placental supply of maternal thyroxine and may not be completely reverted by postnatal treatment ( 9 , 28 ).…”

“…Short- and long-term studies on neurocognitive function in early treated patients with CH have shown that, despite optimal cognitive development is achieved in the majority of CH patients, subtle neurocognitive deficits may still occur ( 8 , 9 ).…”

TRIAC Treatment Improves Impaired Brain Network Function and White Matter Loss in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice

“…Here, we could confirm white matter thinning in TH transporter deficient animals which is particularly present in the corpus callosum. A recent MRI study demonstrated that such white matter abnormalities in patients with permanent congenital hypothyroidism were associated with worse cognitive function [ 28 ]. Moreover, our structural MRI analysis revealed a prominent decrease of grey matter volume in Mct8/Oatp1c1 DKO mice within a large cluster covering subcortical striatal regions and prefrontal (OF, PL, IL, Cing, I) and sensorimotor cortical areas.…”

TRIAC disrupts cerebral thyroid hormone action via a negative feedback loop and heterogenous distribution among organs

“…Even milder attenuation of TH actions in the CNS could pose a significant risk to neurodevelopment. For example, children with permanent congenital hypothyroidism were reported to have lower cognitive scores than those with transient congenital hypothyroidism and control subjects even if they received replacement therapy (39).…”