Trigeminal neuralgia

Objectives: To investigate the central trigeminal system in idiopathic trigeminal neuralgia (TN).

Materials and methods: Short latency responses can be recorded in sternocleidomastoid (SCM) muscles after stimulation of the trigeminal nerve (trigemino-cervical reflex). This brainstem reflex was investigated in 40 healthy subjects and in 17 patients suffering from idiopathic TN before and after therapy for 2 months with carbamazepin.

Results: Before therapy, six patients presented abnormalities of SCM responses on the painful side, six patients with bilateral abnormalities, and five patients with normal responses. A significant variation in the responses after therapy was found only in the patients with unilateral abnormalities: these patients and the patients with normal reflexes before therapy also had a good response to the therapy with significant pain relief.

Conclusions: Our findings suggest that the trigemino-cervical reflex could be useful in the clinical assessment of TN prior to instituting non-surgical treatment. The bilateral location of the abnormalities in some patients seems to point to a centrally located dysfunction; therefore, this study supports the idea that mechanisms in the central nervous system may play an important role in the pathophysiology of trigeminal neuralgic pain. [Neurol Res 2005; 27: 36-40]

Keywords: Trigeminal neuralgia; trigemino-cervical reflex; carbamazepin

INTRODUCTION

Trigeminal reflexes (corneal reflex, blink reflex, masseter inhibitory periods, jaw-jerk) are usually normal in idiopathic trigeminal neuralgia (TN)1"13; in contrast to data on brainstem reflexes, studies of trigeminal somatosensory evoked potentials (nerve, root, brainstem, subcortical) evoked by percutaneous trigeminal nerve stimulation have yielded contradictory results probably as a result of technical differences4"6.

Recently, it has been demonstrated that short latency responses can be recorded in tonically active neck muscles after stimulation of branches of the trigeminal nerve7. Such a trigemino-cervical reflex consists of a bilateral positive/negative wave in the average of the unrectified surface electromyograph, corresponding to a short period of inhibition of voluntary motor unit firing. Because these reflexes in humans bear a remarkable similarity in both their distribution and latency to those in the cat, they are probably produced by disynaptic or oligosynaptic trigeminal input to neck motoneurons mediated by neural networks confined within the lower brainstem8'9. In agreement with previous studies, the clearest responses were seen in the tonically active sternocleidomastoid (SCM) muscle after stimulation of the infra-orbital nerve10,11.

The aim of the present study was to obtain a neurophysiological evaluation of the trigeminal system (with particular reference to the central mechanisms) and of the effects of non-surgical treatments-conventional medical therapy with carbamazepin (CBZ)-in patients suffering from idiopathic TN.

METHODS AND PATIENTS

Wc investigated the trigemino-cervical reflex in 17 consecutive outpatients with idiopathic TN and in 40 healthy subjects.

Neurophysiologic procedures

Surface EMC activity was recorded bilaterally from symmetrical sites over the upper half of each SMC muscle ~8 cm above a reference electrode on the clavicle, while subjects raised their head slightly when lying supine. The EMG was amplified, bandpass filtered (30-3000 Hz), and averaged (usually 512 trials) from 20 ms before the stimulus to 80 ms afterward. Electrical stimuli (100 µs duration) were applied to the infraorbital nerve via bipolar surface electrodes fixed near the point of exit from the skull. The intensity was adjusted to be three times perceptual threshold, which most subjects regarded as strong but not painful. The repetition rate was usually 3 Hz.

Amplitudes were measured peak-to-peak in the unrectified average. Because the size of EMG responses is linearly related to the degree of background muscle contraction, we expressed the size of the potentials as a ratio to the mean rectified surface EMG activity preceding the stimulus; flexion of the head against gravity gave a mean EMG activity ranging from 50 to 140 µV, and the normal amplitude limits were determined for this level of activity. The size of the responses varied considerably from subject to subject. To transform the distribution of the data into a more Gaussian form, we took the square root of the amplitude values before determining the normal limits. Normal limits were defined as mean ±2.5 SD of the values in control subjects; for transformed data, the limit of normal was converted back to an untransformed ratio.

Patients

We studied the trigemino-cervical reflex in 17 patients suffering from typical tic doloureux (ten women and seven men, mean age 39.7 years), with pain in the distribution of the maxillary division alone or of the maxillary and mandibular divisions.

The patients had no history of neurological illness, headache or facial pain and were asymptomatic between neuralgic attacks. Thorough neurological examination was normal.

Brain magnetic resonance imaging, performed in all patients on a super-conducting 2 Tesla unit using multiplanar echo and fast spin echo to obtain T1 and T2 weighted images, did not show any abnormalities.

Patients were taking no medication with neurotropic drugs at the time of the first examination: occasionally only non-steroidal anti-inflammatory drugs were used. The patients were asked not to take non-steroidal analgesics at least 5 days before the study.

Electrophysiological analysis was performed before the treatment and after a 2-month therapy; CBZ was initiated at 200 mg/day and titrated to a maximum dose of 1400 mg daily in three to four divided doses. The neurophysiological findings were correlated with the neurological disability; subjective pain level was rated utilizing the four-point anchored Verbal Rating Scale (VRS-4; pain severity: 0=no pain, 1 =some pain, 2 = considerable pain, 3 = pain that could not be more severe).

The control group consisted of 40 healthy subjects (1 7 women and 23 men, mean age 41.5 years, range 22-69 years); they had no history of neurological illness, headache or facial pain and a normal neurological examination. The investigators were blinded as to the status of the subject (patient/control).

Statistical analysis was performed using χ2 tests. The relation between different variables was evaluated by means of the Spearman's r correlation coefficient.

The institutional ethical committee approved the study. Prior to the investigation, patients and healthy subjects gave their informed consent according to the Declaration of Helsinki.

RESULTS

Control subjects

In all control subjects, stimulation of the infra-orbital nerve on one side produced bilateral short latency responses in the unrectified averaged surface EMG. The evoked responses consisted of a positive and negative wave described with the mean latency preceded by lowercase letters indicating polarity (p19/n31). The mean ( ± SD) onset latency of the positive peak (p19) was 12.9 ± 1 ms for the SCM ipsilateral and 12.8 ± 1 ms for the SCM contralateral to the stimulus, and the peak latency of the positive wave was 19.0 ± 1.2 ms ipsilateral and 18.9 ± 1.3 ms contralateral. The mean latency of the negative peak (n31) was 30.2 ± 3.8 ms on the ipsilateral side and 29.7 ± 3.4 ms on the contralateral side.

The mean square root of the ratio between the amplitude of the p19/n31 wave (peak-to-peak) and the mean rectified surface EMG activity preceding the stimulus was 1.15±0.28 for the SCM ipsilateral to the stimulus and 1.08 ± 0.24 for the contralateral SCM. The lower confidence limit of the ratio between the amplitude of the p19/n31 wave and the mean rectified surface EMG preceding the stimulus was calculated as the mean value minus 2.5 SD of the square root transformed data. This corresponded to a square root value of 0.53 and to a ratio of 0.28 for SCM ipsilateral to the stimulus and to a square root value of 0.52 and to a ratio of 0.27 for SCM contralateral to the stimulus. There were no significant differences in the latency or size of the responses on either side. The electrophysiological findings in normal subjects are summarized in Table 1.

Patients

Abnormalities of the trigemino-cervical response were detected before therapy in 12 patients, in six of them only on the painful side, in six bilaterally. These patients had at least one abnormality in the size or latency of the SCM responses. The most common electrophysiological abnormality was reduced amplitude of the p19/n31 response after stimulation of the infra-orbital nerve. Latency abnormalities were observed in five patients, present as an isolated finding or associated with amplitude abnormalities. There were no short latency responses or hardly recognizable responses in three patients (Figure 7). The difference was statistically significant (p

After the 2-month therapy with daily CBZ there was only a significant reduction of the electrophysiological abnormalities (p

Five among the six patients showing abnormal unilateral responses before CBZ therapy had normal trigemino-cervical reflexes after therapy.

In contrast, we cannot find a significant variation in the trigemino-cervical reflexes between the values recorded before and after therapy in the patients with bilateral abnormalities (p>0.05).

In the patients with normal SCM responses or unilateral abnormalities the CBZ was also significantly more effective at producing pain relief, defined as a reduction in severity from severe or moderate pain to mild or no pain, respectively (p

We found a strong positive correlation between the trigemino-cervical reflex parameters and the intensity of the neurological pain (p0.10; Spearman's r. Therefore, the neuralgic pain relief did not correlate with the CBZ dose. There were no modifications of the trigemino-cervical reflexes after administration of CBZ in the ten examined control subjects.

The electrophysiological findings in the patients are summarized in Table 2.

DISCUSSION

The pathophysiology of the idiopathic TN is not well understood. There are no satisfactory animal models of TN, and it is difficult to obtain essential data from patients.

The trigemino-cervical reflexes in patients with idiopathic TN were evaluated and correlated with the effectiveness of the conventional medical therapy with CBZ.

Trigeminal reflexes are usually normal in idiopathic TN and abnormal in TN secondary to tumors or multiple sclerosis3. However, the patients with idiopathic TN had abnormal short latency trigeminal SEPs more often than those found with conventional electrically elicited trigeminal evoked potentials.

The trigemino-cervical reflex could be a suitable method to evaluate the trigeminal system in both idiopathic and secondary TN. As reported previously10, the trigemino-cervical reflex is more sensitive in disclosing brainstem lesions than the R2 component of the blink reflex. The form of the trigemino-cervical reflex is much simpler than the polyphasic R2 response, and hence its peak-to-peak amplitude is more reliable as a clinical measure. After stimulation of the infraorbital nerve the onset of the short latency response is quite similar to the R1 component of the blink reflex and the initial part of the masseter silent period, suggesting the involvement of the oligosynaptic pathway. Our results are thus indicative of abnormalities of the interneuronal brainstem pathways mediating the oligosynaptic trigemino-cervical reflexes.

Our study shows that brainstem reflex responses are often abnormal in idiopathic TN. Such results support the hypothesis that the pathophysiological mechanisms of pain in the idiopathic and secondary TN may be the same, even if in patients with idiopathic TN the aetiology remains unknown and the lesion usually undetected by conventional brainstem reflex studies. In fact, early scalp evoked trigeminal potential recordings before, during and after microvascular decompression of the trigeminal nerve root have demonstrated focal damage to the trigeminal root also in patients with idiopathic TN12.

TN is probably a multi-factorial disorder with several concurrent pathophysiological mechanisms. One of them is the contact between of the trigeminal root at the pons entry zone and benign lesions, including vascular anomalies, otherwise asymptomatic and undetected by radiological examination but founded during surgery or at necroscopy. Different types of physiological dysfunction cause the classical TN symptom complex.

One important and unexpected finding in our study is that in some patients the abnormalities are bilateral. In most previous studies the contralateral electrically elicited responses are normal. Only a study using laser-evoked potentials report abnormalities after stimulation of the non-painful side13. The bilateral location of these abnormalities in TN seems to point to a centrally located dysfunction, presumably at the brainstem level.

However, the disturbed brainstem modulation of nociceptive afferents could be related to cerebral descending influences rather than to a primary brainstem dysfunction, although supratentorial lesions seem to have little effect, if any, on the trigemino-cervical reflex, in contrast with the R2 component of the blink reflex10. In any case, our findings indicate that patients with TN have hypoactivity of the central inhibitory control of the trigeminal reflex circuits and therefore support the theory that the mechanisms of pain in TN involve pathophysiological mechanisms in the central nervous system. Structural and functional changes in the trigeminal system may result in a functional derangement in the receptive field organization of wide-dynamic-range neurons in the spinal trigeminal nucleus14-17. It is likely that in TN the nociceptive system undergoes a still unrecognized bilateral dysfunction; in particular, a failure of central inhibitory mechanisms may play a significant role in the pathogenesis of TN. Also, the phenomenon of trigger zones could arise from central mechanisms.

The evaluation of the trigemino-cervical reflexes would allow early identification of patients with idiopathic TN refractory and hence early treatment with conventional medical therapy.

In conclusion, our findings indicate that the trigemino-cervical reflex may be a useful tool in neurophysiological exploration of the trigeminal nerve; additionally, these procedures produce reliable evoked potential measures of trigeminal nerve function noninvasively, which can provide an objective index of treatment efficacy.

REFERENCES

1 Ongerboer de Visser BW, Goor C. Electromyographic and reflex study in idiopathic and symptomatic trigeminal neuralgias: Latency of the jaw and blink reflexes. J Neural Neurosurg Psychiatry 1974; 37: 1225-1230

2 Cruccu G, Leandri M, Feliciani M, ef a/. Idiopathic and symptomatic trigeminal pain. J Neurol Neurosurg Psychiatry 1990; 53: 1034-1042

3 Cruccu G, Deutschl G. The clinical use of brainstem reflexes and hand-muscle reflexes. CUn Neurophysiol 2000; 111: 371-387

4 Stohr M, Petruch F, Scheglmann K. Somatosensory evoked potentials following trigeminal nerve stimulation in trigeminal neuralgia. Ann Neurol 1981; 9: 63-66

5 Bennett MH, Lunsford LD. Percutaneous retrogasserian glycerol rhizotomy for tic douloureux: Part 2. Results and implications of trigeminal evoked potential studies. Neurosurgery 1984; 4: 431435

6 Leandri M, Parodi Cl, Favale E. Early trigeminal evoked potentials in tumors of the base of the skull and trigeminal neuralgia. F.lectmenceph din Neurophysiol 1988; 71: 114-124

7 Di Lazzaro V, Quartarone A., Higuchi K, et al. Short latency trigemino-cervical reflexes in man. Exp Brain Res 1995; 102: 474-482

8 Astelmark B, Pinter MJ, Sasaki S, ef al. Trigeminal excitation of dorsal neck motoneurones in the cat. Exp Brain Res 1992; 92: 183-193

9 Nishimura M, Asahara T, Higuchi K, ef al. Synaptic inhibition of accessory motoneurones evoked by stimulation of the trigeminal nerve in the cat. Brain Res 1992; 585: 291-294

10 Di Lazzaro V, Restuccia D, Nardone R, ef al. Preliminary clinical observations on a new trigeminal reflex: The trigemino-cervival reflex. Neurology 1996; 46: 479-485

11 Ertekin C, Celebisoy N, Uludag B. Trigeminocervical reflexes elicited by stimulation of the infraorbital nerve: Head retraction reflex. J CHn Neurophysiol 2001; 18: 378-385

12 Leandri M, Eldridge P, Miles JB. Recovery of nerve conduction following microvascular decompression for trigeminal neuralgia. Neurology 1 998; 51: 1641-1646

13 Cruccu G, Leandri M, lannetti GD, ef al. Small-fiber dysfunction in trigeminal neuralgia. Carbamazepine effect on laser evoked potentials. Neurology 2001; 56: 1722-1726

14 Burchiel KJ. Abnormal impulse generation in focalIy demyelinated trigeminal roots. J Neurosurg 1980, 53: 674-683

15 Fromm GH, Chattha AS, Terrence CF. Role of inhibitory mechanisms in trigeminal neuralgia. Neurology 1981; 31: 683687

16 Dubner R, Sharav Y, Gracely RH. Idiopathic trigeminal neuralgia: Sensory features and pain mechanisms. Pain 1987; 31: 23-33

17 Bowsher D. Trigeminal neuralgia: An anatomically oriented review. CUn Anat 1997; 10: 409-415

Raffaele Nardone, Massimo F. Matullo and Frediano Tezzon

Department of Neurology, 'F.Tappeiner' Hospital, Merano, Italy

Correspondence and reprint requests to: Dr Raffaele Nardone, Department of Neurology, 'F. Tappeiner' Hospital, Via Rossini, 5, 39012 Merano (BZ), Italy, [raffaele.nardone@asbmeran-o.it] Accepted for publication January 2004.

Copyright Maney Publishing Jan 2005
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