Alterations in peripheral nerves are well documented in overt myxedema but not in subclinical hypothyroidism. We performed electrophysiologic studies to ...
THYROID Volume 5, Number 4, 1995 Mary Ann Liebert, Inc.
Peripheral Neuropathy
in Subclinical
Hypothyroidism
A. MISIUNAS, H. NIEPOMNISZCZE, B. RAVERA, G. FARAJ, and E. FAURE
ABSTRACT Alterations in peripheral nerves are well documented in overt myxedema but not in subclinical hypothyroidism. We performed electrophysiologic studies to investigate such abnormalities in patients with normal serum total T4 and hyperresponsiveness of TSH to TRH, either with normal or high levels of basal circulating TSH. Subjects were divided in three groups: (i) Hypothyroidism Stage I (group I) (« = 17, mean age = 39 ± 4 years), T4 = 9 ± 0.7 /Kg/dL, TSH = 4.3 ± 0.4 /*U/mL, TSH post-TRH (peak value) = 37.6 ± 1.6 /¿U/mL; (ii) Hypothyroidism Stage II (group II) (n = 10, mean age: 43 ± 6 years), T4 = 7.7 ± 0.8 ¿ttg/dL, TSH = 20 ± 5 j*U/mL, TSH post-TRH > 50 /uU/mL; (iii) Control Group (n = 20, mean age 41 ± 5 years), healthy subjects. All patients and controls were women. TRH test consisted in the iv injection of 200 µ% TRH (normal peak value up to 25 ¿ilJ/mL, normal basal TSH < 5.5 µ /mL). None of the patients had carpal tunnel syndrome or any other neurological or metabolic dis¬ turbances. We studied the distal motor latencies, motor and sensory amplitudes, and nerve conduction velocities. The motor parameters were measured in the median and external sciatic popliteal (ESP) nerves, and the sensory parameters in the median and sural nerves. In most cases values were obtained from both right and left nerves. Motor parameters: no differences were found between all groups for conduction velocities (CV). The motor distal latencies (MDL) in median nerves in groups I and vs. controls were 3.6 ± 0.1 and 3.6 ± 0.2 vs 3.0 ± 0.1 msec < ± 0.1 and 4.9 ± 0.2 vs 4.2 ± 0.1 msec (p < 0.05). Amplitudes controls vs were 4.5 The MDL in ESP nerves (p 0.05). in group I were only decreased in the ESP nerves when compared to controls: 4.8 ± 0.8 vs 6.6 ± 0.5 mV (p < 0.05). However, group II showed a significant shortening of the amplitude in both the median and ESP nerves when com¬ pared to controls: 6.9 ± 0.9 vs 8.6 ± 0.2 mV (p < 0.05) and 3.4 ± 0.7 vs 6.6 ± 0.5 mV (p < 0.05), respectively. Sensory parameters: no differences were observed for CV between the three groups. The amplitudes were signifi¬ cantly decreased in sural nerves in groups I and II when compared to the control group: 26.8 ± 2.4 and 21.3 ± 2.0 vs 32.1 ± 2.5 µ ( < 0.05). However, measurements in median nerve showed significant differences only between group II and controls: 41.3 ± 3.8 vs 52.5 ± 4.1 µ\ ( < 0.05). As shown, MDL are increased in both stages of sub¬ clinical hypothyroidism; amplitudes are low in stage II but are affected in the leg nerves only in stage I. Nervous conduction speeds are normal in all groups. It is concluded that an incipient axonal alteration is present in sub¬ clinical hypothyroidism. The abnormality is more evident when basal levels of TSH are increased. However, most of these alterations are also present when hyperresponsiveness of TSH to TRH is the apparent unique abnormal¬ ity of thyroid function.
INTRODUCTION is one of the most causes endocrine Several of neurological abnormalities follow long standing well documented in overt myxedema (2-12). They are consistent with polyneuropathic patterns involving a significant demyelinating component and axonal degeneration (13-15). However, some hypothyroid patients express subjective com-
of Hypothyroiperipheral dism neuropathies (1).frequenthypothyroidism, types
Services of Endocrinology and
plaints of polyneuropathy without objective clinical findings. Nevertheless, a definite diagnosis can be achieved by electrophysiologic criteria in most of them (3,16). Although symptomatic polyneuropathies are seldom observed in hypothyroid subjects, subclinical alterations in the conduction of motor and sensory fibers are relatively common (3,7,9,11,14). The influenee of subclinical hypothyroidism on the function of peripheral nerves is uncertain (17). To investigate this influence we have performed electrophysiologic studies in patients with nor-
Neurology, Complejo Médico (P.F.A.) "Churruca-Visca," 283
Buenos
Aires, Argentina.
284
MISIUNAS ET AL.
mal serum T4 and hyperresponsiveness of TSH to TRH, either with normal or high levels of basal circulating TSH.
PATIENTS AND METHODS
Forty-seven
women were
divided in three groups:
patients with subclinical hypothyroidism stage I (hyperresponsiveness of TSH to TRH with normal
Group I:
17
Group II:
basal TSH and T4) Mean age 39 ± 4 years. 10 patients with subclinical hypothyroidism stage II (high basal TSH with normal T4). Mean age 43 ± 6 years.
Control
Group:
20
healthy subjects,
mean
age 41 ± 5 years.
Patients had previously received no treatment and they were studied at admission. Total serum T4, TSH, and TRH-TSH test (basal and 25 min post-iv 200 pg TRH) (Table 1) and electromyographic studies were performed in all subjects. No dis¬ eases affecting peripheral nerves such as diabetes, renal fail¬ ure, alcoholism, toxins, or carpal tunnel syndrome were found. A commercial kit (SERONO "T4 Bridge" Biodata s.p.a, Guidonia Montecelio, Italy) was used for T4 measurements (normal values: 4.5-12 pg/dL). TSH MAIA clone immunoradiometric assay (SERONO, Norwell, MA) was used for TSH measurements
(normal values: 0.5-5.5 µ /niL).
The electromyographic studies were done on a DISA type 05 A 02-TROLLEI-Denmark, equipment. During these studies the temperature of the extremities was kept constant at 34 ± 2°C. The motor conduction velocity (MCV), distal motor latency (DML), and motor potential amplitude (MPA) in the median (M) and external sciatical popliteal (ESP) nerves were studied using surface electrodes, 0.5 X 5 cm silver ribbon on the mus¬ cle inervated by the nerve to be explored. The distal motor latency (DML) was expressed in msec, the conduction velocity (CV) in m/sec, and the muscle evoked po¬ tential amplitude in mV. The sensory parameters studied in the median and sural nerves were the sensory conduction velocity (SCV) and the sen¬ sory evoked potential amplitude (SPA). One ring electrode was used for the median nerve, and two needle monopolar elec¬ trodes, for the sural nerve. We used two bipolar 5-mm-diameter surface silver disc stimulating electrodes with center to cen-
separating 2 cm. Once a stable response from the nerve was obtained, we measured the SCV in m/sec. The amplitude is ex¬ pressed in µ, . Group I: 28 motor determinations were performed on the me¬ dian nerve (bilateral in eleven patients and unilateral in the other six); 25 measurements were conducted on the ESP nerve (bi¬ lateral in ten patients and unilateral in five); 28 sensory stud¬ ies, for median and sural nerves, were bilateral in 11 patients ter
and unilateral in 6. Group II: 17 motor determinations were performed on the median and ESP nerves (bilateral in 7 patients and unilateral in 3); 17 sensitive studies on the median nerve were bilateral in seven patients and unilateral in three. For the sural nerve, seven were bilateral and one unilateral. Control group: 40 motor determinations were carried out on the median nerves (bilateral in all subjects); 30 motor and sen¬ sory determinations were done on ESP (bilateral in ten). For the sural nerve in all cases they were unilateral. The results were expressed as mean value ± SEM. For dif¬ ferences between group I and II versus controls, Student's t test was used.
RESULTS Motor parameters There were no differences among all groups in the conduc¬ tion velocities (CV); the motor distal latencies (MDL) were sig¬ nificantly increased (p < 0.05) in patients from groups I and II when compared to the control group, but not between them¬ selves. Patients from Group I showed decreased amplitudes only in the ESP nerve. However, patients from group II showed decreased amplitudes in both the median and ESP nerves
(Table 2).
Sensory parameters No differences were observed in the conduction velocities of the three groups. The amplitudes were significantly decreased (p < 0.05) in the sural nerve of groups I and II when compared to the control group. However, the median nerve showed sig¬ nificant differences (p < 0.05) only between group II and con¬ trols (Table 3).
DISCUSSION The published electromyographic data revealed that myxedepatients have a mixed polyneuropathy (15,16). In those cases in which a sural nerve biopsy was performed, the diag¬ nosis was confirmed, showing that the primary abnormality is mainly axonal (7,14). The hypothyroid peripheral neuropathy can be clinical or subclinical, although usually presenting with some degree of electrophysiological alterations (3,7,9,11,14). It is known that measurements of nerve conduction velocities involve only one-third of all myelinic fibers of bigger size, and when the speed decreases, it expresses some extent of demyelination (18). When it is focal, it may be due to an entrap¬ ment syndrome (1,15,19,20) with the carpal tunnel syndrome matous
Table 1. Tests Performed
T4 (Mg/dL)
TSH (¿lU/ml) Peak TSH postTRH (µ /mL) "± SEM.
Stage I
Stage
II
Controls
17
10 7.7 ± O.i 20 ±5 >50
20 8.9 ± 0.4 2.0 ± 0.2 13 ± 1
9 4.3 37.6
±
± ±
0.7" 0.4 1.6
285
PERIPHERAL NEUROPATHY IN HYPOTHYROIDISM Table 2. Comparison of Motor Conduction Velocities, Motor Distal Latencies, Motor Amplitudes in Groups I and II vs Controls
ESP
Median
Group I Group
II
Controls
and
CV
MDL
A
CV
MDL
A
(m/s)
(ms)
(mV)
(m/s)
(ms)
(mV)
58.8
(n 58.8
(n 57.05
(n
± =
± =
± =
9.1
±
1.4
50.9
28)
(n
=
28)
(n
=
28)
(n
2.0
3.6
±
0.2*
6.9
±
0.9*
52.2
17)
(n
=
17)
(n
=
17)
(n
3.0 ±0.1
8.6
±
0.2
49.2
40)
(n
=
40)
(n
3.6 ±0.1*
1.9°
0.8
40)
(n
=
1.6
±
± ±
=
2.0
17)
=
4.8
±
0.8*
(n
=
25)
(n
=
25)
4.9
±
0.2*
3.4
±
0.7*
(n
=
17)
(n
=
17)
4.2 ±0.1
6.6
±
0.5
(n
=
30)
4.5 ±0.1*
25)
=
0.9
30)
(n
=
30)
"± SEM.
*p < 0.05. We have seen that in the earliest stage of hypothyroidism (Group I), the motor parameters were more affected in the longer nerves and, also, in a higher proportion than the sensory
its best example in some patients with overt hypothyroidism (3-7). The subclinical neuropathies of hypothyroid subjects are characterized by prolonged distal latencies (11). These findings agree with the lack of alterations in the nerve conduction speed, commonly observed in adult hypothyroid patients (11). However, neonatal thyroid failure, which involves an impor¬ tant demyelinating component (21,22), causes slowed conduc¬ tion velocities when measured in the ulnar and posterior tibial nerves of children with untreated congenital hypothyroidism (23). The amplitudes of the motor and sensory nerve action po¬ tentials represent the number of activated axons, and they are one of the earliest parameters affected in axonal neuropathies (18). as
nerves.
As we found in a previous study (17), the initial alteration the median nerve was first observed in the motor distal la¬ tencies while the amplitude and the conduction velocities re¬ mained unchanged. On the other hand, alterations in the am¬ plitude and in the distal latencies developed in the longer nerves (ESP and sural). As known, the high specialization of neurons and the long distance between the cellular core and the most distal terminals makes the nerves more vulnerable to lesions producing neuroselective terminal degeneration, which usually begin at the longer axons (26). Such specialization involves the electrical conduction of the nerve impulse and the slow and rapid active transport of micro- and macromolecules, both by ortho- and antidromic pathways (27,28). The progression of thyroid insufficiency to subclinical hy¬ pothyroidism stage II correlated with the diminution of the mo¬ tor and sensory amplitudes in all the studied nerves. These find¬ ings agree with the alterations in the rapid axonal transport observed in experimental polyneuropathies in rats, and in pa¬ tients who have received chemotherapy treatments (29). In summary, our findings confirm a true subclinical polyneuropathy of probable axonal origin in patients with subclinical hypothyroidism, and correlate the magnitude of the neurologi¬ cal lesion with the degree of thyroid insufficiency. at
It has been reported that sensory and motor alterations found with similar frequency in hypothyroid patients (3,6,8,9,12), regardless of the origin of thyroid insufficiency (24). On the other hand, there is no correlation between the de¬ crease of conduction velocities and the severity of the clinical illness (3,4). It is believed that affected nerves may not return to normality after treatment; however, such nerves may recover normal function clinically (1,18). Clinical and electromyo¬ graphic remissions are observed in hypothyroid patients after treatment with thyroid hormones (1,4,6,13,15,25) unless the nerve underwent mechanical compression (1,15,19,20). We found some extent of electromyographic alterations, even in the earlier stages of subclinical hypothyroidism. Such electrophysiological changes are qualitatively similar to those ob¬ served in patients with overt myxedema. are
Table 3. Sensorial Parameters
of
Groups I
and
II
Controls
vs
Sural
Median
Group
I
Group II Controls
*p < 0.05.
A
CV
A
(pV)
(m/s)
(µ )
69.3
( 63.2
( 68.1
( "± SEM.
CV
(m/s) ± =
± =
± =
2.0a
28)
49.3
±
(
=
2.7
41.3
17)
=
2.0
(
52.5
30)
(
=
± ±
4.3
57.8
28)
(
3.8*
57.8
17)
(
4.1
58.9
30)
(
1.9
±
=
28)
±
=
±
=
2.6
15)
2.1
20)
26.8
( 21.3
± =
±
(
=
(
=
32.1
±
2.4*
28) 2.0*
15) 2.5
20)
286
MISIUNAS ET AL.
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