P300 event-related potential in children with hypothyroidism

ABSTRACT

Background:

Hypothyroidism is a common endocrine disorder, which adversely affects the developing central nervous system in the pediatric population. Despite treatment, patients may continue to experience neurological impairments such as cognitive dysfunction. P300 is an event-related potential (ERP) which is often considered as a marker for cognition. In this study, P300 was recorded in hypothyroid children.

Materials and Methods:

This study involved 52 children between the ages of 8 and 15 years who were newly diagnosed with hypothyroidism. Auditory P300 latencies and amplitudes were recorded in the study population at the time of diagnosis, 1-month and 6-months follow-up. A P value of < 0.05 was assigned for statistical significance, and Kruskal-Wallis test was used to assess the same.

Results:

Although the amplitudes and latencies of P300 appeared to increase and decrease respectively, during successive follow-ups compared to the values recorded at the time of diagnosis. However, these changes were not statistically significant (P > 0.05).

Conclusion:

This study did not show any significant changes in P300 latencies and amplitudes. A shorter follow-up timeframe and a smaller sample size are possible limitations of this study. There is a possibility that P300 may show considerable changes over a longer course of disease management.

Introduction

Hypothyroidism affects millions globally.[1] In India, iodine deficiency is considered to be the commonest cause of hypothyroidism and the Government of India made it mandatory to iodize all edible salt in 1986.[2] Despite several decades of mandatory iodization of table salt, with a prevalence of 10.95%,[3] India is among the countries with the highest prevalence of hypothyroidism.[1,2]

A nationwide study in India was conducted by Marwaha et al.[4] in 2012, which evaluated thyroid disorders in 38,961 school children across 25 schools in 19 cities and found that the prevalence of hypothyroidism in children between the age group of 5 and 18 years to be 6.5%. Even though the overall goiter prevalence reduced from 23% in 2002 to 15.5% in 2012, it was still way above the WHO recommended target of <5%.

Several risk factors have been associated with the development of hypothyroidism. Predominant among which are iodine deficiencies or excesses,[5] female gender,[1] selenium deficiency,[6] presence of other associated autoimmune conditions predominantly rheumatoid arthritis, genetic chromosomal abnormalities, Down’s syndrome, and Turner syndrome.[7] Apart from these, a number of drugs have been implicated in the causation of iatrogenic hypothyroidism; these include interferon’s and monoclonal antibodies,[8] amiodarone,[9] lithium,[10] administration of radiographic contrast agents.[11]

Hypothyroidism impacts the developing central nervous system severely in the pediatric population.[12,13] Despite receiving treatment, children with hypothyroidism may have subclinical neurological problems which can manifest itself later on in life.[12,13,14] Some of these neurological deficits include cognitive deficits in areas pertaining to attention, memory, concentration, intelligence, and language.[12,13,14] These deficits can be assessed using neurophysiologic tests. The results of such tests have facilitated clinical decision-making and have impacted patient outcomes.[12,13,14]

One such neurophysiological test is P300 evoked potential. The P300 event-related potential is elicited when a subject is given an auditory or visual oddball task. The wave is a positive deflection between 250 ms and 600 ms in response to a stimulus discrimination [Figure 1]. It is defined in terms of its latency and amplitude. The latency represents the timing of the classification of the stimulus. Amplitude provides important information on the degree to which the resources of attention have been employed. P300 is often used as a marker for cognition.[15,16,17]

Figure 1.

P300 auditory evoked potential that was recorded in a child with hypothyroidism

Materials and Methods

This study was a prospective study that was carried out after obtaining approval from the Institutional Human Ethics Committee (IHEC) and was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

A total of 40 girls and 12 boys (n = 52) between the ages of 8 and 15 years who were newly diagnosed with hypothyroidism were recruited for the study. Children with a history of seizures, hydrocephalus, head injury, cranial surgery, meningitis, encephalitis, visual or auditory defects, chronic medical conditions, congenital hypothyroidism, attention deficit hyperactivity disorder, mental retardation, learning disabilities, cerebral palsy, and any other psychological disorders, were excluded from this study.

Thyroid function tests which showed an increase in TSH levels of >5 mIU/L along with normal or reduced free T3 and/or free T4 were considered as a diagnostic criteria for hypothyroidism.[1]

A study by Tütüncü et al.[18] titled “Prolonged P300 latency in Thyroid failure: A paradox. P300 latency recovers later in mild hypothyroidism than in severe hypothyroidism” was used for sample size estimation, and the total sample size thus calculated was 50; we managed to enroll 52 children.

Recording of P300 ERP

Nihon Kohden Neuropack X1 was used for recording the latencies and amplitudes of P 300, and for each child, P300 was recorded initially at the time of diagnosis, next at 1 month, and finally at 6-months follow-up. Recordings were done under identical conditions each time, following an oddball paradigm, and the EEG electrodes were applied in accordance with the international 10-20 convention. Active electrodes were applied at Fz, Cz, and Pz sites, electrode at FPz was used as ground, and reference electrodes were applied over both the mastoids. Impedance of <5kΩs was used as the standard at each electrode site. P300 was elicited using an auditory oddball paradigm with 20% odd stimuli being presented randomly. Oddball stimulus of 2kHz, 40 dB at 0.5 Hz was interspersed with assigned stimuli of 1 kHz, 40 dB at 0.5 Hz. A bandpass of 0.1-50 Hz was used for acquisition. A total of 30 waves were averaged and processed for smoothening to 19 points, and then the waves were marked manually for latencies and amplitudes. The latencies and amplitudes thus recorded were used for analysis [Figure 1].

Statistical analysis

The data collected was analyzed using R statistics software version 4.0.0. The variables have been expressed as mean ± standard deviation. Kruskal-Wallis test was applied to look for statistical significance among the groups. A P value < 0.05 was considered to be statistically significant.

Results

52 children, 12 (23%) boys, and 40 (77%) girls newly diagnosed with hypothyroidism were included in this study. The P300 latencies in ms were recorded in all the children at the time of diagnosis (baseline), 1-month follow-up, and 6-months follow-up at Fz, Cz, and Pz sites [Table 1]. The values were not statistically significant when analyzed using Kruskal-Wallis test [Figure 2].

Table 1.

P300 latencies at various sites

P300 latency (ms) (n=52)	Baseline mean (±SD) (ms) (median)	1st follow-up mean (±SD) (ms) (median)	2nd follow-up mean (±SD) (ms) (median)	P
Fz	337 (±36) (330)	334 (±30) (338)	329 (±24) (326)	0.572
Cz	323 (±27) (324)	334 (±31) (334)	324 (±18) (324)	0.121
Pz	333 (±38) (328)	329 (±26) (326)	325 (±20) (325)	0.685

Figure 2.

P300 latencies in ms (mean ± SD) at various sites

Just like the latencies, the P300 amplitudes in μV at Fz, Cz, and Pz sites were measured at baseline, and two successive follow-ups [Table 2]. Kruskal-Wallis test did not reveal any statistically significant changes among the values [Figure 3].

Table 2.

P300 amplitudes at various sites

P300 amplitude (µV) (n=52)	Baseline mean (±SD) (µV) (median)	1st follow-up mean (±SD) (µV) (median)	2nd follow-up mean (±SD) (µV) (median)	P
Fz	12.5 (±3.1) (12.6)	12.7 (±3.5) (13.0)	13.1 (±3.6) (13.2)	0.621
Cz	14.1 (±3.8) (13.8)	14.9 (±3.8) (14.9)	14.2 (±3.6) (14.7)	0.532
Pz	12.1 (±3.7) (12.6)	11.7 (±3.7) (11.1)	12.6 (±3.6) (12.6)	0.443

Figure 3.

P300 amplitudes in μV (mean ± SD) at various sites in all the children

Discussion

P300 was described for the very first time by Sutton et al.,[19] in the year 1965. P300, also referred to as P3 is an important ERP and is often used in the assessment of cognitive function. P300 is elicited in a subject when they are presented with an auditory or visual oddball task. The wave is commonly seen as a positive deflection in response to stimulus discrimination. Neurophysiologically, it is defined in terms of its latency and amplitude. Latency is a measure of timing of the classification of stimulus and usually ranges from 250 ms to 500 ms. Whereas the amplitude indicates the degree to which the resources of attention have been employed. An increase in P300 amplitude has been demonstrated in relation to an improved level of attention towards a particular stimulus. On the contrary, when attention is not paid to a particular stimulus and is ignored, the P300 amplitudes tend to stay low. This phenomenon of attentional engagement was demonstrated in 1980 by Becker and Shapiro.[20]

The clinical features of hypothyroidism are well-established. The common signs and symptoms of hypothyroidism in children are goiter, fatigue, weight gain, delayed growth, cold intolerance, constipation, bradycardia, delayed development in puberty, menstrual disturbances, edema, and delayed deep tendon reflexes.[14] A 2018 study in India on hypothyroid adolescents with a median age of 13 found that the following presenting complaints occurred more frequently short stature, neck swelling, weight gain, severe headache, irregular menstrual cycles, hair fall, dryness of skin, abdominal pain, abnormal gait, and reduced appetite.[21]

Most studies have shown hypothyroidism to be more prevalent among the female gender compared to males.[3,4] In our study too hypothyroidism was more common among girls, more than 3 times the number of boys affected, with a female-to-male ratio of 3.33:1.

In the study titled, “Prolonged P300 latency in Thyroid failure: A paradox. P300 latency recovers later in mild hypothyroidism than in severe hypothyroidism” by Tütüncü et al.,[18] published in 2004. P300 event-related evoked potentials were measured in 37 patients with hypothyroidism secondary to Hashimoto’s thyroiditis via an auditory oddball paradigm. The P300 latencies were measured at the time of diagnosis, 1- and 6-months following treatment, which is similar to the follow-up durations in our study. The study found that P300 latencies showed statistically significant prolongation in both mild and severe hypothyroidism groups. In the severe hypothyroidism group, the latencies of P300 significantly shortened during the 1-month follow-up and showed no change at 6-months follow-up. In contrast, the P300 latencies in mild hypothyroidism group showed no change at 1-month follow-up but normalized at 6-month interval.

In a study from India titled “Cognitive status in hypothyroid female patients: Event-related evoked potential study,” by Anjana et al.,[22] published in 2008, P300 ERP in 26 newly diagnosed women with hypothyroidism and healthy age-matched women controls were measured. ERPs were measured using the auditory oddball paradigm in them at the time of diagnosis and at 3-months follow-up. The results revealed no significant changes in P300 latencies and amplitudes between the normal women and hypothyroid women. However, in women with hypothyroidism, P300 latencies reduced significantly and P300 amplitudes increased significantly at 3-months follow-up.

In this study, there were no significant changes in the latencies and amplitudes of P300 ERP in hypothyroid children at 1-month and 6-months follow-up following treatment.

Conclusion

In this study, latencies and amplitudes of auditory P300 ERP were measured using an oddball paradigm in children with hypothyroidism at the time of diagnosis, at 1-month and 6-months post-treatment, under identical conditions. On statistical analysis, we did not find any statistically significant changes in P300 parameters during the follow-ups. A shorter period of follow-up of 6 months may be a limitation in this study. Additionally, all children with hypothyroidism were clubbed together irrespective of the etiology. Some etiological causes of hypothyroidism are relatively easier to treat compared to others.

Declaration of patient consent

Informed consent was obtained from all individuals included in this study or their legal guardians or wards.

Ethical declaration

The authors declare that the study was conducted after obtaining clearance from Institutional Human Ethics Committee (IHEC) and that the study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Conflict of interest

The authors do not have any conflicts of interest to declare.

Funding Statement

The study was funded by the Indian Council of Medical Research (ICMR) MD/MS thesis grant.