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Reversible alteration of the visual evoked potential in hypothyroidism
Reversible Alteration of the Visual Evoked Potential in Hypothyroidism
PAUL
W. LADENSON,
JOHN
W. STAKES,
E. CHESTER
M.D.*
M.D.
RIDGWAY,
M.D.
Boston, Massachusetts
From the Thyroid Unit, Medical Service, and the Clinical Neurophysiology Laboratory, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts. This work was supported in part by Grants RR-1066, AM-16791, and HL07354 from the National Institutes of Health, Bethesda, Maryland. An abstract based upon a portion of this study was presented at the 56th Annual Meeting of the American Thyroid Association, Quebec, Canada, 1982. Dr. Ladenson is a Teaching and Research Scholar of the American College of Physicians, Philadelphia, Pennsylvania. Manuscript accepted June 14, 1984. Current address and address for reprint requests: Division of Endocrinology and Metabolism, Sinai Hospital, Baltimore, Maryland 21215. l
1010
The pattern-shift evoked potential was measured in 19 hypothyroid patients before treatment, and after short- (one week) and long-term (12 to 24 weeks) thyroid hormone replacement therapy. Before treatment, nine patients had an abnormally prolonged visual evoked potential latency, more than 115 msec. After one week of therapy with 50 pg per day of L-triiodothyronine, the mean visual evoked potential latency for the entire group was unchanged, 114 f 8 to 114 f 7 msec. However, long-term therapy with 100 to 200 pg per day of L-thyroxine significantly shortened the visual evoked potential latency to 105 f 1 msec (p
December1984 The American Journal of Medicine Volume77
EVOKED POTENTIALS IN HYPOTHYROIDISM-LADENSDN ET AL
TABLE I
Thyroid Function Results before and during Thyroid Hormone Therapy Afier After L-T&dO-
thyronlne (50 Ccg/day) for one Week (n = 11)
L-Thyroxine (100-200 Mdsy) for 12 to 24 Weeks (n = 17)
Parameter
Range
Before Treatment (n = 19)
Serum thyroxine
4.0-12.0
0.9 f 0.2
0.8 f 0.2
75-195
46 f 9
301 f 25
140 f 4’
103 f 22
9f5’
8f
Normal
@g/d!) Serum triiodothyronine (ng/dl) Serum thyrotropin
0.5-3.5
9.0 f 0.6’
5’+
MU/ml) Values are mean f SEM; n is the number of patients studied. Significantly different from pretreatment values, p
stimulation by a reversing black-and-white checkerboard image (4 mm checks subtending a visual angle of 14 minutes) as previously described for our laboratory [ 111. At least two computer-averaged determinations of the responses of 128 consecutive stimuli recorded from the occipital scalp for each eye were employed to determine the stimulus-to-peak latency and maximal amplitude of the principal positive wave form generated, the PI00 (Figure 1). The intra-subject reproducibility of Ploo latency measurements in normal subjects (n = 12) studied on at least two separate occasions is f 2 msec. In normal subjects (n = 41), the Ploo latency is 102 f 5 msec (mean f SD) and the amplitude is 10 f 4 @. In this study the upper limit of normal for the PIOOlatency was considered to be 115 msec (mean + 2.5 SD). Although the Ploo amplitude may be altered by changes in visual acuity or attention, the latency is relatively independent of these effects. All tested eyes had a corrected visual acuity of 20/100 or better. Electroretinographic studies [23] were performed in the two eyes of one patient with bilateral prolongations of the Ploo latency. Data Analysis. The statistical significance of changes in study parameters was assessed by the Student paired t test. The unpaired t test was employed for comparisons of patient groups. Results are expressed as mean f SEM.
RESULTS Visual Evoked Potentials before Treatment. Before treatment, the visual evoked potentials were studied in
PATIENTS AND METHODS Patients. Nineteen patients with clinical and laboratory features of hypothyroidism (Table I) were studied in the General Clinical Research Center after giving informed consent. Hypothyroidism was caused by autoimmune thyroiditis (11 patients) or previous radioactive iodine ablation therapy (eight patients). Although the majority of patients complained of recent somnolence, subtle intellectual impairment, difficulty with balance, or paresthesia& these symptoms were temporally attributable to hypothyroidism. On physical examination, apathy and delayed deep tendon relaxation were frequently noted. No patient with other clinical manifestations of primary neurologic or ophthalmologic disease, anemia, or macrocytosis was included. Three patients had stable exophthalmic Graves’ ophthalmopathy without active inflammation. In one of these patients, one eye with severely impaired visual acuity due to previous exposure keratitis was excluded from study. Study Protocol. Study parameters were assessed in 19 patients before treatment, after seven days of parenteral sodium L-triiodothyronine (Sigma Chemical Co., St. Louis, Missouri) therapy at a dosage of 50 pg per day in 11 patients, and after 12 to 24 weeks of long-term oral sodium L-thyroxine (Flint-Travenol Laboratories, Deerfield, Illinois) replacement in 17 patients. The long-term L-thyroxine dose was adjusted to restore clinical euthyroidism and/or a normal serum thyrotropin concentration (Table I). Serum thyroxine, triiodothyronine, and thyrotropin concentrations were determined by previously described radioimmunoassay methods [ 2 1,221 in serum samples obtained 24 hours after administration of the last thyroid hormone dose. Visual Evoked Potentials. The pattern-shift visual evoked potential was measured separately for each eye following
the 37 eyes of 19 hypothyroid
patients.
FRETREATMNT
The mean ia-
f\
FOST-TREATMENT
:: ‘108
I-
7b
/cb
B-0
LATENCY lmsec)
&ure 1. Visual evokedpotential tracings in a hypothyro~d patient before (upper tracing) and after (lower tracing) 24 weeks of ~-thyroxine therapy. Each of the paired lines at the two time points is an average of the occipital signals (OZ) in response to 128 consecutive photic stimuli. The upper limit of normal for the visual evoked potential latency is 115 msec.
December 1984
The American Journal of Medicine
Volume 77
1011
EVOKED POTENTIALS IN HYPOTHYROIDISM-LAMNSON ET AL
0
4
8
12-24
a
12-24
T/ME heeksl
efi
0
4
TIME (weeks)
-_
_‘__
FIgwe 2.
Visual evoked potential latency (upper panel) and amplitude (lower panel) in hypothyroid patients before treatment, after 50 pg per day of L-triiodothyronine for one week, and after 100 to 200 pg per day of L-thyroxine for 12 to 24 weeks. Values are mean f SEM. Significance versus pretreatment: lp
tions (1 .O f 0.1 versus 0.9 f 0.2 pg/dl) or the duration of clinical hypothyroidism (18 f 6 versus 14 f 6 months). The pretreatment amplitude of the visual evoked potential was less than 4 PV in the 15 tested eyes of nine patients. Five of these patients also had prolonged PIso latencies. Visual Evoked Potential Responses to Thyroid Hormone Therapy. The visual evoked potential was minimally affected during the first week of parenteral Ltriiodothyronine therapy. The mean PIOOlatency was not altered (113.7 f 7.9 to 113.8 f 7.3 msec). A small increase in the Ploo amplitude (4.5 f 0.7 to 6.2 f 0.9 I.LV, p <0.02) was observed within this time. Following 12 to 24 weeks of long-term oral L-thyroxine treatment, the mean Ploo latency was significantly reduced (112.1 f 1.8 to 104.7 f 1.4 msec, p
tency of the PIOOpeak was 113.1 f 1.5 msec for the entire group. Nine patients had pretreatment PI00 latencies that were abnormal (122.2 f 1.9 msec), and 10 patients had values within the normal range (105.4 f 0.8 msec). Patients with initially abnormal Ploo latencies were significantly older than those with normal values (61 f 4 versus 47 f 4 years, p <0.05) but did not differ in pretreatment serum thyroxine concentra-
1012
December 1984
The American Journal of Mediclne
The latency of the visual evoked potential is thyroid hormone-dependent in humans. The reversible alteration of this readily measurable parameter in our hypothyroid patients reflects an effect of thyroid hormones on central nervous system function. Although the clinical manifestations of neurologic dysfunction in hypothyroidism are well described [l-3], they have been difficult to quantify. Previous electroencephalographic studies have demonstrated changes in resting alpha
Volume 77
EVOKED POTENTIALS IN HYPOTHYROIDISM-LADENSON ET AL
rhythm and impaired “photic driving” in patients with myxedema [ 1,241. Abnormal cortical evoked responses have also been reported in thyroid hormonedeficient experimental animals [25,26] and in humans [ 18-201. Our study illustrates a use of this neurophysiologic parameter to examine the short- and long-term effects of thyroid hormones on brain function. Since parenteral L-triiodothyronine therapy has been shown to be capable of rapidly reversing a number of pituitary and peripheral (nonpituitary) organ abnormalities in hypothyroid patients [27], one purpose of this study was to define and compare the short-term effects of L-triiodothyronine on the central nervous system. The absence of short-term change in the visual evoked potential latency that we observed stands in contrast to the rapid responsiveness of the pituitary, i.e. suppressed thyrotropin secretion, and of previously studied cardiovascular, pulmonary, renal, and metabolic parameters within this time frame. A possible explanation for these discordant response rates may be a difference between organs in the relative contributions to nuclear thyroid hormone receptor binding made by circulating triiodothyronine and by the triiodothyronine that is locally produced in target tissues by the intracellular 5’-monodeiodination of thyronine. It has been shown that the proportion of locally derived nuclear triiodothyronine is higher in the cerebral cortex and cerebellum than in the anterior pituitary of rats as reported by Crantz and Larsen [28]. L-triiodothyronine therapy in our hypothyroid patients may, therefore, have saturated pituitary nuclear receptors more completely than those in brain, which relies more heavily upon circulating thyroxine as a substrate for intracellular triiodothyronine production. Long-term thyroid hormone therapy uniformly shortened the visual evoked potential latency in these hypothyroid patients. The mechanism of this thyroid hormone effect on cerebral function remains enigmatic. Hypothyroidism due to autoimmune thyroiditis may be associated with pernicious anemia or Graves’ ophthalmopathy. Optic nerve involvement by these disorders may cause prolongation of the visual evoked potential latency [ 14,151. This does not represent an adequate
explanation for the neurophysiologic changes observed in our patients since these diseases were neither clinically apparent nor treated during the course of this study. Alterations in vitamin A metabolism occur in hypothyroidism [29], and a reversible reduction in the electroretinographic amplitude has been described in myxedema [30,31]. However, the markedly prolonged visual evoked potential latencies in our patients and the normal pretreatment electroretinographic results argue against a reversible metabolic retinopathy as the explanation for our findings. An age-related prolongation of the visual evoked potential latency is known to occur after 60 years. This cannot, however, account for the changes we have observed over a short time period, with each visual pathway serving as its own control. The thyroid hormones have been shown to affect myelin synthesis [32], an important factor in determining the speed of impulse transmission along complex polysynaptic pathways such as those mediating the visual evoked potential. The time course of recovery observed in our patients would seem consistent with an effect of myelin generation. The availability of a precise and reproducible measure of central nervous response to thyroid hormone may have clinical and investigative applications. These observations extend the differential diagnosis of metabolic encephalopathies associated with an abnormal visual evoked potential. Since hypothyroidism causes a reversible form of dementia, the visual evoked potential latency may provide helpful diagnostic and therapeutic information defining the role of thyroid hormone deficiency in demented elderly patients with myxedema. This parameter may also prove valuable in future studies assessing the relative roles of triiodothyronine and thyroxine on central nervous system function and the time course of their actions. ACKNOWLEDGMENT We are grateful to Dr. Eliot L. Berson for electroretinographic studies performed in the Berman-Gund Laboratory at the Massachusetts Eye and Ear Infirmary, to Dr. Keith Chiappa for review of the manuscript, to Ms. Ellen Gill for technical support, and Ms. Lyndsay Lazzara and Ms. Cherry Meeks for secretarial sl:pport.
REFERENCES 1. Nickel SN. Frame B: Neurolcgic manifestations of myxedema. 2. 3.
4.
Neurology (Minneap) 1958; 8: 51 l-517. Sanders V: Neurologic manifestations of myxedema. N Engl J Med 1962; 266: 547-552,599-603. Swanson JW, Kelly JJ, McConahey WM: Neurologic aspects of thyroid dysfunction. Mayo Clin Proc 1981; 56: 594512. Cremer GM, Goldstein NP, Paris J: Myxedema and ataxia.
5. 6. 7. 8.
December 1984
Neurology (Minneap) 1969; 19: 37-46. Asher R: Myxoedematous madness. Br Med J 1949; 2: 555-562. Royce PC: Severely impaired consciousness in myxedema-a review. Am J Med Sci 1971; 261: 46-50. Blum M: Myxedema coma. Am J Med Sci 1972; 264: 432443. Nickel SN, Frame B, Bevin J, Tourtellotte WW, Parker JA,
The American Journal of Medicine
Volume 77
1013
EVOKED
9.
10. 11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
1014
POTENTIALS
IN HYPOTHYAOIDISM-LAMNSON
ET Al
Fk@es BR: Myxedema neuopathy and myopathy: a clinical and patftologic study. Neurology (Minneap) 1961: 11: 125-137. Dyck PJ. Lambert Eli: Polyneuropathy associated with hypothyroidism. J Neuropathol Exp Neural 1970; 29: 631658. Chiappa KH, Ropper AH: Evoked potentials in clinical mediclne. N Engl J Med 1982; 306: 1140-l 150. shahroki F, Chfappa KH. Young RR: Pattern shff visual evoked responses: two hundred patients wlth optic neuitis and/or multiple sclerosis. Arch Neurol 1978: 35: 65-71. Rossinl PM, Marchionno LI, Gambi D, Albertarzi A, DiPaolo B: Transient and steady-state visual evoked potentials by checkerboard reversal pattern in renal diseases. In: Courjcn J. Mauguiere F, Revel M, eds. Clinical applications of, evoked potentials in neurology. New York: Raven Press, 1982; 125130. Kriss A, Carroll WM. BluTlhardt LD, Halliday AM: Pattern- and flash-evoked potential changes in toxic (nutritional) optic neuropatfty. In: Courjon J, Mauguiere F, Revel M. eds. Clinical applications of evoked potent&Is in neuology. New York: Raven Ress, 1982; 11-19. Troncoso J, Mancall EL, Schatz NJ: Visual evoked responses in pernicious anemia. Arch Neurol 1979; 36: 188-189. Krumholr A, Weiss HD, Goldstein PJ. Harris KC: Evoked responses in vitamin B12 deficiency. Ann Neurol 1980; 9: 407-409. fakahashi K, Fujitani Y: Somatosensory and visual evoked potentials in hyperthyroidism. Electroencephalogr Clin Neurophysiol 1970; 29: 551-556. O’Malfey BP. Abbott RI, Bamett DB, No&over BJ, Rosenthal FD: Propranolor versus carbimazoks as the sole treatment for thyrotoxicosis. A consideration of circulating thyroid hormone levels and tissue thyroid function. Clin Endocrinol 1982; 16: 545-552. Nishltani H, Kool KA: Cerebral evoked responses in hypothyroidism. Electroencephalogr Clin Newophysiol 1968; 24: 554-560. Mastaglia FL, Black JL, Collins DWK. Gutterklge DH. Yuen RWM: Slowing of conduction in visual pathway in hypothyroidism. Lancet 1979; I: 387-388. Hrf& A, Fallstrom SP, Karlberg P, Olsson T: Clinical application of evoked eeg responses in infants. Ill: Congenital
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1984
The Amerlcen
Journal of Medlclne
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22.
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25.
28.
27.
28.
29.
30.
31. 32.
Volume 77
hypothyroidism. Dev Med Child Neurol 1982; 24: 164172. Gautvik KM. Tashjian AH, Kourides IA. et al: Thyrotropin-releasing hormone is not the sole physiologic mediator of pro&tin release during suckling. N Engl J Med 1974; 290: 1162-1165. Ridgway EC, Weintraub BD. Cevallos JF. Rack C. Maloof F: Suppression of pitultary TSH secretion in the patient with a hyperfunctioning thyroid nodule. J Clin Invest 1973; 52: 2783-2792. Berson EL: Electrical phenomena in the retina. In: Mcdes RA. ed. Adler’s physiology of the eye, 7th ed. St. Louis: CV Mosby, 1981; 486-529. Lansing RW, Trunnell JB: Electroencephalographic changes accompanying’thyrofd deficiency in man. J Clin Endocrinol Metab 1963; 23: 470-480. Rubenstein M, Peristein TP, Hikfesheimer M: Cochlear action potentials in experimentally induced hypothyroidism in guinea pigs. Acta Dtolaryngol (Stockh) 1975; 331 (suppl): l-10. Uziel A. Ftabie A. Mafot M: The effect of hypothyroidism on the onset of cochlear potentials in developing rats. Brain Res 1980; 1: 172-175. Ladenson PW, Goldenheim PD, Ridgway EC: Rapid pituitary and peripheral tissue responses to intravenous I-triiodothyronine in hypothyroidism. J Clin Endocrinol Metab 1983; 56: 1252-1259. Crantz FR. Larsen PA: Rapid thyroxine to 3,5.3’-triiodothyro nine ccnversicn and nuclear 3,5,3’-trkodofhyrcnine binding in rat cerebral cortex and cerebellum. J Clin Invest 1980; 65: 935-938. Rivlin RS: Hypothyroidism: vitamin metabolism. In: Werner SC, lngbar SH, eds. The thyroid. Hagerstown. Maryland: Harper a Row, 1978; 878-883. Torrents E, Cervino JM, Maggiolo J. et al, et al: Modifications de I’electroretinogramme (ERG) darts le myxoedeme. Presse Med 1954: 62: 1716. Pearlman JT. Burian HM: Electroretinographic findings in thyroid dysfunction. J Ophthalmol 1964; 58: 216-226. Bhat NR. Shanker G. Pieringer RA: Investigations on myelination in vitro: regulation of 2.3’-cyclic nucleotide 3’-pho sphof@olase by thyroid harone in culhres of dissociated brain cells from embryonic mice. J Neurochem 1981; 37: 895-701.
PAUL
W. LADENSON,
JOHN
W. STAKES,
E. CHESTER
M.D.*
M.D.
RIDGWAY,
M.D.
Boston, Massachusetts
From the Thyroid Unit, Medical Service, and the Clinical Neurophysiology Laboratory, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts. This work was supported in part by Grants RR-1066, AM-16791, and HL07354 from the National Institutes of Health, Bethesda, Maryland. An abstract based upon a portion of this study was presented at the 56th Annual Meeting of the American Thyroid Association, Quebec, Canada, 1982. Dr. Ladenson is a Teaching and Research Scholar of the American College of Physicians, Philadelphia, Pennsylvania. Manuscript accepted June 14, 1984. Current address and address for reprint requests: Division of Endocrinology and Metabolism, Sinai Hospital, Baltimore, Maryland 21215. l
1010
The pattern-shift evoked potential was measured in 19 hypothyroid patients before treatment, and after short- (one week) and long-term (12 to 24 weeks) thyroid hormone replacement therapy. Before treatment, nine patients had an abnormally prolonged visual evoked potential latency, more than 115 msec. After one week of therapy with 50 pg per day of L-triiodothyronine, the mean visual evoked potential latency for the entire group was unchanged, 114 f 8 to 114 f 7 msec. However, long-term therapy with 100 to 200 pg per day of L-thyroxine significantly shortened the visual evoked potential latency to 105 f 1 msec (p
December1984 The American Journal of Medicine Volume77
EVOKED POTENTIALS IN HYPOTHYROIDISM-LADENSDN ET AL
TABLE I
Thyroid Function Results before and during Thyroid Hormone Therapy Afier After L-T&dO-
thyronlne (50 Ccg/day) for one Week (n = 11)
L-Thyroxine (100-200 Mdsy) for 12 to 24 Weeks (n = 17)
Parameter
Range
Before Treatment (n = 19)
Serum thyroxine
4.0-12.0
0.9 f 0.2
0.8 f 0.2
75-195
46 f 9
301 f 25
140 f 4’
103 f 22
9f5’
8f
Normal
@g/d!) Serum triiodothyronine (ng/dl) Serum thyrotropin
0.5-3.5
9.0 f 0.6’
5’+
MU/ml) Values are mean f SEM; n is the number of patients studied. Significantly different from pretreatment values, p
stimulation by a reversing black-and-white checkerboard image (4 mm checks subtending a visual angle of 14 minutes) as previously described for our laboratory [ 111. At least two computer-averaged determinations of the responses of 128 consecutive stimuli recorded from the occipital scalp for each eye were employed to determine the stimulus-to-peak latency and maximal amplitude of the principal positive wave form generated, the PI00 (Figure 1). The intra-subject reproducibility of Ploo latency measurements in normal subjects (n = 12) studied on at least two separate occasions is f 2 msec. In normal subjects (n = 41), the Ploo latency is 102 f 5 msec (mean f SD) and the amplitude is 10 f 4 @. In this study the upper limit of normal for the PIOOlatency was considered to be 115 msec (mean + 2.5 SD). Although the Ploo amplitude may be altered by changes in visual acuity or attention, the latency is relatively independent of these effects. All tested eyes had a corrected visual acuity of 20/100 or better. Electroretinographic studies [23] were performed in the two eyes of one patient with bilateral prolongations of the Ploo latency. Data Analysis. The statistical significance of changes in study parameters was assessed by the Student paired t test. The unpaired t test was employed for comparisons of patient groups. Results are expressed as mean f SEM.
RESULTS Visual Evoked Potentials before Treatment. Before treatment, the visual evoked potentials were studied in
PATIENTS AND METHODS Patients. Nineteen patients with clinical and laboratory features of hypothyroidism (Table I) were studied in the General Clinical Research Center after giving informed consent. Hypothyroidism was caused by autoimmune thyroiditis (11 patients) or previous radioactive iodine ablation therapy (eight patients). Although the majority of patients complained of recent somnolence, subtle intellectual impairment, difficulty with balance, or paresthesia& these symptoms were temporally attributable to hypothyroidism. On physical examination, apathy and delayed deep tendon relaxation were frequently noted. No patient with other clinical manifestations of primary neurologic or ophthalmologic disease, anemia, or macrocytosis was included. Three patients had stable exophthalmic Graves’ ophthalmopathy without active inflammation. In one of these patients, one eye with severely impaired visual acuity due to previous exposure keratitis was excluded from study. Study Protocol. Study parameters were assessed in 19 patients before treatment, after seven days of parenteral sodium L-triiodothyronine (Sigma Chemical Co., St. Louis, Missouri) therapy at a dosage of 50 pg per day in 11 patients, and after 12 to 24 weeks of long-term oral sodium L-thyroxine (Flint-Travenol Laboratories, Deerfield, Illinois) replacement in 17 patients. The long-term L-thyroxine dose was adjusted to restore clinical euthyroidism and/or a normal serum thyrotropin concentration (Table I). Serum thyroxine, triiodothyronine, and thyrotropin concentrations were determined by previously described radioimmunoassay methods [ 2 1,221 in serum samples obtained 24 hours after administration of the last thyroid hormone dose. Visual Evoked Potentials. The pattern-shift visual evoked potential was measured separately for each eye following
the 37 eyes of 19 hypothyroid
patients.
FRETREATMNT
The mean ia-
f\
FOST-TREATMENT
:: ‘108
I-
7b
/cb
B-0
LATENCY lmsec)
&ure 1. Visual evokedpotential tracings in a hypothyro~d patient before (upper tracing) and after (lower tracing) 24 weeks of ~-thyroxine therapy. Each of the paired lines at the two time points is an average of the occipital signals (OZ) in response to 128 consecutive photic stimuli. The upper limit of normal for the visual evoked potential latency is 115 msec.
December 1984
The American Journal of Medicine
Volume 77
1011
EVOKED POTENTIALS IN HYPOTHYROIDISM-LAMNSON ET AL
0
4
8
12-24
a
12-24
T/ME heeksl
efi
0
4
TIME (weeks)
-_
_‘__
FIgwe 2.
Visual evoked potential latency (upper panel) and amplitude (lower panel) in hypothyroid patients before treatment, after 50 pg per day of L-triiodothyronine for one week, and after 100 to 200 pg per day of L-thyroxine for 12 to 24 weeks. Values are mean f SEM. Significance versus pretreatment: lp
tions (1 .O f 0.1 versus 0.9 f 0.2 pg/dl) or the duration of clinical hypothyroidism (18 f 6 versus 14 f 6 months). The pretreatment amplitude of the visual evoked potential was less than 4 PV in the 15 tested eyes of nine patients. Five of these patients also had prolonged PIso latencies. Visual Evoked Potential Responses to Thyroid Hormone Therapy. The visual evoked potential was minimally affected during the first week of parenteral Ltriiodothyronine therapy. The mean PIOOlatency was not altered (113.7 f 7.9 to 113.8 f 7.3 msec). A small increase in the Ploo amplitude (4.5 f 0.7 to 6.2 f 0.9 I.LV, p <0.02) was observed within this time. Following 12 to 24 weeks of long-term oral L-thyroxine treatment, the mean Ploo latency was significantly reduced (112.1 f 1.8 to 104.7 f 1.4 msec, p
tency of the PIOOpeak was 113.1 f 1.5 msec for the entire group. Nine patients had pretreatment PI00 latencies that were abnormal (122.2 f 1.9 msec), and 10 patients had values within the normal range (105.4 f 0.8 msec). Patients with initially abnormal Ploo latencies were significantly older than those with normal values (61 f 4 versus 47 f 4 years, p <0.05) but did not differ in pretreatment serum thyroxine concentra-
1012
December 1984
The American Journal of Mediclne
The latency of the visual evoked potential is thyroid hormone-dependent in humans. The reversible alteration of this readily measurable parameter in our hypothyroid patients reflects an effect of thyroid hormones on central nervous system function. Although the clinical manifestations of neurologic dysfunction in hypothyroidism are well described [l-3], they have been difficult to quantify. Previous electroencephalographic studies have demonstrated changes in resting alpha
Volume 77
EVOKED POTENTIALS IN HYPOTHYROIDISM-LADENSON ET AL
rhythm and impaired “photic driving” in patients with myxedema [ 1,241. Abnormal cortical evoked responses have also been reported in thyroid hormonedeficient experimental animals [25,26] and in humans [ 18-201. Our study illustrates a use of this neurophysiologic parameter to examine the short- and long-term effects of thyroid hormones on brain function. Since parenteral L-triiodothyronine therapy has been shown to be capable of rapidly reversing a number of pituitary and peripheral (nonpituitary) organ abnormalities in hypothyroid patients [27], one purpose of this study was to define and compare the short-term effects of L-triiodothyronine on the central nervous system. The absence of short-term change in the visual evoked potential latency that we observed stands in contrast to the rapid responsiveness of the pituitary, i.e. suppressed thyrotropin secretion, and of previously studied cardiovascular, pulmonary, renal, and metabolic parameters within this time frame. A possible explanation for these discordant response rates may be a difference between organs in the relative contributions to nuclear thyroid hormone receptor binding made by circulating triiodothyronine and by the triiodothyronine that is locally produced in target tissues by the intracellular 5’-monodeiodination of thyronine. It has been shown that the proportion of locally derived nuclear triiodothyronine is higher in the cerebral cortex and cerebellum than in the anterior pituitary of rats as reported by Crantz and Larsen [28]. L-triiodothyronine therapy in our hypothyroid patients may, therefore, have saturated pituitary nuclear receptors more completely than those in brain, which relies more heavily upon circulating thyroxine as a substrate for intracellular triiodothyronine production. Long-term thyroid hormone therapy uniformly shortened the visual evoked potential latency in these hypothyroid patients. The mechanism of this thyroid hormone effect on cerebral function remains enigmatic. Hypothyroidism due to autoimmune thyroiditis may be associated with pernicious anemia or Graves’ ophthalmopathy. Optic nerve involvement by these disorders may cause prolongation of the visual evoked potential latency [ 14,151. This does not represent an adequate
explanation for the neurophysiologic changes observed in our patients since these diseases were neither clinically apparent nor treated during the course of this study. Alterations in vitamin A metabolism occur in hypothyroidism [29], and a reversible reduction in the electroretinographic amplitude has been described in myxedema [30,31]. However, the markedly prolonged visual evoked potential latencies in our patients and the normal pretreatment electroretinographic results argue against a reversible metabolic retinopathy as the explanation for our findings. An age-related prolongation of the visual evoked potential latency is known to occur after 60 years. This cannot, however, account for the changes we have observed over a short time period, with each visual pathway serving as its own control. The thyroid hormones have been shown to affect myelin synthesis [32], an important factor in determining the speed of impulse transmission along complex polysynaptic pathways such as those mediating the visual evoked potential. The time course of recovery observed in our patients would seem consistent with an effect of myelin generation. The availability of a precise and reproducible measure of central nervous response to thyroid hormone may have clinical and investigative applications. These observations extend the differential diagnosis of metabolic encephalopathies associated with an abnormal visual evoked potential. Since hypothyroidism causes a reversible form of dementia, the visual evoked potential latency may provide helpful diagnostic and therapeutic information defining the role of thyroid hormone deficiency in demented elderly patients with myxedema. This parameter may also prove valuable in future studies assessing the relative roles of triiodothyronine and thyroxine on central nervous system function and the time course of their actions. ACKNOWLEDGMENT We are grateful to Dr. Eliot L. Berson for electroretinographic studies performed in the Berman-Gund Laboratory at the Massachusetts Eye and Ear Infirmary, to Dr. Keith Chiappa for review of the manuscript, to Ms. Ellen Gill for technical support, and Ms. Lyndsay Lazzara and Ms. Cherry Meeks for secretarial sl:pport.
REFERENCES 1. Nickel SN. Frame B: Neurolcgic manifestations of myxedema. 2. 3.
4.
Neurology (Minneap) 1958; 8: 51 l-517. Sanders V: Neurologic manifestations of myxedema. N Engl J Med 1962; 266: 547-552,599-603. Swanson JW, Kelly JJ, McConahey WM: Neurologic aspects of thyroid dysfunction. Mayo Clin Proc 1981; 56: 594512. Cremer GM, Goldstein NP, Paris J: Myxedema and ataxia.
5. 6. 7. 8.
December 1984
Neurology (Minneap) 1969; 19: 37-46. Asher R: Myxoedematous madness. Br Med J 1949; 2: 555-562. Royce PC: Severely impaired consciousness in myxedema-a review. Am J Med Sci 1971; 261: 46-50. Blum M: Myxedema coma. Am J Med Sci 1972; 264: 432443. Nickel SN, Frame B, Bevin J, Tourtellotte WW, Parker JA,
The American Journal of Medicine
Volume 77
1013
EVOKED
9.
10. 11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
1014
POTENTIALS
IN HYPOTHYAOIDISM-LAMNSON
ET Al
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