ORIGINAL RESEARCH
Blink Reflex Studies in Postparalytic Facial Syndrome and Blepharospasm: Trigeminal and Extratrigeminal Somatosensory Stimulation Gulcin Benbir and Meral E. Kiziltan
Purpose: The somatosensory-evoked blink reflex (SBR) is one of the release phenomena of blink reflex, possibly resulting from increased excitability of brainstem reticular formation. Methods: The authors investigated trigeminal blink responses and SBR in 26 patients with postparalytic facial syndrome (PFS) with synkinesia, 18 patients with essential blepharospasm, and 36 healthy volunteers (control participants). Results: Trigeminal blink reflex responses were elicited in all participants, whereas SBRs were elicited in 44.4% of control participants, 38.9% of patients with essential blepharospasm, and 65.4% of patients with PFS. The mean R2 amplitude and duration and the mean amplitude and duration of SBR were highest in patients with essential blepharospasm. The mean latency of SBR was shorter on the symptomatic side of patients with PFS when compared with the asymptomatic side. The mean R2 duration on the symptomatic side of the patients with PFS was longer than the control participants. Conclusions: These results showed that somatosensory stimulation could be used as an alternative method to demonstrate increased excitability in facial motor neuron in patients with PFS and essential blepharospasm. Disease states relating to different peripheral and/or suprasegmental structures could also influence blink reflex and change its basal excitability and manner in which the reflex responds to modulatory factors. Key Words: Blink reflex, Trigeminal stimulation, Somatosensory stimulation, Postparalytic facial syndrome, Essential blepharospasm. (J Clin Neurophysiol 2014;31: 535–540)
S
omatosensory-evoked blink reflex (SBR) is elicited by electrical stimulation of a peripheral nerve or the skin of the body or limbs. It was suggested that SBR is one of the released phenomena of the basically programmed blink reflexes for protecting eyes, and that it possibly appears because of increased excitability of the brainstem reticular formation (Miwa et al., 1995, 1996). Because of the fact that the latency and duration of the SBR are shorter and do not occur together with generalized startled jerks of the body/limbs, Miwa et al. suggested that it is not a variant of the startled blink reflex (Miwa et al., 1995, 1996). However, a recent study on single stimulus applied unexpectedly at different nerves randomly with a higher stimulus intensity (Álvarez-Blanco et al., 2009) showed that startled response of orbicularis oculi muscle to somatosensory stimuli, similar to auditory-evoked blink reflex (ABR), might have different characteristics from the response originated.
From the Department of Neurology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey. Address correspondence and reprint requests to Gulcin Benbir, MD, Department of Neurology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul 34098, Turkey; e-mail: [email protected]. Copyright Ó 2014 by the American Clinical Neurophysiology Society
ISSN: 0736-0258/14/3106-0535
Somatosensory-evoked blink reflex is seen most often in patients with postfacial synkynesia and hemifacial spasm, but less seen in patients with different types of dystonia (Erkol et al., 2009; Miwa et al., 1996). The electrophysiological mechanisms of SBR and its relevance in neurological disorders are not completely understood. It was suggested that the asymmetric appearance of SBR in patients with hemifacial spasm was due to increased excitabilities within or near the facial nerve nucleus (Miwa et al., 1996). Somatosensory-evoked blink reflex was not easily elicitable in patients with dystonia and spasmodic torticollis and essential blepharospasm (EB); although dishabituation of blink reflex recovery cycle was demonstrated (Carella et al., 1994; Miwa et al., 1996; Pauletti et al., 1993). The relevance of this difference, however, remains unknown. The pathways of trigeminal blink reflex (TBR) are mediated by trigeminal nerve afferents to the pontomedullary reticular formation (Aramideh et al., 2002, 2003; Ongerboer de Visser and Kuypers, 1978). However, the pathways of SBR are not known; they are hypothesized to be mediated by afferents from the limbs entering the brainstem by means of the medial lemniscus or the spinothalamic tract (Leon et al., 2011). Because the afferent arms of TBR and SBR are different, the integration of the sensory inputs could also be different in clinical conditions. This was recently shown by Leon et al. (2011) who demonstrated the absence of SBR with the preservation of TBR in upper brainstem lesions and the opposite pattern of preservation of the SBR with abnormal TBR in lower brainstem lesions. This striking difference shows the clinical utility of SBR in the neurophysiological assessment of clinical conditions with changes in excitabilities of interneurons in brainstem, such as dystonia (Erdemir-Kiziltan et al., 2005; Esteban, 1999) and hemifacial spasm (Chuke et al., 1996; Evinger et al., 2002) and peripheral facial palsy (Erkol et al., 2009). The aim of this study is to investigate the trigeminal and somatosensory blink reflex pathways in disorders known to cause enhancement of excitability in brainstem circuits such as postparalytic facial syndrome (PFS) and EB.
METHODS Twenty-six patients with PFS caused by synkinesia, 18 patients with EB, and 36 healthy volunteers (control group) were examined. Patients admitted in our electromyography laboratory were consecutively involved in the study. Postparalytic facial syndrome is defined as synkinetic activity between hemifacial muscles triggered by movement, muscle spasms, myokymic discharges, or activation of facial muscles together with voluntary and/or automatic activation of facial and/or nonfacial muscles (Valls-Sole and Montero, 2003; Valls-Sole et al., 1992). The severity of PFS may range from subclinical electrophysiological findings to complex disturbances of voluntary and automatic
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activation of facial muscles. Essential blepharospasm is typically diagnosed as focal-sustained dystonia characterized by involuntary blinking and closure of the eyelids because of spasms of the orbicularis oculi muscles (Fahn, 1988). None of the patients had primary hemifacial spasm or history of any other movement disorders or extrapyramidal diseases; and neurological examinations were otherwise normal. Also, none of the patients have had treatment on botulinum toxin. The grade of facial paralysis was lower than three according to House–Brackmann grading (House and Brackmann, 1985). The control subjects consisted of healthy medical personnel, whose age and gender matched with that of the mean of the patients. None of them had any history of movement disorders or extrapyramidal diseases. All patients and participants signed a consent form, and the study was approved by the Ethical Committee of our institution. An eight-channel electromyography apparatus (NihondKohden) was used for blink reflex studies, which was calibrated every time before data collection. The electrophysiological measurements were assessed with the patients relaxed in a sitting position in a quiet semidarkened room at ambient temperature. The principal investigator (M.E.K.) explained all procedures to the participants before testing. We used pregelled Ag/AgCl surface recording electrodes, and the skin was cleaned by wiping with 95% ethanol to aid electrode adhesion and increase conductivity before electrode application. Electrically stimulated TBR and extratrigeminal SBR’s were studied bilaterally. A pair of surface recording electrodes was placed over the orbicularis oculi muscles on both sides of the lower eyelid, and a pair of stimulating electrodes was attached to the supraorbital nerve, with the cathode at the supraorbital notch and the anode 3 cm away. The participants were asked to keep their eyes slightly closed and fixed in neutral position. Each participant received the same amount and type of stimuli. Each stimulus was given three times consecutively, and the mean values for each variable were calculated. The SBR responses were elicited by the electrical stimulation of median nerve at wrist to obtain M response using supramaximal stimulation. The electrical stimulation was applied as single pulses of 0.2 milliseconds duration through bipolar electrodes at various intensities with an interval of 10 to 15 seconds. We concluded that no response was detected when consecutive four stimuli were used to evoke an M response from the median nerve, which therefore failed to elicit the SBR. In case 1 of the 4 stimuli triggered a motor unit potential, the SBR response was accepted as being “present,” and hence incorporated into the statistical analysis. Filter setting was 3 kHz high cut and 20 Hz low cut. The analysis time was 200 milliseconds with a sensitivity of 0.2 mV and a sweep speed of 20 ms/s. Bilateral R1 and R2 latencies (in milliseconds) elicited by electrical stimulation of ipsilateral supraorbital nerve, R2c latency elicited by electrical stimulation of contralateral supraorbital nerve, R2 amplitude (in microvolts), R2 duration, and the mean R2c/R2 ratio were analyzed on electrically evoked TBR. The analysis of SBR consisted of the frequency of excitability in addition to the latency, amplitude, and duration of the responses. The demographic data and electrophysiological measures obtained by trigeminal and somatosensory stimulation were compared using Pearson x2 test, unpaired t-test, and Kruskal Wallis test. The correlations between demographical and electrophysiological data were explored using Pearson and linear correlation analysis. The mean R2c/R2 ratio values for control subjects and patients were also compared using the unpaired t-test. For statistical analysis, the mean values got from both right and left sides were used in control group and EB patients, whereas the responses obtained from both symptomatic and asymptomatic sides were used for patients with PFS. One-way analysis of variance (with Tukey post-hoc multiple 536
analysis in case of significance) together with Bonferroni correction test and Waller–Duncan analysis was performed to avoid type I/type II error. The threshold level for statistical significance was established at P # 0.05. All values were reported as mean and 95% confidence intervals or percentiles.
RESULTS Patients’ gender was not significantly different between groups, although men were in majority in patients with EB compared with control and patients with PFS (P ¼ 0.056; Table 1). Patients with EB were the oldest group (which was not significant; P ¼ 0.417) among the study population (Table 1). Trigeminal blink reflex responses were elicited in all participants, whereas SBR responses were elicited in 44.4% of healthy subjects, 38.9% of patients with EB, and 65.4% of patients with PFS. The highest SBR frequency was observed in patients with PFS, although not significantly higher than that of controls (P ¼ 0.253). The lowest frequency of SBR was in patients with EB, which was also not significant compared with that of controls (P ¼ 0.440). However, the attainability of SBR was significantly higher in patients with PFS than in patients with EB (P ¼ 0.007). Examples of original recordings of TBR and SBR responses obtained from healthy subjects and patients are illustrated in Figs. 1A–1F. The TBR and SBR parameters are given in Table 2. The mean latencies of R1, R2, and R2c of TBR were the shortest in patients with EB, followed by the control group, whereas patients with PFS had the longest mean latencies on symptomatic side. These differences, however, were not up to the statistical significance. The mean R2 amplitude and duration values were the highest in patients with EB, which is significantly higher than that of the control group (P ¼ 0.003 and P ¼ 0.018, respectively). The mean R2 duration on the symptomatic side of patients with PFS was also significantly longer than that of the control group (P ¼ 0.025) and the mean R2 duration on the asymptomatic side of patients with PFS was not long (Table 2). The mean latency of SBR responses (Rs) was very short on the symptomatic side of patients with PFS and very long in the control group, but not significant (Table 2). The mean Rs latency on the symptomatic side of patients with PFS was significantly shorter compared with that on the asymptomatic side (P ¼ 0.006). The mean Rs amplitude was the smallest in patients with PFS, although not significant, whereas the mean Rs duration was significantly highest in patients with EB (Table 2). We did not observe any significant correlation between demographical and electrophysiological data (Pearson and linear correlation analysis). For each significant comparison with a P value lower than 0.05, we performed one-way analysis of variance (with Tukey post-hoc multiple analysis in case of significance) together
TABLE 1.
Demographic Features of Study Population Gender
Groups
Males, n (%)
Females, n (%)
PFS patients EB patients Control group P
5 (33.3) 8 (66.3) 12 (40) 0.056
10 (66.7) 7 (46.7) 18 (60)
Age, years Mean 6 SD
Min–Max
43.5 6 8.9 49.6 6 11.6 41.6 6 10.8 0.417
30–59 27–66 25–65
EB, essential blepharospasm; PFS, postparalytic facial syndrome.
Copyright Ó 2014 by the American Clinical Neurophysiology Society
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Blink Reflex Studies in PFS and Blepharospasm
FIG. 1. A–F, Trigeminal blink reflex in a healthy subject (A), patients with postparalytic facial syndrome (PFS) (B) and essential blepharospasm (C) and somatosensory blink reflex in a healthy subject (D), patients with PFS (E) and essential blepharospasm (F). The top traces were obtained from the right side and bottom traces from left side. Somatosensory blink reflex obtained in a patient with PFS as shown in (E) is observed asymmetrical because right side (top) being the symptomatic side. Arrows indicate the beginning and end points of motor unit potentials. with Bonferroni correction test and Waller–Duncan analysis to avoid type I/type II error because there were at least eight or more variables analyzed in statistical analysis.
DISCUSSION
One of the main findings of this study is that SBR responses were elicited more significantly in patients with PFS than in patients with EB. Although not significant, the attainability of SBR was higher in patients with PFS, which is similar to our previous findings (Erdemir-Kiziltan et al., 2005; Erkol et al., 2009). The generation of SBR was suggested to result from the combination of excitatory and inhibitory influences of exteroceptive stimuli, relatively independent of brainstem trigeminofacial interneuronal excitability and mediated by neuronal structures with integration capabilities within the brainstem (Leon et al., 2011; Miwa et al., 1998). Although the duration and amplitude of the responses were increased, the attainability of SBR in patients with EB was lower in our study, which was previously shown by Miwa et al. (1996). Other findings in this study are as follows: (1) mean R2 amplitude and duration of TBR were the highest in EB; (2) mean R2 duration on the symptomatic side of PFS was longer than controls; (3) mean Rs latency of SBR was shorter on the symptomatic side of PFS compared with that on the asymptomatic side; and (4) mean Rs amplitude and duration were the highest in EB if positive. The SBR responses resembled the R2 responses elicited by trigeminal stimulation (Miwa et al., 1995). It has been suggested that multiple sensory modalities, such as tactile, auditory and visual sensations may have a common premotor mechanism for the blink reflex (Holstege et al., 1986; Rimpel et al., 1982). Loss of inhibition on brainstem reflex circuits was already shown in patients with EB by TBR studies (Akalin et al., 2013; Tolosa et al., 1988; Valls-Sole et al., 1991). Similarly, enlargement of R2 responses was previously reported in patients with EB and on the symptomatic sides of patients with PFS, which were attributed to Copyright Ó 2014 by the American Clinical Neurophysiology Society
the hyperexcitability of the facial nucleus (Berardelli et al., 1985; Tolosa et al., 1988; Valls-Sole et al., 1992). Alterations in descending projections to inhibitory neurons under indirect modulation of pallidothalamocortical motor circuit were suggested to result in interneuronal excitability in TBR circuits in patients with EB (Vitek, 2002). In this, it was observed that similar changes in R2 and Rs responses could also be elicited by SBR. Although the frequency of SBR positivity is low, the amplitude and duration of the Rs response were enhanced in EB, as in TBR responses. It has been suggested that polysensory inputs enter the brainstem reticular formation and modulate the excitability of the facial nerve nucleus or adjacent structure (Holstege et al., 1995; Rimpel et al., 1982). Generation of SBR was therefore attributed to the sensorimotor gating mechanism responsible for interruption of the excessive inflow of somatosensory stimuli (Miwa et al., 1998). In this context, the appearance of SBR might depend on the level of activity in gating mechanism exerting presynaptic inhibition on the inflow of the somatic input before sensory impulses enter the common blink reflex pathway (Lidsky et al., 1985; Schneider et al., 1985). The increase in SBR positivity in PFS could therefore result from motor hyperexcitability attributed to peripheral enhancement of the blink reflex gain secondary to compensatory mechanisms and reorganization, as observed in circuits of TBR (Cattaneo et al., 2005; Evinger et al., 2002; Manca et al., 2001; Schicatano and Mant, 2002; Valls-Sole and Montero, 2003). Facial nerve injury causes a complex tissue response that affects the microenvironment of the axotomised motor neuron and the affected nerve cell body; it manifests itself as structural, metabolic and molecular alterations of the soma, dendrites of the nerve, and the neighboring glia (Moran and Graeber, 2004). Synaptic associative plasticity using these mechanisms analogous inputs to generate reflex blinks may sometimes produce abnormal reflexes and pathological movements (Dauvergne and Evinger, 2007). In sum, although the effector changes take place in the target motor neurons, anatomic changes secondary to reorganization may play an important role in the gating mechanisms. It seems that the slow attainability of SBR in EB is in conflict with the increased excitability of the electrically stimulated TBR. 537
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TABLE 2.
Trigeminal and Somatosensory Blink Reflex Responses
Electrophysiological Measures
PFS Patients (n ¼ 15) Symptomatic Side
Asymptomatic Side
P*
EB Patients (n ¼ 15)
Control Group (n ¼ 30)
R1 latency (milliseconds)
10.16 6 1.52
10.00 6 1.06
0.648
10.08 6 0.89
10.10 6 0.88
R2 latency (milliseconds)
33.14 6 4.70
31.18 6 4.23
0.214
29.56 6 3.67
31.78 6 3.37
R2c latency (milliseconds)
33.05 6 3.98
31.90 6 5.02
0.533
30.76 6 3.38
32.14 6 4.05
403.80 6 126.57
379.40 6 163.75
0.747
532.50 6 234.45
361.07 6 150.50
R2 duration (milliseconds)
64.80 6 23.61
59.75 6 21.21
0.033
78.06 6 28.5
51.37 6 12.3
SBR response (Rs) latency (milliseconds)
48.31 6 9.50
52.21 6 8.39
0.006
49.90 6 9.5
50.60 6 8.7
205.00 6 113.45
189.47 6 66.94
0.910
283.42 6 150.81
220.52 6 110.06
53.73 6 13.82
50.93 6 14.28
0.377
64.57 6 14.93
58.42 6 35.80
R2 amplitude (mV)
Rs amplitude (mV)
Rs duration (milliseconds)
P 0.908† 0.728‡ 0.772§ 0.672k 0.315† 0.441‡ 0.569§ 0.114k 0.312† 0.635‡ 0.253§ 0.238k 0.035† 0.368‡ 0.924§ 0.003k 0.050† 0.025‡ 0.072§ 0.018k 0.668† 0.628‡ 0.810§ 0.575k 0.050† 0.509‡ 0.484§ 0.265k 0.015† 0.340‡ 0.241§ 0.044k
*P value between symptomatic and asymptomatic sides in PFS patients. †P value between symptomatic side in PFS patients and EB patients. ‡P value between symptomatic side in PFS patients and control group. §P value between asymptomatic side in PFS patients and control group. kP value between EB patients and control group. EB, essential blepharospasm; PFS, postparalytic facial syndrome; SBR, somatosensory-evoked blink reflex.
This suggests that the attainability of SBR could not solely be explained by the increase in excitability. However, the responses were greater in amplitude and duration if SBR could be evoked, which suggests that stimulations of different modalities could trigger an increased excitability at motor neuron level. On this basis, lower attainability of SBR in patients with EB may be caused by an altered sensitivity to selective stimuli. It is known that these patients are extremely sensitive to bright light, or corneal and trigeminal stimulation. It is possible that there may not be an increased sensitivity against somatosensory stimulation but if the stimulus reaches the facial motor or premotor neurons, it would create increased responses in amplitude and duration as observed in our study, which might reflect an enhanced excitability at this level. Similar findings were also shown in patients with progressive supranuclear palsy where SBR responses were absent in the presence of TBR responses with normal latency and amplitudes and enhanced blink reflex excitability recovery curve to paired stimuli (Valls-Sole et al., 1997). The authors proposed that orbicularis oculi response to 538
inputs from peripheral nerves was a form of startled response induced by somatic nerve afferents mediated by brainstem reticular formations, as seen in other startled responses. The underlying pathophysiology differs in patients with progressive supranuclear palsy, where cholinergic neuronal loss is prominent at brainstem level, in addition to involvement of reticular formation. The absence of SBR and auditory startle response was also explained by this primary disturbance. The startled reaction could be induced by auditory, visual or somatosensory stimuli, and the circuit of the startled reaction to somatosensory stimuli may be similar to that of the auditory startle response (Álvarez-Blanco et al., 2009; Yeomans et al., 2002). Muller et al. (2007) showed that auditory startle response increased in masseter, sternocleidomastoid, and biceps muscles, although it was paradoxically decreased in orbicularis oculi muscle. These authors have speculated that this could be a circumferential effect of botulinum toxin injections, although there are contradictory results of botulinum toxin on blink reflex excitability (Valls-Sole et al., 1991). Copyright Ó 2014 by the American Clinical Neurophysiology Society
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Decreased auditory startle response probability may, in part, explain the lower attainability of SBR in EB observed in this study. Nevertheless, this paradoxical finding should cautiously be interpreted because auditory blink reflex was demonstrated in all patients with EB in our previous study, with increased amplitudes and durations. The exact neural pathways subserving the SBR are still not completely understood. The peripheral afferent pathway is probably of cutaneous origin, and the final output should be mediated by facial motor neurons responsible for blinking; but the polysynaptic central pathways are uncertain. As in TBR, which is transmitted through the brainstem reticular formation (Esteban, 1999; Ongerboer de Visser and Kuypers, 1978), it seems likely that the brainstem reticular formation also plays an important role in generating SBR (Miwa et al., 1995). Experimental data have suggested common blink premotor areas, on the pontine and medullary reticular formation, where such multiple sensory modalities might converge (Holstege et al., 1986; Rimpel et al., 1982). Leon et al. (2011) showed the absence of the SBR with preservation of the TBR in patients with upper brainstem lesions whereas patients with Wallenberg syndrome exhibited an opposite pattern of preservation of the SBR with abnormal TBR responses. Furthermore, abnormal responses were obtained from stimulation of both sides of patients with unilateral lesions, suggesting a larger dysfunctional area. It was therefore speculated that the SBR may result from the combination of excitatory and inhibitory influences of exteroceptive stimuli mediated by neuronal structures with integration capabilities within the brainstem, and that it is relatively independent of brainstem trigeminofacial interneuronal excitability (Khoshbin and Hallett, 1981; Leon et al., 2011). Because stimuli at different sites generated different results, a lesion involving the afferent arc of SBR was suggested to be responsible. The upper brainstem, at a site close to the nuclei that control vertical gaze, possibly in the mesencephalic reticular formation was speculated to be the site of integration of the SBR in contrast to the bulbopontine reticular formation in TBR. Indeed, this anatomical difference might also explain the lower attainability of SBR in EB, which seems conflicted compared with the increased excitability of the electrically stimulated TBR. It was proposed in many studies that a hyperexcitable blink reflex in patients with EB secondary to an alteration in the trigeminal sensory motor system implies a wider involvement than brainstem, which implies likely rostral structures with an underlying, acquired or genetical, permissive environment characterized by basal ganglia dysfunction (Berardelli et al., 1985; Elston et al., 1988; Gomez-Wong et al., 1998; Granadas et al., 1988; Jankovic, 1988; Valls-Sole and Montero, 2003). The influence of basal ganglia is not directly on pontine-medullary interneurons subserving blink reflex circuits, but indirectly through descending cortical or superior colliculus projections modulating the blink reflex, which was demonstrated in precollicularly decerebrated rats (Hinrichsen and Watson, 1983). This might be one possible explanation for the differences in SBR patterns in patients with EB, although once stimulated, the amplitudes and durations of responses also increase. Besides the brainstem reticular formation, facial motor neurons also receive excitatory synaptic inputs from various premotor structures including the motor cortex, superior colliculus, and nucleus of the spinal trigeminal tract (Hinrichsen and Watson, 1983; Li et al., 1993; Rekling et al., 2000). The states of disease, in relation to many suprasegmental structures could influence the blink reflex, change its basal excitability and the manner in which it responds to the modulatory factors. In summary, we suggest that the increased SBR in patients with PFS are related with local changes, such as reorganization. In patients with EB, however, the decreased frequency of SBR may Copyright Ó 2014 by the American Clinical Neurophysiology Society
Blink Reflex Studies in PFS and Blepharospasm
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Copyright Ó 2014 by the American Clinical Neurophysiology Society
Blink Reflex Studies in Postparalytic Facial Syndrome and Blepharospasm: Trigeminal and Extratrigeminal Somatosensory Stimulation Gulcin Benbir and Meral E. Kiziltan
Purpose: The somatosensory-evoked blink reflex (SBR) is one of the release phenomena of blink reflex, possibly resulting from increased excitability of brainstem reticular formation. Methods: The authors investigated trigeminal blink responses and SBR in 26 patients with postparalytic facial syndrome (PFS) with synkinesia, 18 patients with essential blepharospasm, and 36 healthy volunteers (control participants). Results: Trigeminal blink reflex responses were elicited in all participants, whereas SBRs were elicited in 44.4% of control participants, 38.9% of patients with essential blepharospasm, and 65.4% of patients with PFS. The mean R2 amplitude and duration and the mean amplitude and duration of SBR were highest in patients with essential blepharospasm. The mean latency of SBR was shorter on the symptomatic side of patients with PFS when compared with the asymptomatic side. The mean R2 duration on the symptomatic side of the patients with PFS was longer than the control participants. Conclusions: These results showed that somatosensory stimulation could be used as an alternative method to demonstrate increased excitability in facial motor neuron in patients with PFS and essential blepharospasm. Disease states relating to different peripheral and/or suprasegmental structures could also influence blink reflex and change its basal excitability and manner in which the reflex responds to modulatory factors. Key Words: Blink reflex, Trigeminal stimulation, Somatosensory stimulation, Postparalytic facial syndrome, Essential blepharospasm. (J Clin Neurophysiol 2014;31: 535–540)
S
omatosensory-evoked blink reflex (SBR) is elicited by electrical stimulation of a peripheral nerve or the skin of the body or limbs. It was suggested that SBR is one of the released phenomena of the basically programmed blink reflexes for protecting eyes, and that it possibly appears because of increased excitability of the brainstem reticular formation (Miwa et al., 1995, 1996). Because of the fact that the latency and duration of the SBR are shorter and do not occur together with generalized startled jerks of the body/limbs, Miwa et al. suggested that it is not a variant of the startled blink reflex (Miwa et al., 1995, 1996). However, a recent study on single stimulus applied unexpectedly at different nerves randomly with a higher stimulus intensity (Álvarez-Blanco et al., 2009) showed that startled response of orbicularis oculi muscle to somatosensory stimuli, similar to auditory-evoked blink reflex (ABR), might have different characteristics from the response originated.
From the Department of Neurology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey. Address correspondence and reprint requests to Gulcin Benbir, MD, Department of Neurology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul 34098, Turkey; e-mail: [email protected]. Copyright Ó 2014 by the American Clinical Neurophysiology Society
ISSN: 0736-0258/14/3106-0535
Somatosensory-evoked blink reflex is seen most often in patients with postfacial synkynesia and hemifacial spasm, but less seen in patients with different types of dystonia (Erkol et al., 2009; Miwa et al., 1996). The electrophysiological mechanisms of SBR and its relevance in neurological disorders are not completely understood. It was suggested that the asymmetric appearance of SBR in patients with hemifacial spasm was due to increased excitabilities within or near the facial nerve nucleus (Miwa et al., 1996). Somatosensory-evoked blink reflex was not easily elicitable in patients with dystonia and spasmodic torticollis and essential blepharospasm (EB); although dishabituation of blink reflex recovery cycle was demonstrated (Carella et al., 1994; Miwa et al., 1996; Pauletti et al., 1993). The relevance of this difference, however, remains unknown. The pathways of trigeminal blink reflex (TBR) are mediated by trigeminal nerve afferents to the pontomedullary reticular formation (Aramideh et al., 2002, 2003; Ongerboer de Visser and Kuypers, 1978). However, the pathways of SBR are not known; they are hypothesized to be mediated by afferents from the limbs entering the brainstem by means of the medial lemniscus or the spinothalamic tract (Leon et al., 2011). Because the afferent arms of TBR and SBR are different, the integration of the sensory inputs could also be different in clinical conditions. This was recently shown by Leon et al. (2011) who demonstrated the absence of SBR with the preservation of TBR in upper brainstem lesions and the opposite pattern of preservation of the SBR with abnormal TBR in lower brainstem lesions. This striking difference shows the clinical utility of SBR in the neurophysiological assessment of clinical conditions with changes in excitabilities of interneurons in brainstem, such as dystonia (Erdemir-Kiziltan et al., 2005; Esteban, 1999) and hemifacial spasm (Chuke et al., 1996; Evinger et al., 2002) and peripheral facial palsy (Erkol et al., 2009). The aim of this study is to investigate the trigeminal and somatosensory blink reflex pathways in disorders known to cause enhancement of excitability in brainstem circuits such as postparalytic facial syndrome (PFS) and EB.
METHODS Twenty-six patients with PFS caused by synkinesia, 18 patients with EB, and 36 healthy volunteers (control group) were examined. Patients admitted in our electromyography laboratory were consecutively involved in the study. Postparalytic facial syndrome is defined as synkinetic activity between hemifacial muscles triggered by movement, muscle spasms, myokymic discharges, or activation of facial muscles together with voluntary and/or automatic activation of facial and/or nonfacial muscles (Valls-Sole and Montero, 2003; Valls-Sole et al., 1992). The severity of PFS may range from subclinical electrophysiological findings to complex disturbances of voluntary and automatic
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activation of facial muscles. Essential blepharospasm is typically diagnosed as focal-sustained dystonia characterized by involuntary blinking and closure of the eyelids because of spasms of the orbicularis oculi muscles (Fahn, 1988). None of the patients had primary hemifacial spasm or history of any other movement disorders or extrapyramidal diseases; and neurological examinations were otherwise normal. Also, none of the patients have had treatment on botulinum toxin. The grade of facial paralysis was lower than three according to House–Brackmann grading (House and Brackmann, 1985). The control subjects consisted of healthy medical personnel, whose age and gender matched with that of the mean of the patients. None of them had any history of movement disorders or extrapyramidal diseases. All patients and participants signed a consent form, and the study was approved by the Ethical Committee of our institution. An eight-channel electromyography apparatus (NihondKohden) was used for blink reflex studies, which was calibrated every time before data collection. The electrophysiological measurements were assessed with the patients relaxed in a sitting position in a quiet semidarkened room at ambient temperature. The principal investigator (M.E.K.) explained all procedures to the participants before testing. We used pregelled Ag/AgCl surface recording electrodes, and the skin was cleaned by wiping with 95% ethanol to aid electrode adhesion and increase conductivity before electrode application. Electrically stimulated TBR and extratrigeminal SBR’s were studied bilaterally. A pair of surface recording electrodes was placed over the orbicularis oculi muscles on both sides of the lower eyelid, and a pair of stimulating electrodes was attached to the supraorbital nerve, with the cathode at the supraorbital notch and the anode 3 cm away. The participants were asked to keep their eyes slightly closed and fixed in neutral position. Each participant received the same amount and type of stimuli. Each stimulus was given three times consecutively, and the mean values for each variable were calculated. The SBR responses were elicited by the electrical stimulation of median nerve at wrist to obtain M response using supramaximal stimulation. The electrical stimulation was applied as single pulses of 0.2 milliseconds duration through bipolar electrodes at various intensities with an interval of 10 to 15 seconds. We concluded that no response was detected when consecutive four stimuli were used to evoke an M response from the median nerve, which therefore failed to elicit the SBR. In case 1 of the 4 stimuli triggered a motor unit potential, the SBR response was accepted as being “present,” and hence incorporated into the statistical analysis. Filter setting was 3 kHz high cut and 20 Hz low cut. The analysis time was 200 milliseconds with a sensitivity of 0.2 mV and a sweep speed of 20 ms/s. Bilateral R1 and R2 latencies (in milliseconds) elicited by electrical stimulation of ipsilateral supraorbital nerve, R2c latency elicited by electrical stimulation of contralateral supraorbital nerve, R2 amplitude (in microvolts), R2 duration, and the mean R2c/R2 ratio were analyzed on electrically evoked TBR. The analysis of SBR consisted of the frequency of excitability in addition to the latency, amplitude, and duration of the responses. The demographic data and electrophysiological measures obtained by trigeminal and somatosensory stimulation were compared using Pearson x2 test, unpaired t-test, and Kruskal Wallis test. The correlations between demographical and electrophysiological data were explored using Pearson and linear correlation analysis. The mean R2c/R2 ratio values for control subjects and patients were also compared using the unpaired t-test. For statistical analysis, the mean values got from both right and left sides were used in control group and EB patients, whereas the responses obtained from both symptomatic and asymptomatic sides were used for patients with PFS. One-way analysis of variance (with Tukey post-hoc multiple 536
analysis in case of significance) together with Bonferroni correction test and Waller–Duncan analysis was performed to avoid type I/type II error. The threshold level for statistical significance was established at P # 0.05. All values were reported as mean and 95% confidence intervals or percentiles.
RESULTS Patients’ gender was not significantly different between groups, although men were in majority in patients with EB compared with control and patients with PFS (P ¼ 0.056; Table 1). Patients with EB were the oldest group (which was not significant; P ¼ 0.417) among the study population (Table 1). Trigeminal blink reflex responses were elicited in all participants, whereas SBR responses were elicited in 44.4% of healthy subjects, 38.9% of patients with EB, and 65.4% of patients with PFS. The highest SBR frequency was observed in patients with PFS, although not significantly higher than that of controls (P ¼ 0.253). The lowest frequency of SBR was in patients with EB, which was also not significant compared with that of controls (P ¼ 0.440). However, the attainability of SBR was significantly higher in patients with PFS than in patients with EB (P ¼ 0.007). Examples of original recordings of TBR and SBR responses obtained from healthy subjects and patients are illustrated in Figs. 1A–1F. The TBR and SBR parameters are given in Table 2. The mean latencies of R1, R2, and R2c of TBR were the shortest in patients with EB, followed by the control group, whereas patients with PFS had the longest mean latencies on symptomatic side. These differences, however, were not up to the statistical significance. The mean R2 amplitude and duration values were the highest in patients with EB, which is significantly higher than that of the control group (P ¼ 0.003 and P ¼ 0.018, respectively). The mean R2 duration on the symptomatic side of patients with PFS was also significantly longer than that of the control group (P ¼ 0.025) and the mean R2 duration on the asymptomatic side of patients with PFS was not long (Table 2). The mean latency of SBR responses (Rs) was very short on the symptomatic side of patients with PFS and very long in the control group, but not significant (Table 2). The mean Rs latency on the symptomatic side of patients with PFS was significantly shorter compared with that on the asymptomatic side (P ¼ 0.006). The mean Rs amplitude was the smallest in patients with PFS, although not significant, whereas the mean Rs duration was significantly highest in patients with EB (Table 2). We did not observe any significant correlation between demographical and electrophysiological data (Pearson and linear correlation analysis). For each significant comparison with a P value lower than 0.05, we performed one-way analysis of variance (with Tukey post-hoc multiple analysis in case of significance) together
TABLE 1.
Demographic Features of Study Population Gender
Groups
Males, n (%)
Females, n (%)
PFS patients EB patients Control group P
5 (33.3) 8 (66.3) 12 (40) 0.056
10 (66.7) 7 (46.7) 18 (60)
Age, years Mean 6 SD
Min–Max
43.5 6 8.9 49.6 6 11.6 41.6 6 10.8 0.417
30–59 27–66 25–65
EB, essential blepharospasm; PFS, postparalytic facial syndrome.
Copyright Ó 2014 by the American Clinical Neurophysiology Society
Journal of Clinical Neurophysiology Volume 31, Number 6, December 2014
Blink Reflex Studies in PFS and Blepharospasm
FIG. 1. A–F, Trigeminal blink reflex in a healthy subject (A), patients with postparalytic facial syndrome (PFS) (B) and essential blepharospasm (C) and somatosensory blink reflex in a healthy subject (D), patients with PFS (E) and essential blepharospasm (F). The top traces were obtained from the right side and bottom traces from left side. Somatosensory blink reflex obtained in a patient with PFS as shown in (E) is observed asymmetrical because right side (top) being the symptomatic side. Arrows indicate the beginning and end points of motor unit potentials. with Bonferroni correction test and Waller–Duncan analysis to avoid type I/type II error because there were at least eight or more variables analyzed in statistical analysis.
DISCUSSION
One of the main findings of this study is that SBR responses were elicited more significantly in patients with PFS than in patients with EB. Although not significant, the attainability of SBR was higher in patients with PFS, which is similar to our previous findings (Erdemir-Kiziltan et al., 2005; Erkol et al., 2009). The generation of SBR was suggested to result from the combination of excitatory and inhibitory influences of exteroceptive stimuli, relatively independent of brainstem trigeminofacial interneuronal excitability and mediated by neuronal structures with integration capabilities within the brainstem (Leon et al., 2011; Miwa et al., 1998). Although the duration and amplitude of the responses were increased, the attainability of SBR in patients with EB was lower in our study, which was previously shown by Miwa et al. (1996). Other findings in this study are as follows: (1) mean R2 amplitude and duration of TBR were the highest in EB; (2) mean R2 duration on the symptomatic side of PFS was longer than controls; (3) mean Rs latency of SBR was shorter on the symptomatic side of PFS compared with that on the asymptomatic side; and (4) mean Rs amplitude and duration were the highest in EB if positive. The SBR responses resembled the R2 responses elicited by trigeminal stimulation (Miwa et al., 1995). It has been suggested that multiple sensory modalities, such as tactile, auditory and visual sensations may have a common premotor mechanism for the blink reflex (Holstege et al., 1986; Rimpel et al., 1982). Loss of inhibition on brainstem reflex circuits was already shown in patients with EB by TBR studies (Akalin et al., 2013; Tolosa et al., 1988; Valls-Sole et al., 1991). Similarly, enlargement of R2 responses was previously reported in patients with EB and on the symptomatic sides of patients with PFS, which were attributed to Copyright Ó 2014 by the American Clinical Neurophysiology Society
the hyperexcitability of the facial nucleus (Berardelli et al., 1985; Tolosa et al., 1988; Valls-Sole et al., 1992). Alterations in descending projections to inhibitory neurons under indirect modulation of pallidothalamocortical motor circuit were suggested to result in interneuronal excitability in TBR circuits in patients with EB (Vitek, 2002). In this, it was observed that similar changes in R2 and Rs responses could also be elicited by SBR. Although the frequency of SBR positivity is low, the amplitude and duration of the Rs response were enhanced in EB, as in TBR responses. It has been suggested that polysensory inputs enter the brainstem reticular formation and modulate the excitability of the facial nerve nucleus or adjacent structure (Holstege et al., 1995; Rimpel et al., 1982). Generation of SBR was therefore attributed to the sensorimotor gating mechanism responsible for interruption of the excessive inflow of somatosensory stimuli (Miwa et al., 1998). In this context, the appearance of SBR might depend on the level of activity in gating mechanism exerting presynaptic inhibition on the inflow of the somatic input before sensory impulses enter the common blink reflex pathway (Lidsky et al., 1985; Schneider et al., 1985). The increase in SBR positivity in PFS could therefore result from motor hyperexcitability attributed to peripheral enhancement of the blink reflex gain secondary to compensatory mechanisms and reorganization, as observed in circuits of TBR (Cattaneo et al., 2005; Evinger et al., 2002; Manca et al., 2001; Schicatano and Mant, 2002; Valls-Sole and Montero, 2003). Facial nerve injury causes a complex tissue response that affects the microenvironment of the axotomised motor neuron and the affected nerve cell body; it manifests itself as structural, metabolic and molecular alterations of the soma, dendrites of the nerve, and the neighboring glia (Moran and Graeber, 2004). Synaptic associative plasticity using these mechanisms analogous inputs to generate reflex blinks may sometimes produce abnormal reflexes and pathological movements (Dauvergne and Evinger, 2007). In sum, although the effector changes take place in the target motor neurons, anatomic changes secondary to reorganization may play an important role in the gating mechanisms. It seems that the slow attainability of SBR in EB is in conflict with the increased excitability of the electrically stimulated TBR. 537
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TABLE 2.
Trigeminal and Somatosensory Blink Reflex Responses
Electrophysiological Measures
PFS Patients (n ¼ 15) Symptomatic Side
Asymptomatic Side
P*
EB Patients (n ¼ 15)
Control Group (n ¼ 30)
R1 latency (milliseconds)
10.16 6 1.52
10.00 6 1.06
0.648
10.08 6 0.89
10.10 6 0.88
R2 latency (milliseconds)
33.14 6 4.70
31.18 6 4.23
0.214
29.56 6 3.67
31.78 6 3.37
R2c latency (milliseconds)
33.05 6 3.98
31.90 6 5.02
0.533
30.76 6 3.38
32.14 6 4.05
403.80 6 126.57
379.40 6 163.75
0.747
532.50 6 234.45
361.07 6 150.50
R2 duration (milliseconds)
64.80 6 23.61
59.75 6 21.21
0.033
78.06 6 28.5
51.37 6 12.3
SBR response (Rs) latency (milliseconds)
48.31 6 9.50
52.21 6 8.39
0.006
49.90 6 9.5
50.60 6 8.7
205.00 6 113.45
189.47 6 66.94
0.910
283.42 6 150.81
220.52 6 110.06
53.73 6 13.82
50.93 6 14.28
0.377
64.57 6 14.93
58.42 6 35.80
R2 amplitude (mV)
Rs amplitude (mV)
Rs duration (milliseconds)
P 0.908† 0.728‡ 0.772§ 0.672k 0.315† 0.441‡ 0.569§ 0.114k 0.312† 0.635‡ 0.253§ 0.238k 0.035† 0.368‡ 0.924§ 0.003k 0.050† 0.025‡ 0.072§ 0.018k 0.668† 0.628‡ 0.810§ 0.575k 0.050† 0.509‡ 0.484§ 0.265k 0.015† 0.340‡ 0.241§ 0.044k
*P value between symptomatic and asymptomatic sides in PFS patients. †P value between symptomatic side in PFS patients and EB patients. ‡P value between symptomatic side in PFS patients and control group. §P value between asymptomatic side in PFS patients and control group. kP value between EB patients and control group. EB, essential blepharospasm; PFS, postparalytic facial syndrome; SBR, somatosensory-evoked blink reflex.
This suggests that the attainability of SBR could not solely be explained by the increase in excitability. However, the responses were greater in amplitude and duration if SBR could be evoked, which suggests that stimulations of different modalities could trigger an increased excitability at motor neuron level. On this basis, lower attainability of SBR in patients with EB may be caused by an altered sensitivity to selective stimuli. It is known that these patients are extremely sensitive to bright light, or corneal and trigeminal stimulation. It is possible that there may not be an increased sensitivity against somatosensory stimulation but if the stimulus reaches the facial motor or premotor neurons, it would create increased responses in amplitude and duration as observed in our study, which might reflect an enhanced excitability at this level. Similar findings were also shown in patients with progressive supranuclear palsy where SBR responses were absent in the presence of TBR responses with normal latency and amplitudes and enhanced blink reflex excitability recovery curve to paired stimuli (Valls-Sole et al., 1997). The authors proposed that orbicularis oculi response to 538
inputs from peripheral nerves was a form of startled response induced by somatic nerve afferents mediated by brainstem reticular formations, as seen in other startled responses. The underlying pathophysiology differs in patients with progressive supranuclear palsy, where cholinergic neuronal loss is prominent at brainstem level, in addition to involvement of reticular formation. The absence of SBR and auditory startle response was also explained by this primary disturbance. The startled reaction could be induced by auditory, visual or somatosensory stimuli, and the circuit of the startled reaction to somatosensory stimuli may be similar to that of the auditory startle response (Álvarez-Blanco et al., 2009; Yeomans et al., 2002). Muller et al. (2007) showed that auditory startle response increased in masseter, sternocleidomastoid, and biceps muscles, although it was paradoxically decreased in orbicularis oculi muscle. These authors have speculated that this could be a circumferential effect of botulinum toxin injections, although there are contradictory results of botulinum toxin on blink reflex excitability (Valls-Sole et al., 1991). Copyright Ó 2014 by the American Clinical Neurophysiology Society
Journal of Clinical Neurophysiology Volume 31, Number 6, December 2014
Decreased auditory startle response probability may, in part, explain the lower attainability of SBR in EB observed in this study. Nevertheless, this paradoxical finding should cautiously be interpreted because auditory blink reflex was demonstrated in all patients with EB in our previous study, with increased amplitudes and durations. The exact neural pathways subserving the SBR are still not completely understood. The peripheral afferent pathway is probably of cutaneous origin, and the final output should be mediated by facial motor neurons responsible for blinking; but the polysynaptic central pathways are uncertain. As in TBR, which is transmitted through the brainstem reticular formation (Esteban, 1999; Ongerboer de Visser and Kuypers, 1978), it seems likely that the brainstem reticular formation also plays an important role in generating SBR (Miwa et al., 1995). Experimental data have suggested common blink premotor areas, on the pontine and medullary reticular formation, where such multiple sensory modalities might converge (Holstege et al., 1986; Rimpel et al., 1982). Leon et al. (2011) showed the absence of the SBR with preservation of the TBR in patients with upper brainstem lesions whereas patients with Wallenberg syndrome exhibited an opposite pattern of preservation of the SBR with abnormal TBR responses. Furthermore, abnormal responses were obtained from stimulation of both sides of patients with unilateral lesions, suggesting a larger dysfunctional area. It was therefore speculated that the SBR may result from the combination of excitatory and inhibitory influences of exteroceptive stimuli mediated by neuronal structures with integration capabilities within the brainstem, and that it is relatively independent of brainstem trigeminofacial interneuronal excitability (Khoshbin and Hallett, 1981; Leon et al., 2011). Because stimuli at different sites generated different results, a lesion involving the afferent arc of SBR was suggested to be responsible. The upper brainstem, at a site close to the nuclei that control vertical gaze, possibly in the mesencephalic reticular formation was speculated to be the site of integration of the SBR in contrast to the bulbopontine reticular formation in TBR. Indeed, this anatomical difference might also explain the lower attainability of SBR in EB, which seems conflicted compared with the increased excitability of the electrically stimulated TBR. It was proposed in many studies that a hyperexcitable blink reflex in patients with EB secondary to an alteration in the trigeminal sensory motor system implies a wider involvement than brainstem, which implies likely rostral structures with an underlying, acquired or genetical, permissive environment characterized by basal ganglia dysfunction (Berardelli et al., 1985; Elston et al., 1988; Gomez-Wong et al., 1998; Granadas et al., 1988; Jankovic, 1988; Valls-Sole and Montero, 2003). The influence of basal ganglia is not directly on pontine-medullary interneurons subserving blink reflex circuits, but indirectly through descending cortical or superior colliculus projections modulating the blink reflex, which was demonstrated in precollicularly decerebrated rats (Hinrichsen and Watson, 1983). This might be one possible explanation for the differences in SBR patterns in patients with EB, although once stimulated, the amplitudes and durations of responses also increase. Besides the brainstem reticular formation, facial motor neurons also receive excitatory synaptic inputs from various premotor structures including the motor cortex, superior colliculus, and nucleus of the spinal trigeminal tract (Hinrichsen and Watson, 1983; Li et al., 1993; Rekling et al., 2000). The states of disease, in relation to many suprasegmental structures could influence the blink reflex, change its basal excitability and the manner in which it responds to the modulatory factors. In summary, we suggest that the increased SBR in patients with PFS are related with local changes, such as reorganization. In patients with EB, however, the decreased frequency of SBR may Copyright Ó 2014 by the American Clinical Neurophysiology Society
Blink Reflex Studies in PFS and Blepharospasm
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