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Abstract

As the distribution of pain in primary headaches suggests involvement of the trigeminal sensory pathways, trigeminal somatosensory evoked potentials (TSEP) and blink reflexes (BR) may provide important information about their functional integrity. Functional differences between symptomatic and non-symptomatic sides and between measurements during and outside attacks may be particularly informative. These tests should therefore be reproducible and should require a suitable number of patients for future studies in patients with primary, paroxysmal headaches. We performed TSEP and BR twice in 22 healthy volunteers, in order to calculate sample sizes based on reproducibility data. This is, to our knowledge, the first study investigating the reproducibility of TSEP and BR measurements. Latencies of TSEP and BR are appropriate for future studies, as their reproducibility allows practical sample sizes (less than 25 subjects). Duration, amplitude and area parameters of the BR responses were less appropriate for longitudinal studies.

Keywords

Trigeminal somatosensory evoked potentials blink reflex reproducibility paroxysmal headaches sample size calculations

Introduction

Primary headaches such as migraine and cluster headache are characterized by recurrent attacks of unilateral head pain in the region of the trigeminal nerve (1). The pathophysiology of these headaches is not completely understood. The distribution of the pain suggests involvement of the trigeminal nerve, which is an integral part of the trigeminovascular system. This system is activated during migraine and cluster headache attacks (2, 3).

Neurophysiological assessment may provide important information about the role of the trigeminal sensory system in headache pathophysiology. Functional differences of the trigeminal system between the symptomatic and non-symptomatic side and between different ‘disease-states’, e.g. during or outside attacks or attack periods, can be studied non-invasively and repeatedly. Two tests seem most informative for investigating such differences: trigeminal somatosensory evoked potential (TSEP) and blink reflexes (BR). TSEP studies are performed to evaluate the function and integrity of the sensory trigeminal system from the peripheral nerve up to and including the sensory cortex. Following stimulation of the distal portion, a series of electrical events occurs in the afferent pathway (4). The BR is a brain-stem reflex evoked by electrical stimulation of the supraorbital nerve (first branch of the trigeminal nerve), resulting in a blink reaction (mediated by the facial nerve) which has two components: an early, ipsilateral response (R1) and a late, bilateral response (R2) (5–7).

In order to evaluate the trigeminal somatosensory system in primary, paroxysmal headache syndromes such as cluster headache and migraine repeatedly in the same patient (e.g. during and outside attack periods), tests need to be well reproducible and should allow studies with a practical number of patients. The aim of the present study was to investigate the reproducibility of the TSEP and BR and to determine the required number of patients for future studies.

Methods

Study population

TSEP and BR were performed in 22 healthy volunteers. Exclusion criteria were a history of migraine or other primary headaches. Individuals were investigated twice with several weeks to months between recordings.

TSEP procedure

Subjects lay down on an examination bench with their eyes closed, while keeping their facial and jaw musculature as relaxed as possible, under auditory feedback if necessary. Lights were dimmed to improve relaxation. AgAgCl EEG-electrodes were placed at C5′ and C6′ of the 10–20 system (8) after cleaning with an abrasive solution, using Cz as the earth electrode and Fz as the reference electrode. Impedance had to be <10 kΩ. For stimulation, one half of a Nicolet disposable silver chloride stimulator electrode (25×30 mm) was placed on the corner of the mouth and the other half was placed further medial, almost next to the midline, covering both upper and lower lips. The ground electrode was placed on the cheek. Sensory threshold was determined twice, by increasing the stimulus intensity by 0.2 mA/s. Subjects were asked to raise their hand when any sensation was felt at the corner of the mouth. Electrical stimulations (400 at 3.7 Hz, 0.2 ms duration) were then delivered on both sides in all subjects at three times sensory threshold, unless the subject did not tolerate this intensity. Any visible contraction of the orbicularis oris muscle was avoided, by decreasing the stimulus intensity. Two individual trial blocks of 400 stimuli were averaged for contralateral and ipsilateral responses of both sides; cathode and anode were switched after 200 stimulations to combat stimulus artefacts (9). Stimulation, recording and analysis were performed on a Nicolet Viking IV apparatus (Madison, WI, USA). Latencies of N1, P1 and N2 were evaluated.

BR procedure

Subjects were seated on the examination chair with their eyes open. Nicolet disposable silver chloride electrodes were placed on the orbicularis oculi muscle, below and lateral to the eye on both sides. The ground electrode was placed on the forehead. The supraorbital nerve was stimulated directly over the supraorbital notch. The current intensity of the stimulus was set at 10 mA, but increased if necessary until stable, reproducible reflexes were obtained. Four blink reflexes were obtained on both sides, with unpredictable intervals of at least 10 s to minimize habituation. Latencies, duration, amplitude and area were subsequently assessed. The four BR records obtained for each of the four stimulation and recording site combinations were overlaid. Cursors were placed by hand to determine onset and offset latencies of R1 and R2. The rectified curves were then averaged, and amplitude of R1 and R2 was automatically measured as the maximum value of the averaged rectified response in the time window defined by the appropriate cursors; area was measured as the area under the curve of the same window.

Statistical analysis

All parameters were expressed as mean±SD, with the coefficient of variability (SD expressed as percentage of the mean) indicating the inter-individual variability. Non-parametric tests were used to analyse differences between measurements or sides. P<0.05 was considered statistically significant. To evaluate agreement between two measurements, we used the method described by Bland and Altman (10): differences between two measurements were plotted against their mean. The limits of agreement were defined as means of differences +2 SD (upper limit) and −2 SD (lower limit). Assuming a normal distribution of the differences between measurements, 95% of the differences will lie within this interval. The coefficient of repeatability was defined as twice the SD of the differences with lower values indicating better agreement. Further, univariate anova tests were used to evaluate the influence of subject characteristics such as gender and age on the outcomes.

Power calculation was performed to estimate the required sample size of headache patients in future studies. We used the formula N=(Zα+Zβ)²×(SD _δ ²/Δ²) and set α (the chance of a false-positive result) to 0.05 and β (chance of a false-negative result) to 0.10 (SD _δ is the standard deviation of the differences between two measurements within one subject, Δ is the expected difference). For Δ of TSEP latencies, values of 0.5, 1.5, 2.0 and 4.0 ms were used. For BR parameters, the same differences for R1 and R2 latencies were used. To assess the suitability of a test for practical studies, we chose the number of patients required as the defining variable. An outcome of 15 required patients or less for future studies was defined as excellent, 15–25 patients was qualified as reasonable and more than 25 patients needed for future headache studies was qualified as an unpractical number of patients. We also calculated the detectable difference of all parameters with a required sample size of 25.

Results

We investigated 17 men and nine women (mean age was 40±13 years, range 24–68 years). In total 22 subjects underwent two separate TSEP recordings and 23 subjects underwent two BR recordings. Time between measurements ranged from 3 weeks to 13 months (median was 2 months).

TSEP

Mean sensory threshold was at 1.8±0.2 mA and mean stimulation strength was 6.4±0.4 mA. As one subject did not tolerate stimulation at three times sensory threshold, the stimulation strength was decreased in that measurement. Mean TSEP latencies ±S.D. and differences between sides and between measurements are given in Table 1. Mean latencies of contralateral N1, P1 and N2 were compared. There were no statistically significant differences between latencies of first and second, nor between right and left measurements. Limits of agreement for repeated TSEP measurements are shown in Table 2 (upper part) with the differences between two measurements of an individual subject plotted against their mean (Fig. 1a). There was no influence of gender on the latencies of the TSEP potentials. Age influenced latencies with older subjects having longer TSEP latencies (P=0.06 for N1, P=0.001 for P1 and P=0.02 for N2).

Table 1

Contralateral trigeminal somatosensory evoked potential (TSEP) latencies

	First measurement
	Right	Left	Side-to-side differences
N1	13.49 ± 2.04 (15)	13.49 ± 2.40 (18)	−0.08 ± 1.03
P1	18.89 ± 2.69 (14)	18.75 ± 2.72 (15)	0.14 ± 0.99
N2	25.66 ± 2.83 (11)	25.09 ± 3.05 (12)	0.40 ± 2.10
	Second measurement
	Right	Left	Side-to-side differences
N1	13.33 ± 2.07 (16)	13.73 ± 2.16 (16)	−0.40 ± 1.00
P1	18.76 ± 2.53 (13)	18.83 ± 2.54 (13)	−0.08 ± 0.78
N2	24.80 ± 3.01 (12)	24.78 ± 3.44 (14)	0.18 ± 1.48
Repeat-differences
N1	0.16 ± 1.60	−0.24 ± 1.52
P1	0.14 ± 1.75	0.08 ± 1.59
N2	0.85 ± 2.80	0.31 ± 2.30

Side-to-side-differences indicate differences between left and right-sided stimulation and repeat-differences indicate differences between the first and second measurement. No statistically significant differences were found in these comparisons. All values are expressed as mean±S.D. Numbers in parentheses indicate coefficient of variation (S.D. as % of the mean).

Table 2

Reproducibility data of both trigeminal somatosensory evoked potential (TSEP) and blink reflex (BR) measurements (data of right-sided stimulation are given)

	Average of two measurements	Mean difference	Coefficient of repeatability	Limits of agreement
TSEP
N1	13.43	0.16	3.19	−3.03 to 3.35
P1	18.80	0.14	3.50	−3.36 to 3.64
N2	25.04	0.86	5.60	−4.74 to 6.46
Blink reflex
R1 latency	10.57	−0.07	2.59	−2.66 to 2.52
R1 duration	9.23	−0.13	4.59	−4.72 to 4.46
R1 amplitude	136.31	−13.55	203.90	−217.45 to 190.35
R1 area	545.03	−126.47	675.62	−802.09 to 549.15
R2 ipsi latency	34.10	−0.09	5.21	−5.30 to 5.12
R2 ipsi duration	48.43	−1.34	22.13	−23.47 to 20.79
R2 ipsi amplitude	114.16	−15.19	72.86	−88.05 to 57.67
R2 ipsi area	2444.72	−480.95	2001.61	−2482.56 to 1520.66
R2 contra latency	35.05	0.15	4.90	−4.75 to 5.05
R2 contra duration	47.26	−3.46	21.86	−25.32 to 18.40
R2 contra amplitude	105.07	−18.81	79.12	−97.93 to 60.94
R2 contra area	2158.07	−452.59	2035.77	−2488.36 to 1583.18

Coefficient of repeatability is defined as 2 SD of the difference.

Figure 1

Repeatability characteristics of (a) trigeminal somatosensory evoked potential (TSEP) and (b) blink reflex (BR) latencies. The differences between two different measurements are plotted against their mean. The limits of agreement are shown according to the method described by Bland and Altman (mean difference between two recordings ± 2 SD of the differences). The coefficient of repeatability is defined by 2 SD of the differences. Only right-sided stimulation data are shown. For BR data, latencies are shown for R1 and R2 responses. As an example of less reproducible results, one figure showing R1 amplitude is demonstrated, with wider limits of agreement.

Blink reflex

Mean (±SD) latencies, duration, amplitude and area of R1 and R2 responses are given in Table 3. Mean stimulation strength was 11.3±2.3 mA (mean±SD). No significant differences were found between first and second measurements for R1 and R2 latencies or duration. However, significant differences between first and second measurements were found when area of R1 was compared (P=0.03, right-sided and P=0.01 left-sided stimulation), as well as when amplitude and area of ipsilateral R2 (P=0.04 and P=0.05, right-sided stimulation) and contralateral R2 (P=0.05 and P=0.04, right-sided stimulation) were compared (Table 3). For these parameters (amplitude and area) values were higher during the second measurement. There were also significant differences of duration, amplitude and area when right and left-sided stimulation were compared. Limits of agreement for BR responses are shown in Table 2 (lower part). Bland and Altman plots are shown for BR parameters for right-sided stimulation (Fig. 1b). There was no influence of age or gender on BR latencies and duration.

Table 3

Latencies (ms), duration (ms), amplitude (µV) and area (µVms) of R1 and R2 responses of the blink reflex

	First measurement		Second measurement
	Right	Left	Right	Left
R1
Latency	10.54 ± 1.05 (10)	10.86 ± 0.88 (8)	10.61 ± 0.77 (7)	10.80 ± 0.89 (8)
Duration	9.16 ± 1.97 (22)	9.09 ± 2.64 (29)	9.28 ± 2.22 (24)	9.40 ± 2.12 (23)
Amplitude	129.54 ± 84.00 (65)	148.49 ± 83.46 (56)	143.09 ± 91.82 (64)	183.95 ± 99.99 (54)
Area	481.80 ± 326.04 1 (68)	581.36 ± 363.44 2 (63)	608.27 ± 376.64 (62)	793.18 ± 484.58 (61)
R2 ipsilateral
Latency	34.05 ± 3.44 (10)	34.07 ± 3.66 (11)	34.15 ± 3.87 (11)	33.67 ± 3.31 (10)
Duration	47.76 ± 15.4 1 1 (32)	51.43 ± 20.53 (40)	49.1 ± 18.81 (38)	48.52 ± 13.11 (27)
Amplitude	106.57 ± 65.43^3,1 2 (61)	123.34 ± 67.86 (55)	121.76 ± 64.47 7 (53)	142.14 ± 79.95 (56)
Area	2204.24 ± 1974.37^4,1 3 (90)	2804.15 ± 2629.99 (94)	2685.19 ± 2538.04 8 (95)	2902.15 ± 2133.24 (74)
R2 contralateral
Latency	35.13 ± 4.00 (11)	35.54 ± 4.23 (12)	34.98 ± 4.01 (11)	34.73 ± 3.90 (11)
Duration	45.53 ± 15.35 (34)	49.13 ± 22.13 (45)	48.99 ± 18.93 (39)	44.39 ± 11.60 (26)
Amplitude	95.66 ± 72.26 5 (76)	93.02 ± 47.95 (52)	114.48 ± 75.60 9 (66)	99.80 ± 67.61 (68)
Area	1931.78 ± 1898.30 6 (98)	1874.66 ± 1637.37 (87)	2384.37 ± 2331.32 1 ⁰ (98)	1860.89 ± 517.57 (82)

All values are expressed as mean±SD. Numbers in parentheses indicate coefficient of variation (SD as % of the mean). Repeat differences:

¹ P=0.03;

² P=0.01;

³ P=0.04;

⁴ P=0.05;

⁵ P=0.05;

⁶ P=0.04.

Side-to-side differences: ⁷ P=0.002;

⁸ P=0.004;

⁹ P=0.006; ¹⁰ P=0.03; ¹¹ P=0.03; ¹² P=0.002; ¹³ P=0.001.

Sample size calculations

Sample size calculations were performed on all parameters, comparing two measurements of the same subject. A detectable difference of 1.5 ms required 11–25 patients for N1, P1 and N2 latencies of TSEP, except for right-sided N2, which required 37 patients (Fig. 2a). A detectable difference of 2 ms resulted in a maximum of 21 required patients for all latencies of TSEP. For BR R1 latency, a difference of 1.5 ms resulted in six to eight required patients, whereas a difference of 2 ms resulted in four patients. For ipsilateral and contralateral R2 responses, these numbers were 18–28 and 16–26 patients respectively for a difference of 2 ms (Fig. 2b). For the other BR parameters (duration, amplitude and area), larger numbers of patients were needed for the chosen differences. We took n=25 to calculate detectable differences for duration, amplitude and area. This resulted in the following detectable differences: 1.5 and 2.3 ms for R1 duration, 7.1–11.0 ms for ipsilateral and contralateral R2 duration, 23.6–66.0 µV for R1 and R2 amplitudes, and 219.0–1402.9 msµV for R1 and R2 areas.

Figure 2

Sample size calculations of (a) trigeminal somatosensory evoked potential (TSEP) and (b) blink reflex (BR) R1 and R2 latencies (α=0.05 and β=0.10). Horizontal lines indicate sample sizes of 15 and 25 patients (log scale).

Discussion

We conclude that TSEP and BR latency measurements are appropriate for assessing the functional integrity of trigeminal sensory pathways repeatedly in the same subject. This may be useful in studying patients with paroxysmal headaches, such as migraine or cluster headache, because functional differences of the trigeminal sensory system during and outside attacks can now be compared. Activation of the trigeminovascular system is present during migraine and cluster headache attacks, but central mechanisms are also suggested in the pathophysiology of both headaches (11, 12). Using TSEP and BR measurements, the peripheral, pontine and cortical tracts of the trigeminal system can be investigated.

The limits of agreement for latencies of some parameters were rather wide. As is shown in Fig. 1, this is caused by the divergent values of only some subjects, while most subjects had a very small difference between first and second measurement. Furthermore, practical numbers of patients are required for future studies: less than 25 patients for TSEP studies (N1 and P1 latencies) with a difference of 1.5 ms. It is difficult to estimate if this is a reasonable detectable difference, as studies using TSEPs in primary headaches and facial pain are rare. However, in one study (13), a difference of 1.1 ms between the symptomatic and non-symptomatic side in 18 cluster headache patients was found. Other studies in trigeminal neuralgia have found differences of 1.3 ms (14) and 1.7 ms (15). Our estimation of 1.5 ms thus seems clinically relevant. BR latencies are also sufficiently reproducible, but duration, amplitude and area of the BR are not practical. Meaningful differences can only be detected with unreasonably large numbers of patients. The limits of agreement of duration, amplitude and area are wide. It is therefore concluded that latencies of TSEP and BR are most appropriate parameters for studying functional trigeminal pathways. To our knowledge, this is the first study evaluating the reproducibility of TSEP and BR measurements.

So far, TSEP studies have been relatively difficult to perform and reproduce. The presence of stimulus artefacts and the production of muscle potentials and blinking during stimulation often interfere with the recording of evoked potentials (16). Different methods have been used by various authors to evoke TSEPs; direct needle stimulation (17, 18), and non-invasive methods such as air puffs (19), tapping the face (20), electrical stimulation of the tooth gums (4, 16), and the lips (9, 21). Drawbacks of these methods are that they may be painful and uncomfortable, and seem difficult to perform repeatedly in an out-patient clinic setting. Some authors searched for consistent and comparable responses, using a non-invasive technique, while avoiding muscle artefacts (22). As advised by Findler and Feinsod, we reversed the stimulus polarity after half of the stimulations, which indeed minimized the stimulus artefact (9, 16, 21). TSEP measurements using electrical stimulation of the lips provide, in our opinion, a suitable test for repeated evaluation of the trigeminal sensory pathways. It is not certain if TSEP is an appropriate test for assessing exclusively nociceptive function. However, as electrically evoked TSEP abnormalities have previously been found in a trigeminal pain syndrome (e.g. trigeminal neuralgia) (14, 15), studying sensory processing systems in primary headaches may also be of interest.

No statistically significant difference between men and women was found. However, age influenced the TSEP latencies; slightly longer latencies were found in older subjects. This has not been reported in other studies. In contrast, in one study investigating the influence of age, sex and stimulation side on TSEP latencies, no substantial effects were found for subject age (n=50) (22). These different findings can not be readily explained, as the methodology used in that publication differs only slightly from ours.

The BR has been extensively described (5–7). Aβ and Aδ fibres are thought to be involved (23), making it a tempting investigation for nociceptive function. Recently, novel methods have been described to elicit nociception-specific BR, which are not yet widely available (23, 24). BR duration, amplitude, and area were larger during the second measurement in our study, a finding that is not easy to explain. Amplitude and duration have previously been reported to show a large inter-individual variability: they are highly influenced by the recording method, and in particular by stimulus intensity (25). Our results show that BR latency is the most appropriate parameter for longitudinal research. Using higher, supramaximal stimulus intensities are suggested to elicit less variable amplitudes and area (6). However, higher stimulation intensities proved to be less well tolerated by the subjects.

Both TSEP and BR measure a part of the afferent trigeminal system. TSEP studies can be used to evaluate the functional integrity of peripheral as well as central trigeminal pathways, while the BR conducts sensory stimuli through the brain-stem and the facial nerve. This study proves that both tests are practical, non-painful and reproducible using latencies. TSEP and BR are therefore suitable for longitudinal investigation of primary headache pathophysiology.

Footnotes

Acknowledgements

J.A.v.V. is sponsored by the Asclepiade foundation. This study was performed on behalf of the Dutch RUSSH research group, which comprises, in addition to the authors: J.W.M. ter Berg (Sittard), F.E.A.M. Bussemaker (Hoorn), E.G.M. Couturier (Amsterdam), P.J.E. Eekers (Heerlen), J. Haan (Leiderdorp), D. Herderschee (Hilversum), J.B.M. ten Holter (Deventer), P. Koehler (Heerlen), A. Knuistingh Neven (Krimpen a/d IJssel), J.H. Kok (Den Helder), J.B.M. Kuks (Groningen), J.A.M. Kuster (Haarlem), L.J.J.M. Mulder (Rotterdam), E. Siebenga (Gouda), T.J. Tacke (Hengelo), J.L. van der Zwan (Amersfoort).

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Reproducibility and Feasibility of Neurophysiological Assessment of the Sensory Trigeminal System for Future Application To Paroxysmal Headaches

Abstract

Keywords

Introduction

Methods

Study population

TSEP procedure

BR procedure

Statistical analysis

Results

TSEP

Blink reflex

Sample size calculations

Discussion

Footnotes

Acknowledgements

References