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October2013 Vol.50 Issue:      4 Table of Contents
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Impact of Primary Hypothyroidism on Electroencephalography in Infants

Basma Abdelmoez Ali1, Laila Elmorsi Aboul-Fotoh1, Sayed Sobhy Sayed2


Department of Pediatrics1, Minia University; Neuropsychiatry2, Fayom University; Egypt



ABSTRACT

Background: Thyroid hormones are essential for brain maturation and function. Conditions associated with impaired action of thyroid hormones to the brain during development may lead to various degrees of mental retardation and neurological impairment. Objective: Assess the impact of hypothyroidism on electro-encephalography in infants with primary hypothyroidism before and during replacement therapy with thyroid hormone. Methods: This study included 55 infants with primary hypothyroidism during regular follow up in pediatric endocrinology outpatient clinic in Minia University Children Hospital. They were subjected to electroencephalography (EEG) before and after 8-12 weeks of replacement therapy with thyroid hormone at a dose of 10-15 µg/Kg/day. In addition, thyroid function was assessed (TSH and Free T4). Results: Infants with hypothyroidism before replacement therapy had significant higher frequency of abnormal EEG than after replacement with thyroid hormone where (P=0.0001). There was a significant association between electro-encephalographic changes and Free T4. Conclusion: EEG is potentially useful in the detection of central nervous system effects of thyroid deficiency and in monitoring the efficacy of hormonal replacement therapy. Therefore, early and proper replacement therapy with thyroid hormone in infants with hypothyroidism is very essential to prevent and eliminate any electro-encephalographic changes. [Egypt J Neurol Psychiat Neurosurg.  2013; 50(4): 383-388]

Key Words: Infants, Primary hypothyroidism, EEG.  

Correspondence to Basma Abdelmoez Ali, Pediatric department, Minia University, Egypt. Tel.:+201006227847. Email: basmaelmoez@yahoo.com  





INTRODUCTION

 

The production of T4 and T3 in the thyroid gland is regulated by the hypothalamus and pituitary gland. To ensure stable levels of thyroid hormones, the hypothalamus monitors circulating thyroid hormone levels and responds to low levels by releasing thyrotropin-releasing hormone (TRH). This TRH then stimulates the pituitary to release thyroid-stimulating hormone (TSH).1 When thyroid hormone levels increase, production of TSH decreases, which in turn slows the release of new hormone from the thyroid gland.2 Thyroid hormone secreted from the gland is about 80-90% T4 and about 10-20% T3. 3 T3 is the biologically active form of thyroid hormone. The majority of T3 is produced in the peripheral tissues by conversion of T4 to T3 by a selenium-dependent enzyme. Various factors including nutrient deficiencies, drugs, and chemical toxicity may interfere with conversion of T4 to T3. 4 Cells of the developing brain are a major target for the thyroid hormones T3 and T4. Thyroid hormones play a particularly crucial role in brain maturation during fetal development.5 Regulation of actin polymerization by T4 is critical to cell migration in neurons and glial cells and is important to brain development.6 In the blood, T4 and T3

 

are partially bound to thyroxin-binding globulin (TBG), transthyretin, and albumin. Only a very small fraction of the circulating hormone is free (unbound) - T4 0.03% and T3 0.3%. Only the free fraction has hormonal activity. Ninety-nine percent of circulating thyroid hormones are bound to carrier proteins, rendering them metabolically inactive.3

In the early 1900s, investigators learned to record the electrical activity of the brain using electroencephalography (EEG). These recordings consisted of waves of different amplitudes (different voltage levels) and frequencies. Over the years brain wave studies have provided us with a greater understanding of the brain and its role in mediating behavior and associated learning, thought, and emotional processes.7  

 

Aim of the study

We aimed to assess the impact of hypothyroidism on electroencephalography in infants with primary hypothyroidism before and during replacement therapy with thyroid hormone.

 

SUBJECTS AND METHODS

 

This study included 55 infants with primary hypothyroidism before beginning replacement therapy, during regular follow up in the pediatric endocrinology outpatient clinic in Minia University Children Hospital and they were classified as Group I .They were included in the study after taking an informed consent from every caregiver of them to be enrolled in the study. They were subjected  to thorough history talking, clinical examination, electroencephalography (EEG) and laboratory investigations including thyroid function which was assessed by measuring Thyroid Stimulating Hormone (TSH) by ELISA method with a normal range of  0.7-6.4 ulU/ml8, and Free Thyroxin (fT4) which  was measured by radio-immune assay using commercial kits with a normal range of  0.8-2.0 ng/ml.9 Another 50 apparently healthy  infants age and sex matched to the hypothyroid group were subjected to EEG  and were enrolled as a control group. After 8-12 weeks of replacement therapy with thyroid hormone in a dose of 10-15 ug/Kg/day, fifty four infants of  group I (one infant did not come for follow up) were subjected to  another EEG and were reassessed for thyroid function (TSH and fT4)  and were classified as Group II.  Two different neurologists for confidence evaluated electroencephalographs.

 

Statistical Methodology

Standard computer program SPSS for windows, release 15.0 (SPSS Inc, USA) was used for data entry and analysis. All numeric variables were expressed as mean ±standard deviation (SD). Comparison of different variables in various groups was done using student t-test and Mann Whitny test for normal and non-parametric variable respectively. Chi square test (χ2) was used to compare frequency of qualitative variables among the different groups. Pearson's and Spearman's correlation tests were used for correlating normal and non-parametric variables respectively. We also used Correlation (r) where 0.00-0.24 is weak or no association, 0.25-0.49 is fair association, 0.50-0.74 is moderate association, and ≥0.75 is strong association.10

 

RESULTS

 

This study included 55 infants with primary hypothyroidism whose ages ranged from 5-16 months with a mean of 9.3 ±3.56 months, their duration of illness was 10-14 weeks with a mean of 8.1±1.1 weeks. The dose of L-thyroxin ranged from 10-15 µg/kg/day. Concerning suggestive history of epilepsy, it was positive in 12 (30%) of them (Table 1). As regard the frequency of abnormal EEG among the studied groups, 40 (72.7%) of hypothyroid infants had abnormal EEG versus 9 (18%) of the control with significant difference between them where P=0.00001 (Table 2). Comparison between group I and group II (before and after replacement therapy) showed that group I had significant higher frequencies of abnormal EEG than group II (72.7% versus 29.6%) with P=0.0001 (Table 3). Concerning demographic data, comparison between hypothyroid infants with abnormal EEGs before replacement therapy  and after replacement therapy showed that most of those with abnormal EEG were females (60%) with significant difference than those with normal EEG where (P=0.003), also most of them were from rural areas (70%) with insignificant difference from those with normal EEG where (P=0.128). As regard suggestive history of epilepsy, there was insignificant difference between them where P=0.521. In addition, hypothyroid infants with abnormal EEG had significant lower levels of fT4 where P=0.004 (Table 4). Concerning EEGs findings, comparison between group I and group II before and after replacement therapy, showed that group I had significant slower EEG and smaller amplitude than group II where P=0.0001 and 0.006 respectively (Table 5). Finally, as regard different correlations, the current study found that there were significant correlations between fT4 and EEGs abnormalities where there was a significant positive correlation between fT4 and both activity and amplitude while there was a significant negative correlation between TSH and amplitude only as shown in Table (6).


Table 1. Some Descriptive data of the studied group.

 

Age (months)                                      

Range

Mean±SD

5-16

9.3±3.56

Age at diagnosis of the disease (months)

Range

Mean±SD

4-14

8.5±2.9

Duration of the  Disease (weeks)

Range

Mean±SD

10-14

8.1±1.1

Gender                                            

Male:       n (%)

Female:    n (%)

     26 (47.3)  

    29 (52.7)

Residence                                      

Rural:   n (%)

Urban:  n (%)

35 (63.63)   

20 (36.36)   

Dose of L-thyroxin (µg/ Kg/day)

Range

Mean±SD

10-15

12.33±2.23

Suggestive history of epilepsy

positive   n (%)

negative  n (%)

12(30)

28(70)

TSH    (µIU/ml)

Range

Mean±SD

5.2-13.8

9.53±2.56

fT4 (ng/ml)

Range

Mean±SD

0.3-1.6

0.7±0.3

fT4 Free Thyroxin, TSH Thyroid-stimulating hormone

Table 2. Comparison between hypothyroid group and the control as regard the frequency of abnormal EEG.

 

 

Hypothyroid group

Control

P-value

n

%

n

%

Abnormal  EEG

40

72.7

9

18

0.00001*

Normal EEG

15

27.3

41

82

Total

55

100

50

100

* Significant at p<0.01

 

Table 3. Comparison between the studied hypothyroid groups (before and after replacement therapy) as regards abnormal EEG.

 

 

Group I

(Before  replacement therapy)

Group  II

(After replacement therapy)

P-value

n

%

n

%

Abnormal EEG

Normal EEG

40

15

72.7

27.3

16

38

29.6

70.1

0.0001*

Total

55

100

54

100

 

* Significant at p<0.01

 

Table 4. Comparison between hypothyroid infants before replacement therapy with normal and abnormal EEG as regard some demographic data and thyroid functions.

 

Datum

Patients with abnormal

EEG (n=40)

Patients with normal                                                         EEG (n=15)

P-value

Gender

Male        n (%)

Female     n (%)

16 (40)

24 (60)

10 (75)

5 (25)

0.003*

Residence

Rural        n (%)

Urban       n (%)

28 (70)

12 (30)

7 (46.7)

8 (53.3)

0.128

Suggestive history of epilepsy

Positive    n (%)

Negative   n (%)

12(30)

28(70)

3 (20)

12 (80)

0.521

TSH  (µIU/ml)

Mean±SD

9.35±256

7.23±1.32

0.006*

fT4 (ng/ml)

Mean±SD

0.7±0.3

0.9±1.8

0.004*

fT4 Free Thyroxin, TSH Thyroid-stimulating hormone

*Significant at p<0.01

 

Table 5. Comparison between the hypothyroid groups (before and after replacement therapy) as regards some EEG findings.

 

 

Generalized Slowness

Normal

Amplitude

Small

Normal

n

%

n

%

n

%

n

%

Group I

38

69

17

31

8

14.5

47

85.5

Group II

14

26

40

74

0

0

54

100

P-value

0.0001*

0.006*

* Significant at p<0.05

 

Table 6. Correlations between EEGs abnormality with TSH and Free T4 .

 

 

 

Activity

Amplitude

Slowness Background

r

P

r

P

r

P

TSH (µIU/ml

-0.204

0.13

-0.748

0.01

0.174

0.204

fT4(ng/ ml)

0.566

0.001*

0.404

0.002*

-0.226

0.96

fT4 Free Thyroxin, TSH Thyroid-stimulating hormone

*Significant at p<0.05


                                                    DISCUSSION

 

Conditions associated with impaired action of thyroid hormones to the brain during development include iodine deficiency, maternal and fetal hypothyroidism, maternal hypothyroxinemia, prematurity and mutations of thyroid hormone transporters and nuclear receptors. All these conditions may lead to various degrees of mental retardation and neurological impairment.7 Concomitantly, in hypothyroidism a decrease in electroencephalogram amplitudes and frequencies11, a reduced cortical excitability, as indicated by transcranial magnetic stimulation12, as well as a slowing of peripheral conduction velocities  have been reported.13  On the other hand, hyperthyroidism, in turn, leads to nervousness, restlessness, and tremors14 accompanied by increased frequencies of electroencephalogram waves15 and can, in some cases, cause epileptic seizures.16  

Regarding the results of the current study, it found that the frequency of abnormal EEG among the studied group of hypothyroid infants versus the control with significant difference of p=0.00001 (Table 2). A possible explanation has been previously shown in experimental studies that a lack of T3 down-regulates the voltage-gated Na+ current density (Nav-D) in hippocampal neurons from postnatal rats17, leading to slowed action potential upstrokes and decreased firing frequencies.18  Also, there was an experimental study which demonstrated that basic fibroblast growth factor (bFGF), known to be released from cerebellar glial cells after treatment with T319, increases the Nav-D in the absence of glial cells. Treatment of conditioned medium obtained from T3 treated astrocytes with anti-bFGF blocked the effect on the Nav-D. Therefore, it was suggested that bFGF is a major component in the cascade of T3 action and involved in the regulation of the Nav-D in hippocampal neurons. Moreover, an additional, nongenomic pathway for T4-dependent modulation of Na+ currents has been reported in sensory neurons from zebrafish embryos20 where, an acute up-regulation of the Na+ current density by T4 (not T3) has been described to be mediated by T4 binding to αVβ3-integrins. This suggested that multiple mechanisms leading to thyroid hormone-dependent Na+ current regulation are present.

Comparison between group I and group II (infants with abnormal EEGs before and after replacement therapy) showed that group I had significant higher frequencies of abnormal EEG with p= 0.0001 (Table 3). This could be explained by that thyroid hormones induce phosphorylation of specific proteins21 and cell proliferation and differentiation of primary astrocyte cultures, transforming flat, polygonal astrocytes into process-bearing cells.22 In addition, glial cells express nuclear thyroid hormone receptors23 and had been shown to influence synapse formation, control synaptic strength, and participate in information processing by coordinating the activity among sets of neurons.24 They modulate synaptic transmission via release of glutamate25, PGE2, and TNF-α.26,27 It had been shown that PGE2 increase Nav1.9 Na+ currents in small dorsal root ganglion neurons.28

Concerning EEG findings among the studied groups (before and after replacement therapy), the current study found that group I had significant slower EEG and smaller amplitude than group II with p= 0.0001 and 0.006, respectively, (Table 5). The activity was defined as being of small amplitude when no waves of more than 50µV occurred and when the greater part of the activity was less than 25µV in amplitude .In view of the maturational changes that occur in the EEG in the first decade of life, it is not possible to define concisely what to be an excess of slow wave activity.29 This result was in agreement with another study, which suggested that hypothyroid state in children reflected mostly on excessive slower EEG frequency, and EEG amplitude (small amplitude) which improved after replacement therapy.30

Finally as regard different correlations, the current study found that Free T4 had significant positive correlations with activity and amplitude with r=0.566, p= 0.001 and r=0.4, p=0.002 respectively as shown in table (6). This result was in agreement with a study which suggested that the thyroid hormone may have influence on the mechanisms of EEG rhythm formation in primary hypothyroidism.30 Moreover, this finding was in agreement with Pohunková and colleagues31 who found that a dominant alpha frequency in healthy controls was always higher than that in hypothyroid subjects and was significantly related to T4 level. A study of Khedr and colleagues32 reported the commonest EEG changes in hypothyroidism were diffuse slowing of background activity. However, they observed no significant correlations with hormonal levels.

 

Conclusion

EEG is potentially useful in the detection of central nervous system effects of thyroid deficiency and in monitoring the efficacy of hormone replacement therapy. Infants with hypothyroidism before replacement therapy had significant higher frequency of abnormal EEG than after replacement with thyroid hormone. There was a significant association between electro-encephalographic changes and free T4 level. Therefore, EEG could be used as a guide and prognostic tool for reassessment of the therapeutic dose of thyroid hormone during replacement therapy. Early and proper replacement therapy with thyroid hormone in infants with hypothyroidism is very essential to prevent and eliminate any permanent CNS pathology that could be reflected in EEG changes. We suggest performing EEG even in asymptomatic ones early in the course of the disease in order to detect CNS involvement.

 

[Disclosure: Authors report no conflict of interest]

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14.     Kudrjavcev T. Neurologic complications of thyroid dysfunction. Adv Neurol. 1978; 19: 619-36.

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16.     Maeda T, Izumi T. Generalized convulsions with diffuse spike and wave bursts emerging with Graves’ disease. Neuropediatrics. 2006; 37(5): 305-7.

17.     Potthoff O, Dietzel ID. Thyroid hormone regulates Na+ currents in cultured hippocampal neurons from postnatal rats. Proc Biol Sci. 1997; 264(1380): 367-73.

18.     Hoffmann G, Dietzel ID. Thyroid hormone regulates excitability in central neurons from postnatal rats. Neuroscience. 2004; 125(2): 369-79.

19.     Trentin AG, Alvarez-Silva M, Moura Neto V. Thyroid hormone induces cerebellar astrocytes and C6 glioma cells to secrete mitogenic growth factors. Am J Physiol Endocrinol Metab. 2001; 281(5): E1088-94.

20.     Yonkers MA, Ribera AB. Sensory neuron sodium current requires nongenomic actions of thyroid hormone during development. J Neurophysiol. 2008; 100(5): 2719-25.

21.     Ruel J, Gavaret JM, Luo M, Dussault JH. Regulation of protein phosphorylation by triiodothyronine (T3) in neural cell cultures. Part I. Astrocytes. Mol Cell Endocrinol. 1986; 45(2-3): 223-32.

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25.     Araque A, Sanzgiri RP, Parpura V, Haydon PG. Calcium elevation in astrocytes causes an NMDA receptor-dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons. J Neuroscil 1998; 18(17): 6822-9.

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27.     Miller RF. D-Serine as a glial modulator of nerve cells. Glia. 2004; 47(3): 275-83.

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29.     Harris R, Della Rovere M, Prior PF. Electroencephalographic studies in infants and children with hypothyroidism. Arch Dis Child. 1965; 40(214): 612-7.

30.     Kamei H, Sasaki H, Abe H, Nishimaru K, Okumura M. [The quantitative analysis of  electroencephalography in primary hypothyroidism]. Rinsho Shinkeigaku. 1990; 30(8): 891-3. Japanese.

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الملخص العربى

 

تأثير نقص هورمون الغدة الدرقية الأولى على رسم المخ فى الأطفال

 

مقدمة: هورمونات الغدة الدرقية ضرورية  لوظيفة ونضوج المخ. والحالات المصحوبة بضعف مفعول هورمونات الغدة الدرقية أثناء فترة النمو قد تؤدى إلى درجات متفاوتة من التأخر العقلى والعصبى.

الهدف من البحث:  دراسة تأثير نقص هورمونات الغدة الدرقية على رسم المخ الكهربائى فى الأطفال المرضى بنقص الهورمون الأولى  قبل وأثناء العلاج التعويضى بهورمون الغدة الدرقية

المرضى والطرق: أجريت الدراسة على 55 طفلا مصابا بنقص هورمون الغدة الدرقية الأولى وذلك أثناء متابعتهم فى عيادة الغدد الصماء بمستشفى الأطفال الجامعى بالمنيا وذلك قبل وبعد البدء العلاج الأستكمالي بهورمون الغدة الدرقية. وقد أخذت عينة ضابطة للمقارنة من حيث رسم المخ. أما الأطفال المصابين بنقص هورمون الغدة الدرقية الأولى تم أخذ التاريخ المرضي لهم و تحليل هورمون الغدة الدرقية ورسم المخ  قبل بدء العلاج وبعد بدء العلاج بفترة 8-12 أسبوع تم عمل تحليل هورمون الغدة الدرقية ورسم المخ مرة أخرى وذلك لأربع وخمسون طفلا فقط من عادوا للمتابعة.

النتائج: وجدت الدراسة أن نسبة رسم المخ الغير طبيعي هي 72.2% في الأطفال المرضى بنقص الهرمون الأولى مقابل 18% في الأطفال الأصحاء وكان لذلك دلالة إحصائية وكذلك في 72.2% في الأطفال المرضى بنقص الهرمون الأولى قبل العلاج  مقابل 29.6% بعد البدء بالعلاج وكان لذلك دلالة إحصائية أيضا. وقد وجد أن هناك علاقة ذات دلالة إحصائية بين هرمون الغدة الدرقية الحر و التغيرات في رسم المخ.

الاستنتاج: نستنتج من هذه الدراسة أن رسم المخ ضروري ومهم في الأطفال المرضى بنقص الهورمون الأولى للكشف عن تأثير نقص هذا الهورمون علي الجهاز العصبي المركزي وكذلك متابعة كفاءة و كفاية تعويض الأط


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