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Median Nerve Conduction Velocity and Central Conduction Time Measured With Somatosensory Evoked Potentials in Thyroxine-Treated Infants With Down Syndrome

^a Departments of Pediatric Endocrinology
^c Neurology and Clinical Neurophysiology
^d Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
^b Department of Pediatrics, Erasmus Medical Center-Sophia Children's Hospital, University Medical Center, Rotterdam, Netherlands

	ABSTRACT

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OBJECTIVE. The aim of this study was to determine whether thyroxine treatment would improve nerve conduction in infants with Down syndrome.

METHODS. A single-center, nationwide, randomized, double-blind, clinical trial was performed. Neonates with Down syndrome were assigned randomly to thyroxine (N = 99) or placebo (N = 97) treatment for 2 years. Daily thyroxine doses were adjusted regularly to maintain plasma thyrotropin levels in the normal range and free thyroxine concentrations in the high-normal range. The outcome measures were nerve conduction velocity and central conduction time, determined through median nerve somatosensory evoked potential recording, at the age of 24 months.

RESULTS. At the age of 24 months, somatosensory evoked potential recordings for 81 thyroxine-treated and 84 placebo-treated infants were available for analysis. Nerve conduction velocity and central conduction time did not differ significantly between the 2 treatment groups (nerve conduction velocity: thyroxine: 51.0 m/second; placebo: 50.1 m/second; difference: 0.9 m/second; central conduction time: thyroxine: 8.83 milliseconds; placebo: 8.73 milliseconds; difference: 0.1 milliseconds).

CONCLUSIONS. Postnatal thyroxine treatment of infants with Down syndrome did not alter somatosensory evoked potential-measured peripheral or central nerve conduction significantly. The absence of favorable effects suggests that pathologic mechanisms other than mild postnatal hypothyroidism underlie the impaired nerve conduction. The absence of adverse effects suggests that longstanding plasma free thyroxine concentrations in the high-normal range are not harmful to nerve maturation.

Key Words: Down syndrome • congenital hypothyroidism • thyroxine • median nerve somatosensory evoked potentials • nerve conduction velocity • central conduction time

Abbreviations: DS—Down syndrome • CNS—central nervous system • CH—congenital hypothyroidism • SEP—somatosensory evoked potential • NCV—nerve conduction velocity • CCT—central conduction time

With an incidence of 5 to 13 per 10000 live births, Down syndrome (DS) is among the most common identifiable causes of moderate/severe mental retardation.^1–4 One of the well-known medical problems associated with DS is a greater tendency to develop autoimmune thyroid disease, which results in higher prevalences of acquired overt and subclinical hypothyroidism, both in adults and in children.^5,6 To prevent morbidity resulting from longstanding hypothyroidism, many adults and children with DS are offered regular thyroid function testing and, if indicated, thyroxine treatment.⁷ In addition to this increase in thyroid autoimmunity with aging, especially young children with DS have a very high prevalence of mild plasma thyrotropin elevation of unknown cause.^8–10 On the basis of our observation that neonates with DS generally have a tendency to lower plasma thyroxine concentrations, compared with neonates without DS, we hypothesized that all neonates with DS have mild congenital hypothyroidism (CH).¹¹ To test this hypothesis, we conducted a randomized, clinical trial in which either thyroxine or placebo was administered during the first 2 years of life, with mental and motor development as primary outcomes. Thyroxine treatment resulted in subtle improvements in motor development and somatic growth, which confirmed that young infants with DS have genuine mild CH.¹²

Thyroid hormone is indispensable for normal prenatal and postnatal brain development, and hypothyroidism during this period of life interferes with these maturational processes. The nature and extent of deficits are determined by timing (early prenatal, late prenatal, or postnatal) and the degree of thyroid hormone deficiency.¹³ In the past 2 decades, it has been shown that postnatal thyroxine treatment initiated early not only prevents many of the developmental deficits associated with untreated moderate/severe sporadic CH in children without DS^14–16 but also partially restores impaired nerve conduction properties, as determined in somatosensory evoked potential (SEP) studies.^17,18 However, animal studies suggest that the normal myelination process can be harmed by prolonged hyperthyroidism early in life, which may lead ultimately to impaired nerve conduction.^19,20

Given the presumed mildly hypothyroid state of neonates with DS and their reported somewhat slower-than-normal nerve conduction throughout life,^21–24 we hypothesized that, in addition to improving development and growth, thyroxine treatment initiated early might improve nerve conduction. To test this hypothesis and to monitor for possible unwanted effects of longstanding plasma free thyroxine concentrations in the upper part of the reference interval, we conducted SEP studies for all infants with DS participating in our randomized, clinical trial.¹²

	METHODS

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Patients and Study Design
The clinical characteristics of the participating infants and the study design were reported previously, in accordance with the CONSORT guidelines.^12,25 In short, between June 1999 and September 2003 we conducted a single-center, randomized, double-blind, 24-month trial (enrollment until August 2001), with nationwide recruitment, comparing thyroxine administration with placebo administration for 196 neonates with DS. Neonates were allowed to participate in the trial when their CH screening results were normal, their gestational age was 252 days, their 5-minute Apgar score was 7, their postnatal age was 28 days, and 1 parent had sufficient command of the Dutch language. The study was conducted in the Academic Medical Center, University of Amsterdam, after approval by its ethics committee. Written informed consent was obtained from all parents.

Thyroxine (8 µg/kg per day) or placebo treatment was started within 24 hours after randomization and continued until the age of 24 months. Thyroxine doses were adjusted to reach and to maintain normal plasma thyrotropin concentrations (0.4–4.0 mIU/L, the thyrotropin reference range provided by our laboratory) and high-normal plasma free thyroxine concentrations (18–24 pmol/L). Thyroxine (and placebo) dose adjustments were made by one of the pediatric endocrinologists (T.V.), who had exclusive access to laboratory data but who did not have any contact with participants during the study. Of the 196 neonates with DS enrolled in the trial, 99 neonates were assigned randomly to thyroxine and 97 to placebo. Ninety-one infants in the thyroxine group and 90 infants in the placebo group completed the trial. The primary outcome was mental and motor development at the age of 24 months, as assessed with the Bayley Scales of Infant Development II.

Measurements
Median nerve SEPs were recorded at baseline (mean age: 0.8 months) and at the ages of 2, 6, and 24 months, with a Viking IV P system (Nicolet, Madison, WI). The left median nerve was stimulated electrically at the wrist, with surface electrodes, at a frequency of 4.1 Hz. The stimulus intensity (usually 3–8 mA) of the 0.2-millisecond square-wave pulses was adjusted to produce a minimal thumb movement. SEPs were recorded, with surface electrodes, from Erb's point (N9 potential), the spinous process of the fifth cervical vertebra (Cv-5, N11/13 complex), and the ipsilateral and contralateral scalp 2 cm posterior to C3 (C3') and C4 (C4', N20 potential) (10–20 system). Reference electrodes were placed in the midfrontal (Fz for Cv-5, C4', and C3') and midcentral (Cz for Erb) positions and the ground electrode on the left forearm. Electrode impedances were <5 kOhm. Room temperature was always maintained at 20°C to 22°C. The overall bandpass width was 150 Hz to 1.5 kHz, with analysis time of 40 milliseconds. All recordings were conducted in duplicate and consisted of 2 series of 512 amplified and averaged potentials.

Peripheral nerve conduction velocity (NCV) was calculated by dividing the arm length (from the point of stimulation at the wrist to Erb's point, measured directly before the SEP recording) by the latency time to N9. Central conduction time (CCT) was calculated by subtracting the latency to N11 onset from N20 onset. The change in NCV was calculated by subtracting NCV at 0.8 months of age from NCV at 24 months of age. Before disclosure of treatment assignments and subsequent analyses, all recordings were assessed for quality with respect to configuration and reproducibility. Only recordings of satisfactory quality and reproducibility (ie, clearly identifiable and comparable potentials in both recordings) were included in the analysis. The investigators carrying out the SEP recordings (A.S.P.v.T., M.D.-v.d.S., and J.C.D.R.) were blinded to treatment assignments throughout the study.

Statistical Analyses
N9 and N20 peak latencies, N11 and N20 onset (N11' and N20'), arm length, NCV, change in NCV, and CCT of the thyroxine- and placebo-treated infants at 24 months of age were compared with the independent-samples t test. The courses of NCV and CCT during thyroxine and placebo treatment for infants with complete recording series between the ages of 2 and 24 months were compared by using general linear model repeated-measures analysis. The relationships between the actual free thyroxine concentrations of the thyroxine-treated infants with DS and NCV and CCT were studied by computing the Pearson correlation coefficients. All reported P values are 2-sided. As reported previously, several infants were diagnosed as having central nervous system (CNS) disease during the trial.¹² Because CNS disease might influence central conduction negatively, the CCT analyses were repeated after exclusion of all infants with CNS disease (additional analysis). All statistical analyses were performed with SPSS for Windows, release 11.0.1 (SPSS, Chicago, IL).

	RESULTS

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Characteristics of Patients
At the age of 24 months, SEP recordings of satisfactory quality and reproducibility for 81 thyroxine-treated and 84 placebo-treated infants with DS were available for analyses (Fig 1). At baseline, the clinical and laboratory data for these 2 groups of infants were more or less similar (Table 1 and Fig 2). In both groups, 1 child had experienced neonatal convulsions.

View larger version (34K): [in this window] [in a new window]   FIGURE 1 Trial profile. aDevelopmental testing (Bayley Scales of Infant Development testing) at 24 months of age. bTechnical reasons (hyperactive behavior obstructing recording), 2; inconvenience, 6. cTechnical reasons (hyperactive behavior obstructing recording), 2; inconvenience, 2.

View larger version (11K): [in this window] [in a new window]   FIGURE 2 Plasma thyrotropin (TSH) and free thyroxine (FT4) concentrations at baseline and during the study. Thyrotropin levels are expressed as geometric mean ± SD, after (natural) logarithmic transformation of the original measurements, and free thyroxine levels as mean ± SD. For all ages, calculations were based on measurements performed for the infants with DS included in the NCV and CCT analyses at 24 months of age (circles: thyroxine group, n = 81; squares: placebo group, n = 84). P values refer to the comparison of measurements for the thyroxine group and the placebo group from 2 to 24 months of age, with general linear model repeated-measures analysis.

Latencies and Arm Length
Figure 3 shows a representative SEP recording series of satisfactory quality and reproducibility. At the age of 24 months, the latencies to N9, N11 onset, and N20 onset and top did not differ significantly between the 2 treatment groups. Thyroxine-treated infants had slightly longer arms than did placebo-treated infants (26.3 ± 1.8 cm vs 25.7 ± 1.7 cm; difference: 0.6 cm; 95% confidence interval: 0.1-1.1 cm) (Table 2).

View larger version (38K): [in this window] [in a new window]   FIGURE 3 Representative SEP recordings at 0.8 month (A), 2 months (B), 6 months (C), and 24 months (D) of age. Relevant latencies are indicated. I, II, III, and IV denote the recording positions Erb, Cv-5, C4', and C3', respectively. The distance between the dotted vertical lines corresponds to a time of 4 milliseconds.

For 75 thyroxine-treated and 77 placebo-treated infants, complete recording series of satisfactory quality and reproducibility were available for analysis. From the age of 2 months to the age of 24 months, the difference in NCV between the thyroxine-treated and placebo-treated infants increased from 0.74 m/second to 1.18 m/second (P = .063), whereas CCTs remained comparable (Fig 4).

View larger version (9K): [in this window] [in a new window]   FIGURE 4 Median NCV and CCT at baseline (age: 0.8 months) and at ages 2, 6, and 24 months for the thyroxine-treated (circles) and placebo-treated (squares) infants with DS for whom complete recording series of satisfactory quality and reproducibility were available for analysis (thyroxine group, n = 75; placebo group, n = 77). P values refer to the comparison of measurements for the thyroxine-treated and placebo-treated infants from 2 to 24 months of age, with general linear model repeated-measures analysis.

Additional Analyses
With exclusion of the 11 infants with CNS disease at baseline or as comorbidity during the study, the CCTs of the thyroxine-treated and placebo-treated infants were similar (Table 2).

NCV Versus Actual Free Thyroxine Concentrations at 2, 6, and 24 Months of Age
Figure 5 shows that the NCVs and CCTs of the thyroxine-treated infants with DS were not related to their actual free thyroxine concentrations. However, both parameters were clearly age related. Analysis of the placebo-treated infants yielded similar findings.

View larger version (19K): [in this window] [in a new window]   FIGURE 5 Correlations between the actual plasma free thyroxine (FT4) concentrations and the median NCV and CCT values at ages 2 months (squares), 6 months (circles), and 24 months (diamonds) for the thyroxine-treated infants with DS for whom complete recording series of satisfactory quality and reproducibility were available for analysis (n = 75). The solid, dashed, and dotted lines are the linear regression lines for the groups at 2, 6, and 24 months, respectively. The numbers represent the Pearson correlation coefficients and the P values.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

The main reason for conducting the randomized, clinical trial was to test our hypothesis that all young infants with DS have a mild form of CH that might be responsible for part of their ever-present mental and motor developmental delays and their impaired somatic growth. The finding that neonatally started thyroxine treatment resulted in subtle improvements in motor development and growth confirmed that infants with DS indeed have mild CH, at least during their first weeks of life.¹² Because thyroid hormone plays an important role in myelination, the maturational process that enables rapid nerve impulse conduction, we also hypothesized that the mild CH is partly responsible for the somewhat impaired nerve conduction observed in DS. Under normal conditions, nerve conduction increases rapidly during the first 3 years of life, reflecting progressive myelination.^26,27 Since the 1960s, evoked potentials have been used to study the role of thyroid hormone in this process, in humans as well as in laboratory animals. SEP studies for children without DS with moderate/severe CH detected through neonatal screening showed substantially decreased central and peripheral conduction, which was partially restorable with thyroxine treatment instituted early.^{17,18,28–30} In rat studies, the role of thyroid hormone was pinpointed to controlling the differentiation of myelin-forming glial cells in the central and peripheral nervous systems^31,32 and to increasing expression of myelin genes.³³

In DS, impaired SEP-measured central and peripheral nerve conduction was first reported for adults and was attributed to premature aging.²⁴ This explanation was abandoned when slower central conduction also was observed for children with DS.²² Recently, Chen and Fang²¹ reported 18.5% slower median nerve, SEP-measured, central conduction for 6- to 18-month-old infants with DS, compared with age-matched, healthy, control subjects; their peripheral NCV was 8.7% slower (53.9 m/second, compared with 59.0 m/second for control subjects; values were calculated by dividing the reported arm lengths by the reported latencies to N9).²¹ Chen and Fang,²¹ as well as other investigators studying children with DS,^1,22,34 suggested that the impaired nerve conduction was related to DS-specific neuropathologic and neurochemical abnormalities, such as abnormal dendritic spine morphologic features and numbers and different myelin composition. The results of our study (ie, the absence of positive effects of postnatal thyroxine treatment on conduction) do not contradict these views.

Nevertheless, mild CH cannot be completely ruled out as a causal factor in the impaired nerve conduction in DS. Bongers-Schokking et al¹⁸ reported that children without DS with moderate/severe CH had somewhat slower-than-normal SEP-measured central conduction at the age of 1 year, despite the start of thyroxine treatment in the third week of life. Weber et al³⁵ showed that patients without DS with CH that was detected through neonatal screening and was treated adequately with thyroxine from the age of 1 month onward had normal intelligence, whereas the IQ scores of patients with CH that were not detected through screening and were treated from the age of 10 months were 30 points lower. Compared with healthy control subjects, however, early thyroxine-treated children had slower long-latency, SEP-measured, central conduction, as did the children for whom thyroxine treatment was started at the end of the first year of life.³⁵ In a subsequent study, the same investigators showed that thyroxine treatment started earlier for children without DS with CH detected through screening (treatment started before versus after 30 days of age) resulted in better mental development but not in better central conduction. The degrees of conduction impairment, compared with healthy control subjects, for early- and late-treated children were approximately the same.³⁶ All of these results can be explained by time-dependent differences in thyroid hormone action on brain development, in which prenatal and/or early postnatal somatosensory maturation processes are more sensitive to the disturbing effects of thyroid hormone deficiency than are those occurring later.¹³ Given the fact that thyroxine treatment was started at an average age of 24 days in our trial and the observation that the mildly hypothyroid state in DS may already exist in utero,³⁷ thyroid hormone deficiency may still be causally related to the persistent nerve conduction abnormalities in DS.

Perhaps an even more important finding was that the thyroxine treatment during the first 2 years of life apparently had no adverse effects on nerve conduction in the studied infants with DS. In rat studies, it was shown that sustained postnatal hyperthyroidism first accelerates myelination but later results in a state of myelin deficiency. This is probably attributable to precocious oligodendroglial differentiation, followed by increased oligodendroglial apoptotic cell death.^19,20 Hypothetically, impaired nerve conduction might be an indication of long-term overtreatment with thyroxine for humans as well. From that perspective, our not finding adverse effects suggests that our thyroxine dosing strategy (ie, aiming at high-normal plasma free thyroxine concentrations throughout the trial period) did not harm the myelination process. Obviously, our results cannot be translated automatically into later childhood and adulthood. As always, long-term follow-up studies are indispensable.

	CONCLUSIONS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
In this randomized, clinical trial, we found that thyroxine treatment of infants with DS did not alter SEP-measured peripheral or central nerve conduction significantly. The absence of favorable effects suggests that pathologic mechanisms other than mild postnatal hypothyroidism underlie impaired nerve conduction. The absence of adverse effects suggests that longstanding plasma free thyroxine concentrations in the high- normal range are not harmful to nerve maturation.

	ACKNOWLEDGMENTS

 
This work was supported financially by the Netherlands Organization for Health Research and Development (grant 2100.0025). Organon Inc donated the study medication.

We are indebted to Bram W. Ongerboer de Visser for his help with the design of the study.

	FOOTNOTES

 
Accepted Apr 12, 2006.

Address correspondence to A. S. Paul van Trotsenburg, MD, Department of Pediatric Endocrinology, Emma Children's Hospital Academic Medical Center, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, Netherlands. E-mail: a.s.vantrotsenburg{at}amc.uva.nl

The authors have indicated they have no financial relationships relevant to this article to disclose.

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 

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