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tropical spastic paraparesis
JOURNAL
OF THE
NEUROLOGICAL SCIENCES
ELSEVIER
Journal
Contralateral
of the Neurological
Sciences
128 (199.5) 51-57
early blink reflex in patients with HTLV-I myelopathy/tropical spastic paraparesis
associated
Fidias E. Leon-S. a,*, Kimiyoshi Arimura a, Yumiko Arimura a, Yoshito Sonoda a,b, Mitsuhiro Osame a a Clinical
Neurology
and Neurophysiology
b Second Department
Unit, Third Department of Internal Medicine, Kagoshima University School of Medicine, 8-35-l Sakuragaoka, Kagoshima 890, Japan Kagoshima University School of Medicine, 8-35-l Sakuragaoka, Kagoshima 890, Japan
of Physiology, Received
24 March
1994; revised
1 August
1994; accepted
10 August
1994
Abstract Thirty-two Japanese patients with HTLV-I-associated myelopathy/ tropical spastic paraparesis (HAM/TSP) were studiedby means of the electrically elicited blink reflex and three responses (Rl, R2, R3) were registered. 69% of the patients displayed a uni- or bilateral crossed Rl response (Rlkl as compared to 11% in the control group. A positive correlation between Rlk and an exaggerated jaw jerk reflex was found in the patients. Central abnormalities of the nervous system with diminished presynaptic inhibition acting in the interneuronal input of the brainstemof HAM/TSP patients was the most likely cause. It could lead to the unmasking of crossed trigemino-facial pathway reflex which is present in the normal population from birth. These results strongly support the supraspinal involvement of the central nervous system (CNS) in HAM/TSP more than usually thought. Keywords:
Blink reflex; Crossed Rl; Facial nucleus; Interneuronal
HAM/TSP;
1. Introduction Reports in the past revealed that some HAM/TSP patients may present with deafness (9%), optic atrophy (14%), ptosis and pupillary changes (20%), hand tremors (27.2%) and exaggerated jaw jerk reflex (30%), suggesting a clinical supraspinal involvement of the central nervous system (CNS) (Cruickshank et al. 1989; Osame et al. 1989, 1992; Rodgers-Johnson 1989; Roman 1989; Bhigjee et al. 1990; Rudge et al. 1991; Osame and McArthur 1992). Likewise, previous neurophysiological studies have attested to supraspinal abnormalities employing EEG, electrooculography, multimodal evoked potentials and magnetic stimulation, among others (Arimura K. et al. 1987; Arimura Y. et al. 1987; Ludolph et al. 1988; Arimura et al. 1989; Cruickshank et al. 1989; Bhigjee et al. 1990; Waddy et al. 1990; Castillo et al. 1991; Rudge et al. 1991; Foster et al. 1993). However, we are unaware of a systematic
network
neurophysiologic study on the trigeminal-facial pathways of these patients (Miyai et al. 1987). It is known that the electrically elicited blink reflex (BR) is a highly sensitive tool to reveal evident and silent brainstem lesions, including their peripheral and central connections (Kimura 1989). This fact prompted us to follow up our previous neurophysiological studies on HAM/TSP (Arimura et al. 1987; Arimura et al. 1989; Leon-S. 1992; Leon-S. et al. 1994a,b) and to perform an age matched study on BR. The results obtained may provide further insights on the pathogenesis of HAM/TSP.
2. Methods
Patients and subjects Patients and subjects were informed about the objective of this study in order to obtain their consent and maximal collaboration.
Patients with HAM/ * Corresponding 0992-65-7164.
author.
Phone:
0022-510X/95/$09.50 0 1995 Elsevier SSDI 0022-510X(94)00205-3
+ 81-0992-75-5332;
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B.V. All rights
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reserved
TSP
Thirty-two patients (11 male, 21 female) with HAM/TSP were studied. All the patients were re-
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et al. /Journal
of the Neurological
ported to test positive for HTLV-I antibodies in serum and cerebrospinal fluid by particle agglutination (Fujirebio, Inc., Tokyo, Japan) or enzyme-linked immunosorbent assay (ELISA) (Easai, Inc., Tokyo, Japan) and confirmed by Western blot (Osame et al. 1990). Their ages ranged from 34 to 76 years (average 59.3 years). The onset of illness ranged from 6 to 73 years (average 51.4 years). They had a clinical picture characterized by spastic paraparesis with hyperreflexia, Babinski sign and mild sensory and sphincteric disturbances. Seven of them had an exaggerated jaw jerk reflex. No patient had clinical involvement of the facial nerve. Twenty three patients underwent brain MRI. Motor disability scores were assigned to these patients according the scale of Osame et al. (1989).
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128 (1995)
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data (Medelec MS20; London, UK). The sweep time was 100 msec with 1024 addresses per channel. In every patient and control subject 5 responses were obtained from each side (Nacimiento et al. 1992). Because changes in amplitudes can appear according to the stimulus strength and methodology differences (Namerow and Etemandi 1970; Rossi et al. 19931, we decided to evaluate the latency only. Latency was measured by inspection of superimposed responses in the optical display using a cursor. Since we did not find significant differences between latencies of the BR regardless of the stimulated side, the shorter latencies of Rl, R2 and R3 elicited directly and consensually were taken into account in this study. For the patients who had Rlk either uni- or bilaterally, the shorter latency of this response was considered.
Control group
Eighteen volunteers (5 men, 13 woman), aged between 39 and 83 years (mean 57.6 years), served as controls. Blink reflex recording
The procedure used by Nacimiento et al. (1992) was adopted. Briefly, the BR was performed in a quiet room where the temperature was maintained at 2226°C. Patients and subjects were seated on an examination chair and instructed to close their eyes gently. Noise, distraction or any event of surprise that might modify blink reflexes were avoided (Willer et al. 1984; Rossi and Vignocchi 1993; Leon-S. et al. 1994b); and all of them were asked to relax as much as possible. Those who used to smoke were instructed to avoid it at least 60 min or more before examination, because it can affect latency values (Evinger et al. 1988). Five of the patients who displayed a crossed Rl response (Rlk) were randomly chosen and BR were additionally recorded with open eyes (Leon-S. et al. 1994b). This was done to determine the influence of voluntary effort on this response (Willer et al. 1984; Soliven et al. 1988; Nacimiento et al. 1992). BR was obtained by electrical stimulation of both right and left supraorbital nerves, with the cathode positioned near the supraorbital foramen and the anode 3 cm above it and at least 2.5 cm away from the midline. Square-wave negative single pulses of 0.2 msec duration were delivered. To prevent habituation in one or all of the three responses of the BR, stimuli were delivered randomly at intervals of 45-60 set (Rossi et al. 1989a). The reflex activities were recorded from both orbicularis oculi muscles (pars inferior) by means of surface electrodes placed on the degreased skin of the lower lid near the outer canthus and the reference electrode on the temple. The ground electrode was placed under the chin (Kimura 1989). The EMG signals were fed into amplifiers (bandwidth 20-2000 Hz) and stored on floppy discs for on-line and subsequent analysis and quantification of
Electroneurography
Direct muscle action potentials (D) of the orbicularis oculi muscles were obtained as described by Nacimiento et al. (1992). The latency ratios of Rl to the D response (R/D ratio) was also measured (Kimura 1982). Clinical correlations
Correlations were assessed between* results of BR and age at onset, duration of illness, age at the time of examination, HTLV-I antibody titers in both serum and cerebrospinal fluid, disability score and jaw jerk reflex. Statistical analysis
The Mann-Whitney U-test for between-group comparison of different variables, and chi-square analysis for between-group comparisons of the frequencies of different nominally scaled variables were used. Differences were considered significant at a p value < 0.05. 3. Results Control group
Electrical stimulation of both supraorbital nerves elicited an Rl (ipsilateral) and an R2 response which was elicited ipsilaterally and contralaterally disregarding the stimulated side. R3 was also obtained directly and consensually in all but one subject (an 83-year-old female) with maximal intensity stimulation. Two women (47 and 52 years old) showed the Rlk response. Patients with HAM/
TSP
The BR of all these 32 patients showed Rl, R2 and R3 responses with the following characteristics. Features of the RI response
Ipsilateral Rl responses were recorded on both sides in all but one patient who presented unilateral absence
F. E. Leon-S. Table 1 Latency values
Rl R2 R3 Direct R/D
(mean
f SD) in patients
et al. /Journal
the Neurological
and controls
Patients (n = 32)
Controls (n = 18)
Comparison P
10.9+ 30.6 f 74.9 + 3.3 f 3.3 +
11.1 kO.6 32.5 f 2.0 76.0 + 5.21 a 3.lkO.2 3.5 f 0.3
N.S. N.S. N.S. N.S. N.S.
1.1 3.0 5.7 0.3 0.4
of
a 17 subjects. N.S.: not significant.
Table 2 Latency values without (group parentheses)
Rl Rlk R2 R3
of Rl with no other abnormal feature. The mean latencies of Rl in the patients group did not differ significantly from controls (Table 1). The most remarkable finding was the Rlk response registered in 22 patients (69%) with HAM/TSP (9 men, 13 women; ages 34-76 years, average 58.2 years). This Rlk response was absent in the remaining ten patients (2 men, 8 women), aged 35-66 years (average 60.3 years) (Fig. 1). The frequency of this Rlk in HAM/TSP patients was higher compared with controls (11%) (p < 0.001). The mean latency of Rl obtained in patients with Rlk was significantly reduced as compared to controls (p < 0.025) and to patients lacking RlK (p < 0.005; Table 2, Fig. 2). Among the 22 patients with Rlk, it was elicited unilaterally in 9 patients (40%) and bilaterally in 13 patients (60%) with HAM/TSP. Rlk latency was delayed up to 5.5 msec and significantly prolonged with relation to the mean of Rl latency obtained in the same group of patients (p < 0.005). However, Rlk was always clearly different from R2 evoked by the same electrical stimulus (Leon-S. et al. 1994b). The patients who were evaluated with eyes open and closed presented Rlk on both occasions. The results obtained in these patients evaluated with eyes open are presented elsewhere (Leon-S. et al. 1994b).
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N.D.:
53
of Rl, Rlk, R2 and R3 of patients with (group I) and II) the crossed Rl response (mean+ SD; range in
Group I (n = 22)
Group II (n = 10)
Comparison P
10.5 * 0.9 (9.1-12.4) 11.8+ 1.8 (9.5-15.8) 29.4 f 2.1 (26.1-34) 74.8 f 5.7 (65-90.7)
11.8kO.S (10.4-12.9) N.D.
< 0.005
33.2+ 1.7 (30.9-36.8) 75.5 f 5.9 (68.4-85.5)
< 0.0015 N.S.
not detected.
Features of the R2 response R2 responses were bilaterally obtained in all patients. The mean latency of R2 response of HAM/TSP patients was not significantly different from controls. However, the mean latencies of R2 in patients with Rlk were significantly reduced compared to controls (p < 0.0025) and also to patients without Rlk (p < 0.0015). Two female patients (66 and 71 years old), one with and one without Rlk, showed a bilateral R2 response clearly distinguishable in two components. These components had a mean latency of 31.6 msec and 53.1 msec in the first patient and 34.5 msec and 60.6 msec in the other one. Features of the R3 response R3 responses were sometimes absent either ipsi- or contralaterally to the stimulation side, but were never absent bilaterally in these patients (unpublished data). Thus, the frequency of R3 in the patient group was not significantly reduced as compared to the control group. Neither the total group of HAM/TSP patients nor those with or without Rlk showed any significant difference in the mean latency of the R3 response compared with controls (Tables 1 and 2, Fig. 2).
Fig. 1. Blink reflexes obtained by electrical stimulation of the left supraorbital branch of the trigeminal nerve in patients with HAM/TSP. Left: 5%year-old male; right: 68-year-old female. Thick arrow shows the crossed Rl response, the thin arrows the R3 response. Asterisk, stimulation side. Calibration, 10 msec. Five superimposed traces.
54
F.E. Leon-S.
Clinical and radiological
et al/Journal
of the Neurological
correlations
A positive correlation was found between the exaggerated jaw jerk reflex (7 of 32 patients or 22%) and the presence of Rlk (p < 0.05). MRI of the brain showed disseminated lesions in the white matter, mostly around of the lateral ventricles, thalamic and basal ganglia (BG) structures, with occasional signs of cortical atrophy. Lesions in the midbrain were occasionally found but were thought not to be sufficient to explain the electrophysiological findings. 4. Discussion
Previous clinical, radiological, neurophysiological and pathological studies suggested an involvement above the spinal cord in patients with HAM/TSP. Electrically elicited BR proves to be sensitive in assessing pathologic states of the brainstem CBS) and/or its related structures in several diseases of the peripheral and central nervous systems (Kimura 1982, 1989; Bram et al. 1993). This fact led us to closely investigate the involvement of these pathways and the surrounding structures concerned with BR responses. It is known
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that the electrically elicited BR displays two responses (Rl and R2) (Kugelberg 1952; Shahani 1970; Kimura 1973, 1989; Bram et al. 1993) and a third response (R3) can also be obtained if appropriate conditions are taken into account (Penders and Delwaide 1973; Rossi et al. 1985; Rossi and Vignocchi 1993; Leon-S. et al. 1994b). Interestingly, Rlk was noted in 69% of our group of patients. This finding has not been described in the literature in patients with HAM/TSP. The fact that Rlk could be obtained with either eyes opened or closed eyes suggested that mechanisms other than voluntary contraction could be the origin of this response (Willer et al. 1984). Elicited Rl is considered an intrapontine oligosynaptic reflex produced through a short chain of interneurons (Trontelj and Trontelj 1973, 19781, that appears ipsilateral to the side of stimulation (Shahani 1970; Kimura 1975, 1989; Bram et al. 1993). Rlk can be obtained either by mechanical or electrical stimulation and is present from the neonatal period (Trontelj and Trontelj 1978; Bynke 1980; Cscecsei 1982; Willer et al. 1984; Soliven et al. 1988; Escudero et al. 1992; Nacimiento et al. 1992). Although present during normal development, it may be masked and undetectable
msec. ‘00
1
.
!
. . .
. . . . . . . . . . . . . . . .A. I.1 .*. ...
!
.
.
.f . A ...-~*.........;i-..--. A-‘I’ .
. Fig. 2. Distribution
of latency
.......
Patlent value mean Of pamlts mean of controls
values
obtained
from
value
patients
with (+)
and without
(-)
the crossed
Rl response.
F.E. Leon-S.
et al. /Journal
of the Neurological
in the majority of normal populations under usual recording conditions. Rlk has been described in patients with hemifacial spasm, Parkinson’s disease, blepharospasm, oromandibular dystonia, facial nerve palsy and postfacial palsy contracture among others (Penders and Delwaide 1973; Bratzlavsky and vander Eecken 1977; Smorto and Basmajian 1977; Trontelj and Trontelj 1978; Bynke 1980; Cscecsei 1982; Willer et al. 1984; Sunohara et al. 1985; Berardelli et al. 1985; Soliven et al. 1988; Escudero et al. 1992; Nacimiento et al. 1992). Both peripheral and central processes in Rlk have been considered regarding its pathology. Bratzlavsky and vander Eecken (1977) suggested that in addition to peripheral causes, an enhanced excitability of the facial motor neurons after facial nerve palsy could contribute to Rlk. It has recently been reported that patients with symptomatic and idiopathic facial palsy also displayed Rlk and it was thought that the response could probably be mediated by the ‘synaptic stripping’ phenomenon, with displacement of inhibitory synapses from facial motoneurons, unmasking the preexistent crossed trigeminal-facial anatomic pathways (Cscecsei 1982; Nacimiento et al. 1992). The fact that Rlk occurred in these HAM/TSP patients without abnormalities that pointed any peripheral lesion on the trigeminal-facial pathway (e.g., prolongation of Rl latency, abnormal R/D ratio, etc.) suggested that central, rather than peripheral lesions were responsible for these BR findings. Such lesions led to the lack of some inhibitory input at the interneuronal level that resulted in facial nucleus hyperexcitability and unmasked the preexistent crossed trigeminal-facial pathways commented elsewhere (Bratzlavsky and van Eecken 1977; Bynke 1980; Cscecsei 1982). The significantly reduced Rl latency in those patients with Rlk compared with those ones who did not display such response on the one hand; and the positive correlation between the presence of Rlk and the exaggerated jaw jerk reflex on the other hand support this contention. Perhaps, unilateral lesions affecting the inhibitory pathways in these patients could lead them to display Rlk either uni-or bilaterally as commented (Bynke 1980; Leon-S et al. 1994b). R2 is a cutaneous polysynaptic reflex (Cruccu et al. 1991) that follows the descending spinal tracts and nuclei and their projections to the adjacent reticular formation (Kimura 1989; Kiers and Carol1 1990). R2 of the BR share the same motor neurons as Rl (Cruccu et al. 1991; Bram et al. 1993). The most remarkable finding of the R2 response in HAM/TSP was its shortened latency in patients with Rlk. Although conclusions based on reflex latencies cannot be exact (Wechsler et al. 1986), Kimura (1973, 1975, 1982, 1989) indicated that a shortened latency of the R2 response may be a sign of interneuronal hyperexcitability and added that in advanced Parkinson’s disease, such hyperexcitability affected the excitability cycle of R2. The
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55
enhanced recovery cycle of the R2 response has also been found in patients with chronic spino-bulbar spasticity pointing to a reduction in the presynaptic inhibition (Rossi and Scarpini 1993). The diminished presynaptic inhibition acting on the interneuronal network (the likely mechanism for the presence of Rlk), may also account for the significantly shortened R2 latency in HAM/TSP. However, further studies to elucidate the relationship between Rlk and R2 in pathological conditions will be necessary (Soliven et al. 1988; Nacimiento et al. 1992). Notably, two cases, one with and the other without Rlk, presented with R2 response that had two components. This finding has been reported in cases involving post-hypoxic intention myoclonus (Young and Shahani 19791, nocturnal myoclonus (Wechsler et al. 1986) and periodic ataxia (Yokota et al. 1990). The mechanism of this phenomenon is yet unclear. R3 is considered a bilateral and consensual polysynaptic response of the BR that normally is present from the neonatal period. However, its central pathways are still unknown (Rossi et al. 1985, 1989a,b; Cruccu et al. 1991; Escudero et al. 1992; Leon-S. et al. 1994b). Since R3 was displayed regardless of the presence Rlk response (Fig. 11, it could be supportive of our suggestion that the regulatory mechanisms between Rl and R3, recently described (Rossi and Vignocchi 19931, may also be altered in these patients (Leon-S. et al. 1994b). In this study, we found electrophysiologically a noteworthy subclinical supraspinal involvement of the CNS in HAM/TSP patients by means of the BR. And BR resulted to be more sensitive in demonstrating such involvement than we had previously found in these patients (Arimura et al. 1987, 1989). Furthermore, we would like to suggest that not only the analysis of the common BR parameters (i.e. latencies, amplitudes, recovery cycles) are important but also the presence of uncommon responses like the Rlk deserves attention, if obtained under stringent methodological considerations.
Acknowledgments The authors would like to thank Amparo Ariza-Deleon, Ph.L., Raymond Rosales, M.D. and Fujio Umehara, M.D., for reviewing the English and for helpful comments. Also, special thanks are given to the Library workers at Kagoshima University School of Medicine for their kind help during the elaboration of this manuscript. We also thank the subjects who participated in the experiment without remuneration for being so cooperative. This work shall be submitted as part of the dissertation for the Ph.D. degree in Clinical
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Neurology and Neurophysiology by Fidias E. Leon-S., M.D to the Faculty of Medicine, University of Kagoshima, Japan.
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Rodgers-Johnson, P. (1989) Tropical myeloneuropathies in Jamaica (Jamaican Neuropathyl. In: Roman, G.C., Vernant, J.C. and M. Osame (Eds.1, HTLV-I and the Nervous System, Alan R. Liss, New York, pp. 123-138. Roman, G. (1989) Tropical spastic paraparesis and HTLV-I myelitis. In: Vinken, P.J., Bruyn, G.W. and R.B. McKendall (Eds.), Handbook of Clinical Neurology, Vol. 56, Elsevier, Amsterdam, pp. 525-542. Rossi, A. and C. Scarpini (19931 Evidence for presynaptic inhibition on trigeminal primary afferents fibres in humans. J. Neurol. Neurosurg. Psychiat., 56: 424-425. Rossi, B. and M.G. Vignocchi (19931 Methodological considerations on the use of the blink reflex R3 component in the assessment of pain in man. Ital. J. Neurol. Sci., 14: 217-224. Rossi, B., Giannini, C., Siciliano, G. and F. Sartucci (1985) The role of the tactile-pressure afferents in the habituation phenomenon of trigemino-facial reflex. Acta Neurol. Stand., 72: 602-605. Rossi, B., Risaliti, R. and A. Rossi (1989a) The R3 component of the blink reflex in man: a reflex response induced by activation of high threshold cutaneous afferents. Electroenceph. clin. Neurophysiol., 73: 334-340. Rossi, B., Vignocchi, G., Rossi, A. and A. Muratorio (1989b) Comparative study of pain perception and polysynaptic blink reflex responses in man. Funct. Neural., 47-51. Rossi, B., Vignocchi, G., Mazzoni, M., Pardossi, L., Bianchi, F. and A. Muratorio. (1993) Causes of the instability of R3 component of electrically evoked blink reflex: role of the attention to the stimulus. Electromyogr. clin. Neurophysiol., 33: 49-53. Rudge, P., Amza, A. and J.K. Cruickshank (1991) Multiple sclerosis, tropical spastic paraparesis and HTLV-I infection in Afro-caribbean patients in the United Kingdom. J. Neurol. Neurosurg. Psychiat., 54: 689-694. Shahani, B. (1970) The human blink reflex. J. Neurol. Neurosurg. Psychiat., 33: 792-800. Soliven, B., Meer, J., Uncini, A., Petajan and R. Lovelace (1988)
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Physiologic and anatomic basis for contralateral Rl in blink reflex. Muscle Nerve, 11: 848-851. Smorto, M.P. and J.V. Basmajian (1977) Electrodiagnosis: A Handbook for Neurologist, Harper & Row, New York, NY, pp. 131145. Sunohara, N., Tomi, H., Satoyoshi, E. and S. Tachibana (19851 Glabella tap sign. Is it due to a lack of R2-habituation? J. Neural. Sci. 70: 257-267. Trontelj, M. and J.V. Trontelj (1973) First component of human blink reflex studied on single facial motor neurones. Brain Res., 53: 214-217. Trontelj, M.A. and J.V. Trontelj (19781 Reflex arc of the first component of the human blink reflex: a single motoneurone study. J. Neurol. Neurosurg. Psychiat., 41: 538-547. Umehara, F., Izumo, S., Nakagawa, M., Ronquillo, A., Takahashi, K., Matsumoro, K., Sato, E. and M. Osame (1993) Immunocytochemical analysis of the cellular infiltrate in the spinal cord lesions in HTLV-I associated myelopathy. J. Neuropathol. Exp. Neurol., 46: 511-521. Waddy, H., Claus, D., Murray, N.M.F. and P. Rudge (1990) Central motor conduction studies in tropical spastic paraparesis (TSP). Electroenceph. clin. Neurophysiol., 75: S159-S160. Weschler, L.R., Stakes, J.W., Shahani, B.T. and N.A. Busis (1986) Periodic leg movements of sleep (nocturnal myoclonus): an electrophysiological study. Ann. Neurol., 19: 168-173. Willer, J.-C., Boulu, P. and M. Bratzlavsky (1984) Electrophysiological evidence for crossed olygosynaptic trigemino-facial connections in normal man. J. Neurol. Neurosurg. Psychiat., 47: 87-90. Yokota, T., Hayashi, H., Hirose, K. and H. Tanabe (1990) Unusual blink reflex with four components in a patient with periodic ataxia. J. Neurol., 237: 313-315. Young, R.R. and B.T. Shahani (1979) Clinical neurophysiological aspects of post-hypoxic intention myoclonus. In: Fahn, S., Davis, J.N. and L.P. Rowland (Eds.), Advances in Neurology, Vol. 26, Raven Press, New York, pp. 85-105.
OF THE
NEUROLOGICAL SCIENCES
ELSEVIER
Journal
Contralateral
of the Neurological
Sciences
128 (199.5) 51-57
early blink reflex in patients with HTLV-I myelopathy/tropical spastic paraparesis
associated
Fidias E. Leon-S. a,*, Kimiyoshi Arimura a, Yumiko Arimura a, Yoshito Sonoda a,b, Mitsuhiro Osame a a Clinical
Neurology
and Neurophysiology
b Second Department
Unit, Third Department of Internal Medicine, Kagoshima University School of Medicine, 8-35-l Sakuragaoka, Kagoshima 890, Japan Kagoshima University School of Medicine, 8-35-l Sakuragaoka, Kagoshima 890, Japan
of Physiology, Received
24 March
1994; revised
1 August
1994; accepted
10 August
1994
Abstract Thirty-two Japanese patients with HTLV-I-associated myelopathy/ tropical spastic paraparesis (HAM/TSP) were studiedby means of the electrically elicited blink reflex and three responses (Rl, R2, R3) were registered. 69% of the patients displayed a uni- or bilateral crossed Rl response (Rlkl as compared to 11% in the control group. A positive correlation between Rlk and an exaggerated jaw jerk reflex was found in the patients. Central abnormalities of the nervous system with diminished presynaptic inhibition acting in the interneuronal input of the brainstemof HAM/TSP patients was the most likely cause. It could lead to the unmasking of crossed trigemino-facial pathway reflex which is present in the normal population from birth. These results strongly support the supraspinal involvement of the central nervous system (CNS) in HAM/TSP more than usually thought. Keywords:
Blink reflex; Crossed Rl; Facial nucleus; Interneuronal
HAM/TSP;
1. Introduction Reports in the past revealed that some HAM/TSP patients may present with deafness (9%), optic atrophy (14%), ptosis and pupillary changes (20%), hand tremors (27.2%) and exaggerated jaw jerk reflex (30%), suggesting a clinical supraspinal involvement of the central nervous system (CNS) (Cruickshank et al. 1989; Osame et al. 1989, 1992; Rodgers-Johnson 1989; Roman 1989; Bhigjee et al. 1990; Rudge et al. 1991; Osame and McArthur 1992). Likewise, previous neurophysiological studies have attested to supraspinal abnormalities employing EEG, electrooculography, multimodal evoked potentials and magnetic stimulation, among others (Arimura K. et al. 1987; Arimura Y. et al. 1987; Ludolph et al. 1988; Arimura et al. 1989; Cruickshank et al. 1989; Bhigjee et al. 1990; Waddy et al. 1990; Castillo et al. 1991; Rudge et al. 1991; Foster et al. 1993). However, we are unaware of a systematic
network
neurophysiologic study on the trigeminal-facial pathways of these patients (Miyai et al. 1987). It is known that the electrically elicited blink reflex (BR) is a highly sensitive tool to reveal evident and silent brainstem lesions, including their peripheral and central connections (Kimura 1989). This fact prompted us to follow up our previous neurophysiological studies on HAM/TSP (Arimura et al. 1987; Arimura et al. 1989; Leon-S. 1992; Leon-S. et al. 1994a,b) and to perform an age matched study on BR. The results obtained may provide further insights on the pathogenesis of HAM/TSP.
2. Methods
Patients and subjects Patients and subjects were informed about the objective of this study in order to obtain their consent and maximal collaboration.
Patients with HAM/ * Corresponding 0992-65-7164.
author.
Phone:
0022-510X/95/$09.50 0 1995 Elsevier SSDI 0022-510X(94)00205-3
+ 81-0992-75-5332;
Science
Fax:
B.V. All rights
+ 81-
reserved
TSP
Thirty-two patients (11 male, 21 female) with HAM/TSP were studied. All the patients were re-
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of the Neurological
ported to test positive for HTLV-I antibodies in serum and cerebrospinal fluid by particle agglutination (Fujirebio, Inc., Tokyo, Japan) or enzyme-linked immunosorbent assay (ELISA) (Easai, Inc., Tokyo, Japan) and confirmed by Western blot (Osame et al. 1990). Their ages ranged from 34 to 76 years (average 59.3 years). The onset of illness ranged from 6 to 73 years (average 51.4 years). They had a clinical picture characterized by spastic paraparesis with hyperreflexia, Babinski sign and mild sensory and sphincteric disturbances. Seven of them had an exaggerated jaw jerk reflex. No patient had clinical involvement of the facial nerve. Twenty three patients underwent brain MRI. Motor disability scores were assigned to these patients according the scale of Osame et al. (1989).
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data (Medelec MS20; London, UK). The sweep time was 100 msec with 1024 addresses per channel. In every patient and control subject 5 responses were obtained from each side (Nacimiento et al. 1992). Because changes in amplitudes can appear according to the stimulus strength and methodology differences (Namerow and Etemandi 1970; Rossi et al. 19931, we decided to evaluate the latency only. Latency was measured by inspection of superimposed responses in the optical display using a cursor. Since we did not find significant differences between latencies of the BR regardless of the stimulated side, the shorter latencies of Rl, R2 and R3 elicited directly and consensually were taken into account in this study. For the patients who had Rlk either uni- or bilaterally, the shorter latency of this response was considered.
Control group
Eighteen volunteers (5 men, 13 woman), aged between 39 and 83 years (mean 57.6 years), served as controls. Blink reflex recording
The procedure used by Nacimiento et al. (1992) was adopted. Briefly, the BR was performed in a quiet room where the temperature was maintained at 2226°C. Patients and subjects were seated on an examination chair and instructed to close their eyes gently. Noise, distraction or any event of surprise that might modify blink reflexes were avoided (Willer et al. 1984; Rossi and Vignocchi 1993; Leon-S. et al. 1994b); and all of them were asked to relax as much as possible. Those who used to smoke were instructed to avoid it at least 60 min or more before examination, because it can affect latency values (Evinger et al. 1988). Five of the patients who displayed a crossed Rl response (Rlk) were randomly chosen and BR were additionally recorded with open eyes (Leon-S. et al. 1994b). This was done to determine the influence of voluntary effort on this response (Willer et al. 1984; Soliven et al. 1988; Nacimiento et al. 1992). BR was obtained by electrical stimulation of both right and left supraorbital nerves, with the cathode positioned near the supraorbital foramen and the anode 3 cm above it and at least 2.5 cm away from the midline. Square-wave negative single pulses of 0.2 msec duration were delivered. To prevent habituation in one or all of the three responses of the BR, stimuli were delivered randomly at intervals of 45-60 set (Rossi et al. 1989a). The reflex activities were recorded from both orbicularis oculi muscles (pars inferior) by means of surface electrodes placed on the degreased skin of the lower lid near the outer canthus and the reference electrode on the temple. The ground electrode was placed under the chin (Kimura 1989). The EMG signals were fed into amplifiers (bandwidth 20-2000 Hz) and stored on floppy discs for on-line and subsequent analysis and quantification of
Electroneurography
Direct muscle action potentials (D) of the orbicularis oculi muscles were obtained as described by Nacimiento et al. (1992). The latency ratios of Rl to the D response (R/D ratio) was also measured (Kimura 1982). Clinical correlations
Correlations were assessed between* results of BR and age at onset, duration of illness, age at the time of examination, HTLV-I antibody titers in both serum and cerebrospinal fluid, disability score and jaw jerk reflex. Statistical analysis
The Mann-Whitney U-test for between-group comparison of different variables, and chi-square analysis for between-group comparisons of the frequencies of different nominally scaled variables were used. Differences were considered significant at a p value < 0.05. 3. Results Control group
Electrical stimulation of both supraorbital nerves elicited an Rl (ipsilateral) and an R2 response which was elicited ipsilaterally and contralaterally disregarding the stimulated side. R3 was also obtained directly and consensually in all but one subject (an 83-year-old female) with maximal intensity stimulation. Two women (47 and 52 years old) showed the Rlk response. Patients with HAM/
TSP
The BR of all these 32 patients showed Rl, R2 and R3 responses with the following characteristics. Features of the RI response
Ipsilateral Rl responses were recorded on both sides in all but one patient who presented unilateral absence
F. E. Leon-S. Table 1 Latency values
Rl R2 R3 Direct R/D
(mean
f SD) in patients
et al. /Journal
the Neurological
and controls
Patients (n = 32)
Controls (n = 18)
Comparison P
10.9+ 30.6 f 74.9 + 3.3 f 3.3 +
11.1 kO.6 32.5 f 2.0 76.0 + 5.21 a 3.lkO.2 3.5 f 0.3
N.S. N.S. N.S. N.S. N.S.
1.1 3.0 5.7 0.3 0.4
of
a 17 subjects. N.S.: not significant.
Table 2 Latency values without (group parentheses)
Rl Rlk R2 R3
of Rl with no other abnormal feature. The mean latencies of Rl in the patients group did not differ significantly from controls (Table 1). The most remarkable finding was the Rlk response registered in 22 patients (69%) with HAM/TSP (9 men, 13 women; ages 34-76 years, average 58.2 years). This Rlk response was absent in the remaining ten patients (2 men, 8 women), aged 35-66 years (average 60.3 years) (Fig. 1). The frequency of this Rlk in HAM/TSP patients was higher compared with controls (11%) (p < 0.001). The mean latency of Rl obtained in patients with Rlk was significantly reduced as compared to controls (p < 0.025) and to patients lacking RlK (p < 0.005; Table 2, Fig. 2). Among the 22 patients with Rlk, it was elicited unilaterally in 9 patients (40%) and bilaterally in 13 patients (60%) with HAM/TSP. Rlk latency was delayed up to 5.5 msec and significantly prolonged with relation to the mean of Rl latency obtained in the same group of patients (p < 0.005). However, Rlk was always clearly different from R2 evoked by the same electrical stimulus (Leon-S. et al. 1994b). The patients who were evaluated with eyes open and closed presented Rlk on both occasions. The results obtained in these patients evaluated with eyes open are presented elsewhere (Leon-S. et al. 1994b).
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N.D.:
53
of Rl, Rlk, R2 and R3 of patients with (group I) and II) the crossed Rl response (mean+ SD; range in
Group I (n = 22)
Group II (n = 10)
Comparison P
10.5 * 0.9 (9.1-12.4) 11.8+ 1.8 (9.5-15.8) 29.4 f 2.1 (26.1-34) 74.8 f 5.7 (65-90.7)
11.8kO.S (10.4-12.9) N.D.
< 0.005
33.2+ 1.7 (30.9-36.8) 75.5 f 5.9 (68.4-85.5)
< 0.0015 N.S.
not detected.
Features of the R2 response R2 responses were bilaterally obtained in all patients. The mean latency of R2 response of HAM/TSP patients was not significantly different from controls. However, the mean latencies of R2 in patients with Rlk were significantly reduced compared to controls (p < 0.0025) and also to patients without Rlk (p < 0.0015). Two female patients (66 and 71 years old), one with and one without Rlk, showed a bilateral R2 response clearly distinguishable in two components. These components had a mean latency of 31.6 msec and 53.1 msec in the first patient and 34.5 msec and 60.6 msec in the other one. Features of the R3 response R3 responses were sometimes absent either ipsi- or contralaterally to the stimulation side, but were never absent bilaterally in these patients (unpublished data). Thus, the frequency of R3 in the patient group was not significantly reduced as compared to the control group. Neither the total group of HAM/TSP patients nor those with or without Rlk showed any significant difference in the mean latency of the R3 response compared with controls (Tables 1 and 2, Fig. 2).
Fig. 1. Blink reflexes obtained by electrical stimulation of the left supraorbital branch of the trigeminal nerve in patients with HAM/TSP. Left: 5%year-old male; right: 68-year-old female. Thick arrow shows the crossed Rl response, the thin arrows the R3 response. Asterisk, stimulation side. Calibration, 10 msec. Five superimposed traces.
54
F.E. Leon-S.
Clinical and radiological
et al/Journal
of the Neurological
correlations
A positive correlation was found between the exaggerated jaw jerk reflex (7 of 32 patients or 22%) and the presence of Rlk (p < 0.05). MRI of the brain showed disseminated lesions in the white matter, mostly around of the lateral ventricles, thalamic and basal ganglia (BG) structures, with occasional signs of cortical atrophy. Lesions in the midbrain were occasionally found but were thought not to be sufficient to explain the electrophysiological findings. 4. Discussion
Previous clinical, radiological, neurophysiological and pathological studies suggested an involvement above the spinal cord in patients with HAM/TSP. Electrically elicited BR proves to be sensitive in assessing pathologic states of the brainstem CBS) and/or its related structures in several diseases of the peripheral and central nervous systems (Kimura 1982, 1989; Bram et al. 1993). This fact led us to closely investigate the involvement of these pathways and the surrounding structures concerned with BR responses. It is known
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that the electrically elicited BR displays two responses (Rl and R2) (Kugelberg 1952; Shahani 1970; Kimura 1973, 1989; Bram et al. 1993) and a third response (R3) can also be obtained if appropriate conditions are taken into account (Penders and Delwaide 1973; Rossi et al. 1985; Rossi and Vignocchi 1993; Leon-S. et al. 1994b). Interestingly, Rlk was noted in 69% of our group of patients. This finding has not been described in the literature in patients with HAM/TSP. The fact that Rlk could be obtained with either eyes opened or closed eyes suggested that mechanisms other than voluntary contraction could be the origin of this response (Willer et al. 1984). Elicited Rl is considered an intrapontine oligosynaptic reflex produced through a short chain of interneurons (Trontelj and Trontelj 1973, 19781, that appears ipsilateral to the side of stimulation (Shahani 1970; Kimura 1975, 1989; Bram et al. 1993). Rlk can be obtained either by mechanical or electrical stimulation and is present from the neonatal period (Trontelj and Trontelj 1978; Bynke 1980; Cscecsei 1982; Willer et al. 1984; Soliven et al. 1988; Escudero et al. 1992; Nacimiento et al. 1992). Although present during normal development, it may be masked and undetectable
msec. ‘00
1
.
!
. . .
. . . . . . . . . . . . . . . .A. I.1 .*. ...
!
.
.
.f . A ...-~*.........;i-..--. A-‘I’ .
. Fig. 2. Distribution
of latency
.......
Patlent value mean Of pamlts mean of controls
values
obtained
from
value
patients
with (+)
and without
(-)
the crossed
Rl response.
F.E. Leon-S.
et al. /Journal
of the Neurological
in the majority of normal populations under usual recording conditions. Rlk has been described in patients with hemifacial spasm, Parkinson’s disease, blepharospasm, oromandibular dystonia, facial nerve palsy and postfacial palsy contracture among others (Penders and Delwaide 1973; Bratzlavsky and vander Eecken 1977; Smorto and Basmajian 1977; Trontelj and Trontelj 1978; Bynke 1980; Cscecsei 1982; Willer et al. 1984; Sunohara et al. 1985; Berardelli et al. 1985; Soliven et al. 1988; Escudero et al. 1992; Nacimiento et al. 1992). Both peripheral and central processes in Rlk have been considered regarding its pathology. Bratzlavsky and vander Eecken (1977) suggested that in addition to peripheral causes, an enhanced excitability of the facial motor neurons after facial nerve palsy could contribute to Rlk. It has recently been reported that patients with symptomatic and idiopathic facial palsy also displayed Rlk and it was thought that the response could probably be mediated by the ‘synaptic stripping’ phenomenon, with displacement of inhibitory synapses from facial motoneurons, unmasking the preexistent crossed trigeminal-facial anatomic pathways (Cscecsei 1982; Nacimiento et al. 1992). The fact that Rlk occurred in these HAM/TSP patients without abnormalities that pointed any peripheral lesion on the trigeminal-facial pathway (e.g., prolongation of Rl latency, abnormal R/D ratio, etc.) suggested that central, rather than peripheral lesions were responsible for these BR findings. Such lesions led to the lack of some inhibitory input at the interneuronal level that resulted in facial nucleus hyperexcitability and unmasked the preexistent crossed trigeminal-facial pathways commented elsewhere (Bratzlavsky and van Eecken 1977; Bynke 1980; Cscecsei 1982). The significantly reduced Rl latency in those patients with Rlk compared with those ones who did not display such response on the one hand; and the positive correlation between the presence of Rlk and the exaggerated jaw jerk reflex on the other hand support this contention. Perhaps, unilateral lesions affecting the inhibitory pathways in these patients could lead them to display Rlk either uni-or bilaterally as commented (Bynke 1980; Leon-S et al. 1994b). R2 is a cutaneous polysynaptic reflex (Cruccu et al. 1991) that follows the descending spinal tracts and nuclei and their projections to the adjacent reticular formation (Kimura 1989; Kiers and Carol1 1990). R2 of the BR share the same motor neurons as Rl (Cruccu et al. 1991; Bram et al. 1993). The most remarkable finding of the R2 response in HAM/TSP was its shortened latency in patients with Rlk. Although conclusions based on reflex latencies cannot be exact (Wechsler et al. 1986), Kimura (1973, 1975, 1982, 1989) indicated that a shortened latency of the R2 response may be a sign of interneuronal hyperexcitability and added that in advanced Parkinson’s disease, such hyperexcitability affected the excitability cycle of R2. The
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55
enhanced recovery cycle of the R2 response has also been found in patients with chronic spino-bulbar spasticity pointing to a reduction in the presynaptic inhibition (Rossi and Scarpini 1993). The diminished presynaptic inhibition acting on the interneuronal network (the likely mechanism for the presence of Rlk), may also account for the significantly shortened R2 latency in HAM/TSP. However, further studies to elucidate the relationship between Rlk and R2 in pathological conditions will be necessary (Soliven et al. 1988; Nacimiento et al. 1992). Notably, two cases, one with and the other without Rlk, presented with R2 response that had two components. This finding has been reported in cases involving post-hypoxic intention myoclonus (Young and Shahani 19791, nocturnal myoclonus (Wechsler et al. 1986) and periodic ataxia (Yokota et al. 1990). The mechanism of this phenomenon is yet unclear. R3 is considered a bilateral and consensual polysynaptic response of the BR that normally is present from the neonatal period. However, its central pathways are still unknown (Rossi et al. 1985, 1989a,b; Cruccu et al. 1991; Escudero et al. 1992; Leon-S. et al. 1994b). Since R3 was displayed regardless of the presence Rlk response (Fig. 11, it could be supportive of our suggestion that the regulatory mechanisms between Rl and R3, recently described (Rossi and Vignocchi 19931, may also be altered in these patients (Leon-S. et al. 1994b). In this study, we found electrophysiologically a noteworthy subclinical supraspinal involvement of the CNS in HAM/TSP patients by means of the BR. And BR resulted to be more sensitive in demonstrating such involvement than we had previously found in these patients (Arimura et al. 1987, 1989). Furthermore, we would like to suggest that not only the analysis of the common BR parameters (i.e. latencies, amplitudes, recovery cycles) are important but also the presence of uncommon responses like the Rlk deserves attention, if obtained under stringent methodological considerations.
Acknowledgments The authors would like to thank Amparo Ariza-Deleon, Ph.L., Raymond Rosales, M.D. and Fujio Umehara, M.D., for reviewing the English and for helpful comments. Also, special thanks are given to the Library workers at Kagoshima University School of Medicine for their kind help during the elaboration of this manuscript. We also thank the subjects who participated in the experiment without remuneration for being so cooperative. This work shall be submitted as part of the dissertation for the Ph.D. degree in Clinical
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Neurology and Neurophysiology by Fidias E. Leon-S., M.D to the Faculty of Medicine, University of Kagoshima, Japan.
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