The recovery potential of central conduction disorder in hypothyroid rats

Journal of the Neurological Sciences 173 (2000) 113–119 www.elsevier.com / locate / jns

The recovery potential of central conduction disorder in hypothyroid rats a a a a, b Chiou-Lian Lai , Ruey-Tay Lin , Chih-Ta Tai , Ching-Kuan Liu *, Shen-Long Howng a

b

Department of Neurology, Kaohsiung Medical College, 100 Shih-Chuan 1 st Road Kaohsiung 807, Taiwan Department of Neurosurgery, Kaohsiung Medical College, 100 Shih-Chuan 1 st Road Kaohsiung 807, Taiwan Received 17 May 1999; received in revised form 22 November 1999; accepted 22 November 1999

Abstract In an aim to detect the dysfunction of central nervous system among rats with varied durations of hypothyroidism and to elucidate the recovery potential after thyroxine replacement, a series of BAEP were conducted and compared with age-matched controls. BAEP was performed in five groups of the hypothyroid animals 1, 3, 5, 7, and 9 months after thyroidectomy respectively. Following initial electrophysiological assessment, thyroxine replacement was administered to each group of hypothyroid rats, and BAEP was performed at two month intervals, up to two successive normal studies or six months after the initiation of therapy, whichever came first. Before thyroxine treatment, prolonged I–V interpeak latency was the most consistent abnormal finding in all groups of hypothyroid rats, and longer hypothyroid state correlated well with more severe central conduction disorder. Hearing impairment was also noted among those with long duration of hypothyroidism. After thyroxine replacement, the central conduction dysfunction usually returned to normal if the hypothyroid state was not more than 5 months in duration. However, when hypothyroid state persisted over 7 months or more, there would be an incomplete recovery for central conduction disorder. The present study brings out the concept of ‘therapeutic window’ in reversing the central nervous dysfunction caused by hypothyroidism in adult rats.  2000 Elsevier Science B.V. All rights reserved. Keywords: Hypothyroidism; BAEP; Recovery potential

1. Introduction Thyroid hormone is of utmost importance for the development of central nervous system (CNS) in the fetus and in the neonatal period [1,2]. A congenital hypothyroidism may cause irreversible mental impairment and various neuromotor disabilities if not promptly diagnosed and treated thereafter [3–5]. Many investigators have emphasized that the initiation of thyroxine therapy must be before the age of 3 months [3,5]; otherwise after this critical therapeutic window, the damage of CNS probably becomes permanent. In adults, an acquired hypothyroidism has a wide spectrum of CNS dysfunction [6,7], in which slow response, apathy, drowsiness, psychosis, and dementia are commonly described [8–11]. As thyroid hormone plays a *Corresponding author. Tel.: 1886-7-315-3175; fax: 1886-7-3162158.

role in modulating carbohydrate, protein, and lipid metabolism, and augmenting oxidative phosphorylation rates [12], these neurological symptoms are believed to be due to the metabolic abnormalities, decreased cerebral blood flow, abnormal deposition of mucopolysaccharide in hypothyroidism [10,13,14]. Although CNS dysfunction in adult hypothyroid patients is generally thought to be reversible after appropriate thyroxine treatment [15,16], residual cognitive deficits, and / or persistent psychosis and depression can be seen in some individuals, even when the hormone therapy was continued for an extended period [17,18]. The age of onset, the duration of illness and probably undertreatment or coexisting diseases were presumed to be responsible for this refractory response [19,20]. However, convincing data are still lacking in reversing the CNS dysfunction among these refractory patients. We therefore conducted a study on thyroidectomized rats (thyrex rats) with varied durations of hypothyroidism

0022-510X / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 99 )00310-X

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to elucidate the CNS functions before and after administration of thyroid hormone. Some of the results have been published elsewhere [21], and the present report puts emphasis on the brainstem auditory evoked potential study (BAEP), which proved itself an objective and quantitative tool to assess the central nervous dysfunction in both human and animal studies [22–25]. Our focus will be on the relationship between the duration of hypothyroid state and the potential for recovery after thyroxine replacement.

2. Materials and methods

2.1. Animal model Fifty adult male Sprague-Dawley (SD) rats, aged 3 months, underwent thyroidectomy under ether anaesthesia. Eight age-matched SD rats, used as the control group (group A), did not receive any operation. The thyroidectomized rats (thyrex rats) were randomly divided into 5 groups (group B, C, D, E, and F). Subcutaneous injection of 3 mg thyroxine (T 4 ) per 100 gm body weight per day [26,27] was initiated 1, 3, 5, 7, and 9 months after thyroidectomy, respectively. Commercially available radioimmunoassay kits (RIA method) were used to evaluate the blood levels of TSH and T 4 of all control and thyrex rats, one month after thyroidectomy and 1 month after thyroxine replacement. This aims to ensure there is a hypothyroid state and a reestablishment of euthyroid state. Blood samples were obtained from tail vein.

2.2. Brainstem auditory evoked potentials ( BAEP) Electrophysiological responses from the central nervous system were recorded in order to elucidate the changes of central nerve conduction in hypothyroid rats. Brainstem auditory evoked potentials (BAEP) were performed before and after thyroxine replacement at 2 month intervals up to 2 successive normal studies or 3 successive follow-up studies. The age-matched controls received the same examinations simultaneously. Rats were anaesthetized with sodium pentobarbital (50 mg / kg, ip.) for this electrophysiological test. The deep rectal temperature was kept between 378C and 37.58C throughout the experiment using a thermoregulator. BAEP was measured using a Signal Processor, 7S11A (San-Ei Company, Japan). The audiosignals were monaural clicks with an alternative polarity, delivered at a repetition rate of 13.3 / s via an earphone 2 cm from the rat’s right ear. The stimulus intensity was set at 90 dB SPL. Recording needle electrodes were placed in right mastoid and left frontal areas to serve as active and reference electrodes, respectively. Another needle electrode was attached to the contralateral mastoid as ground. The recording activities were then amplified and filtered with a bandpass between 80 and 3000 Hz. The response to 1024 stimuli was

averaged in the time epoch of 10 msec following stimulus. The averaged response was displayed on an oscilloscope, and plotted on graph paper using an X–Y recorder for reference. The peak latencies and interpeak latencies (IPLs) were measured from a storage oscilloscope using the cursor. The recording was repeated at least once, to ensure constancy of waves.

2.3. Statistics All results were expressed as mean6SD. Mean peak latencies and IPLs of BAEP obtained from each group for each recording were calculated. The results of experimental and control groups were compared at each stage using ANOVA test with post-hoc multiple comparison of Dunnett’s test. P,0.05 was taken to be statistically significant.

3. Results

3.1. Animal model In the course of thyroidectomy, eight rats died, five due to over-anaesthetization and the other three expired during the operation. Forty rats were accomplished and the success rate was about 83%. All thyrex rats were divided into five groups (group B, C, D, E, and F). Before thyroxine replacement, blood TSH levels were significantly higher (B: .6.4 mU / ml, C: .6.4 mU / ml, D: .6.4 mU / ml, E: .6.4 mU / ml, F: .6.4 mU / ml) and T 4 lower in thyrex rats (B: 1.7960.87 mg / dl, C: 1.4060.30 mg / dl, D: 1.5060.24 mg / dl, E: 1.5460.24 mg / dl, F: 1.6060.35 mg / dl) than in control rats (group A, TSH: 2.4460.60 mU / ml, T 4 : 2.9960.47 mg / dl). After 1 month of thyroxine replacement, the TSH and T 4 levels of each group of thyrex rats were nearly equal to those of control rats. Fourteen of the thyrex rats died during the experimental period, some probably due to prolonged hypothyroid state and some due to anaesthetization for neurophysiological investigations.

3.2. Brainstem auditory evoked potentials ( BAEP) Regarding the BAEP study, ten msec after auditory stimulation, five main components, wave Ia, II, III, IV, and V were discernible in mature rats. We measured the peak latencies (wave Ia, II, III, IV and V) and IPLs (wave I–III, I–V, and III–V) by the cursor for further analysis. The BAEP data from hypothyroid rats for 1, 3, and 5 months (groups B, C, and D) had been published in a previous article [21]. In summary, the mean peak latencies and / or IPLs of hypothyroid rats were delayed even in the group with hypothyroid state for 1 month (group B). Besides, the longer hypothyroid states (groups C and D) correlated well with more severe delay in peak latencies and IPLs. After 2 months of T 4 supply, all the reassess-

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Table 1 Brainstem auditory evoked potentials (BAEPs) measurements showing peak and inter-peak latencies (ms) for controls and rats hypothyroid for 7 months a Group / Wave 4

A (n56) E 1 (n56)a A5 (n55) E 2 (n55)b A6 (n55) E 3 (n55)b A7 (n55) E 4 (n55)b

Ia

II

III

IV

V

I–III

I–V

III–V

1.2660.13 1.2260.05 1.3360.02 1.1960.15 1.3160.02 1.3860.03* 1.3960.06 1.3560.06

2.4060.12 2.5160.41 2.4460.08 2.4260.04 2.5160.11 2.7860.22 2.4660.07 2.6360.08

3.2160.07 3.3260.39 3.3060.30 3.3660.23 3.4460.11 3.6160.14 3.4660.06 3.5460.14

4.0260.04 4.3960.26* 4.0760.19 4.4560.13 4.0560.07 4.5360.20* 4.1660.10 4.5060.09*

4.6060.04 5.3960.18* 4.8660.19 5.2560.17* 4.7260.12 5.3960.09* 4.8360.06 5.2460.05*

1.9460.21 2.0960.42 1.8560.15 2.0460.14 2.1360.14 2.2360.14 2.0760.04 2.1960.17

3.3160.16 4.1960.26* 3.4960.19 3.9960.26 3.3960.11 4.0160.12* 3.4360.08 3.8960.10*

1.3960.06 2.1060.26* 1.5660.20 1.9060.14* 1.2760.19 1.7860.14* 1.3860.08 1.7060.09*

a

A4 –A7 : control groups for E 1 –E 4 respectively. Rats of hypothyroid state for 7 months (E 1 ), then treated with T4 for 2 months (E 2 ), 4 months (E 3 ), and 6 months (E 4 ). a,b: Two rats (a) or one rat (b) had no evoked response, respectively. *P,0.05 by ANOVA test with post-hoc multiple comparison of Dunnett’s test.

ment data showed only partial recovery. Four months after T 4 replacement, the abnormalities of BAEP improved significantly. When therapy continued up to 6 months, all BAEP data of groups B, C and D revealed no significant difference between thyrex rats and the controls. For the group E rats (hypothyroid state for 7 months), the significant delay of mean wave V latency and IPLs of wave I–V and III–V became more evident before treatment, and in that group, two thyrex rats had no evoked potential (Table 1). Two months after T 4 supply, the BAEP assessment revealed a partial recovery in all but one rat, with a significant delay of mean wave V and IPLs of wave III–V. No evoked response could be induced in one rat. When T 4 replacement was continued up to 4 or 6 months, the BAEP showed little improvement with persistent delay of mean wave V latency and IPLs of wave I–V and III–V, and still no evoked potential could be elicited in one rat (Table 1). In the group of 9-month hypothyroid rats (group F), three of the five thyrex rats had no evoked potential, and the mean wave V latency and IPLs of wave I–V and III–V were all significantly delayed before T 4 replacement (Table 2). After 2 and 4 months of T 4 therapy, the improvement was little for the delay of mean wave V latency and the IPLs of wave I–V and III–V. However, the number of non-responsive rats dropped from three (before treatment) to two (2 months of treatment) and to one (4 months of treatment). When therapy continued up to 6

months, the BAEP still revealed significant abnormality which showed no evoked response in one rat and the delay of mean wave V latency and IPLs of wave I–V and III–V in others (Table 2). On the whole, only when the hypothyroid state had reached 5 months or more, did there occur thyrex rats with no evoked potential in BAEP (21, Tables 1 and 2). The number of thyrex rats with no evoked potential increased from one (5 months of hypothyroidism), to two (7 months of hypothyroidism), and to three (9 months of hypothyroidism) before T4 treatment, as the duration of hypothyroidism was prolonged.

3.3. The recovery potential of central conduction Fig. 1. reveals the compared histograms of the interpeak I–V latency in BAEP between controls (group A) and the 5 groups of hypothyroid rats (group B, C, D, E, and F), before and after T 4 treatment. According to the above BAEP data, prolonged I–V interpeak latency was the most consistent abnormal finding in hypothyroid rats, which even occurred in thyrex rats with a short duration (1 month) of hypothyroidism. The abnormality of central conduction dysfunction induced by hypothyroidism always returned to normal after thyroxine (T 4 ) therapy, if the hypothyroid state was not more than 5 months in duration. When the hypothyroid state lasted for 7 or 9 months, the delay in central conduction of thyrex rats turned out to be

Table 2 Brainstem auditory evoked potentials (BAEPs) measurements showing peak and inter-peak latencies (ms) for controls and rats hypothyroid for 9 months a Group / Wave

Ia

II

III

IV

V

I–III

I–V

III–V

A5 (n55) F 1 (n55)a A6 (n55) F 2 (n55)b A7 (n55) F 3 (n55)c A8 (n55) F 4 (n55)c

1.3360.02 1.2660.07 1.3160.02 1.4360.03* 1.3960.06 1.4060.06 1.3760.03 1.4060.08

2.4460.08 2.5160.14 2.5160.11 2.9560.21* 2.4660.07 2.6260.12 2.5360.09 2.5660.15

3.3060.30 3.3460.13 3.4460.11 3.3760.16 3.4660.06 3.5460.15 3.4160.06 3.3260.16

4.0760.19 4.5560.49 4.0560.07 4.5060.10* 4.1660.10 4.6160.20* 4.0060.11 4.4660.22

4.8660.19 5.5060.28* 4.7260.12 5.3460.10* 4.8360.06 5.4560.05* 4.6760.13 5.1460.12*

1.8560.15 2.0860.19 2.1360.14 2.2760.13 2.0760.04 2.1460.14 2.0560.05 1.9260.16

3.4960.19 4.2360.27* 3.3960.11 3.9360.11* 3.4360.08 4.0660.09* 3.3360.09 3.7460.10*

1.5660.20 2.1860.45* 1.2760.19 1.7260.09* 1.3860.08 1.9460.13* 1.2560.10 1.9260.11*

a A5 –A8 : control groups for F 1 –F 4 respectively. Rats of hypothyroid state for 9 months (F 1 ), then treated with T4 for 2 months (F 2 ), 4 months (F 3 ), and 6 months (F 4 ). a, b, c: Three rats (a), two rats (b), or one rat (c) had no evoked response, respectively. *P,0.05 by ANOVA test with post-hoc multiple comparison of Dunnett’s test.

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Fig. 1. Compared histograms of the interpeak I–V latency of brainstem auditory evoked potential study (BAEP) between controls (A) and the 5 groups of hypothyroid rats (B, C, D, E, F: rats of hypothyroid state for 1, 3, 5, 7, 9 months respectively) before and after T 4 treatment. The x-axis represented the time of post-thyroidectomy months in experimental groups and corresponding ages in controls.The value (ms) was expressed as the mean of interpeak I–V latency of each group. * p,0.05 by ANOVA test with post-hoc multiple comparison of Dunnett’s test.

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persistent, even when T 4 replacement had continued for 6 months.

4. Discussion In human beings as well as in rats, BAEP study by scalp recording renders a consistent relationship between the waveforms and specific anatomic structures [23,28–31]. Furthermore, it is altered only by structural pathology and is relatively resistant to agents such as barbiturates and general anaesthesia [32–34]. Under such circumstances, it is generally accepted that BAEP is useful in detecting brain stem dysfunction [35–40]. Regarding the thyrex rats in present study, prolonged I–V interpeak latency was the most consistent abnormal finding, which suggested that central nervous dysfunction caused by hypothyroidism was diffuse in pattern, i.e. from auditory nerve to inferior colliculus. The early prolongation of I–V IPL in BAEP study of thyrex rats suggested the high vulnerability of central nervous system to hypothyroidism, even in rats with merely short period of hypothyroid state (1 month). Regarding the hypothyroid rats for 3 months, both peak latencies (wave II, III, IV, and V) and IPLs (wave I–III and I–V) were delayed, indicating that longer duration of hypothyroid state correlated with the severity of central conduction dysfunction. This was particularly true when hypothyroid state lasted for 5, 7, and 9 months; the abnormal BAEP findings became more definite, presenting as the severe prolongation of peak latencies and IPLs, and even no evoked response could be elicited in some thyrex rats. Most investigators have agreed that in acquired hypothyroidism, the central conduction disorder could develop and present with the delayed conduction between the acoustic nerve and the brain stem [21,37,38,40]. A few authors, however, reported that acquired myxoedema might raise the auditory thresholds without affecting the central conduction in BAEP study [31,41,42], while some authors noted that in hypothyroid animals, a sufficient period of time was required to develop hearing loss [42,43], and this hearing impairment could be conductive, sensorineural, or mixed [31,42]. Our data also showed this correlation between hearing impairment and the duration of hypothyroidism. The number of thyrex rats with no response in BAEP increased as the duration of hypothyroidism became longer and longer; one over six (16.6%) in group D (hypothyroid state for 5 months), two over six (33.3%) in group E (hypothyroid state for 7 months), three over five (60%) in group F (hypothyroid state for 9 months). It seemed that in this study, a duration of 5 months was minimally required to develop hearing impairment among adult thyrex rats, irrespective of whether central conduction dysfunction occurred or not.

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Further study, including correlative electrophysiological and pathological studies, might be helpful to clarify this issue. Generally speaking, the effect of thyroxine treatment on central conduction in thyrex rats is undoubted. However, the recovery pattern would vary with each hypothyroid group. In the young thyrex rats (B rats, 1 month of hypothyroidism), the BAEP showed even longer peak latencies and IPLs after 2 months of T 4 replacement, but they normalized when therapy persisted for 4 months or more. These findings have been discussed in a previous article [21]. For the thyrex rats with hypothyroidism for 3 and 5 months (C and D rats respectively), all peak latencies and IPLs revealed much improvement after T 4 treatment for 2 months and returned to normal range if thyroxine therapy continued up to 4 months or more. Finally, in the thyrex E rats (hypothyroidism for 7 months), the BAEP data revealed partial recovery or even no improvement, although the T 4 treatment had lasted for 6 months. A similar result was obtained in the thyrex F rats (hypothyroidism for 9 months). We speculate, therefore, that in adult thyrex rats, there was recovery potential for central conduction dysfunction after appropriate treatment, if the duration of hypothyroidism was less than 5 months. On the contrary, a duration of hypothyroidism for 7 months or more meant a poor prognosis in reversing the central nervous dysfunction, even though the reestablishment of biological euthyroidism had been maintained for a long time. The present study brings out the concept of ‘therapeutic window’ in reversing the nervous dysfunction when treating hypothyroidism. However, the discrepancies of potential for recovery in varied durations of acquired hypothyroidism need to be reappraised. Our explanations may include the following. First, demyelination combined with axonal degeneration probably occurred in central nervous system among rats with a long duration of hypothyroidism, while in those with a short duration, only demyelination occurred. The former usually showed poor recovery potential, as was true for peripheral nervous dysfunction in hypothyroidism [44–46]. Second, hearing loss in human observation and Corti organ damage in animal experiment [23,31,40,42,43] might both contribute to our concept of refractory response in BAEP study when treating a longterm hypothyroidism. Using BAEP, we demonstrated that the ‘therapeutic window’ also holds true for adult rats with hypothyroidism. Perhaps, this animal study may partly explain some of the refractory cases receiving thyroxine treatment in clinical practice. In such a circumstance, the duration from thyroid insult to the clinical and biological hypothyroidism should also be taken into account, since subclinical hypothyroidism might have been persistent for quite a period and caused central nervous system damage before thyroxine treatment was started.

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Acknowledgements This study was supported by grants from National Science Council, Taiwan, R.O.C. (NSC 81-0412-B037-540 and NSC 83-0412-B037-026).

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