Impaired circadian rhythmicity of nociceptive reflex threshold in cluster headache

BACKGROUND: Alteration of circadian rhythmicity involving several endocrinologic and autonomic parameters has been observed in cluster headache. OBJECTIVES: To explore whether circadian failure of the pain control system may exist in cluster headache. METHODS: The nociceptive flexion reflex threshold was studied in 25 patients with episodic cluster headache (14 active, 11 in remission) and 6 patients with chronic cluster headache, along with 10 normal volunteers throughout a 24-hour period. The reflex response was evoked at the level of the biceps femoris by stimulating the sural nerve at the ankle. Single and population mean cosinor methods were used to detect the circadian rhythmicity. RESULTS: In the patients with episodic cluster headache, a significant reduction in the nociceptive flexion reflex threshold was observed in both the active subgroup and the subgroup in remission (P < .05). In these patients, persistence of a significant 24-hour rhythm during both the active period and remission was observed, but a shift of the phase was observed during clinical activity when compared with the remission period. A lack of circadian nociceptive flexion reflex threshold rhythmicity was found in the patients with chronic cluster headache. CONCLUSIONS: Our findings suggest that in cluster headache there may be impairment of the pain control system that is associated with periodic failure of the mechanisms involved in the organization of biological rhythms.     

Neurophysiological Studies in Chronic Paroxysmal Hemicrania and Hemicrania Continua

SYNOPSIS
To explore the possible involvement of the pain control system, pain pressure threshold (PPT), nociceptive flexion reflex (RIll), blink and corneal reflexes have been studied for pain perception assessment in 12 patients with chronic paroxysmal hemicrania (CPH) and 12 patients with hemicrania continua (HC). PPT was found to be reduced in HC and CPH when separately compared to controls. In addition, a significant reduction of subjective pain perception (Tp) which was most marked on the symptomatic side, has been demonstrated after sural nerve stimulation in CPH. The RIll reflex threshold on the symptomatic side was significantly reduced when patients were compared to controls, No major differences between CPH and HC as regards blink reflex latencies were found; nor was any such difference observed when comparing the two headache groups to controls. The corneal reflex thresholds were found significantly reduced bilaterally in CPH, irrespective of whether the treatment was given or not.     

The trigemino-pupillary response in cluster headache

Central impairment of the integrative neural systems controlling vegetative function and pain perception has been demonstrated in cluster headache (CH). Recently, we described the human pupillary response (trigeminal reflex) to quantified (painless and painful) corneal stimulation with a combined neurophysiological and pharmacological technique. In this study, the trigeminal reflex was evaluated in 26 subjects with episodic cluster headache. During the active phase of the disease, on the side of the pain we observed reduced mydriasis to electrical stimuli with an intensity equal to the corneal reflex threshold, and on both sides to stimuli with intensity that equalled the pain threshold. No difference was found when amplitude of the miotic phase was compared in the different groups. These suggest disordered pupillary activation in response to pain, probably sympathetic in origin, which is bilateral, detectable also during the remission phase and which cannot be explained simply by the antidromic release of pain-related peptides.     

Asymmetrical reduction of the nociceptive flexion reflex threshold in cluster headache

The nociceptive flexion reflex (NFR) of the lower limbs (RIII reflex) was examined bilaterally in 54 cluster headache (CH) patients suffering from episodic CH (ECH) and chronic CH (CCH). Fifteen ECH patients were examined in both remission and active phases. The RIII reflex threshold (Tr) and the threshold of pain sensation (Tp) were significantly reduced on the symptomatic side in patients with episodic CH during the bout. During the active phase of episodic CH an inverse correlation was found between the severity of CH (ratio: number of cluster periods/years of illness duration) and the Tp, which may suggest a role for secondary central sensitization in pain pathways. The lower Tr and Tp on the symptomatic side is in keeping with previous observations exploring pain mechanisms using different methods (i.e. corneal reflex, pain pressure threshold). On the whole, these data tie in with the view of an impairment of the pain control system, which parallels the periodicity of the disorder in the episodic form.     

Comparative study of perceived pain and nociceptive flexion reflex in man

The purpose of this study was to compare the amplitude of the flexion reflex of the biceps femoris muscle (BF) with the intensity of the painful sensation elicited by a nociceptive stimulation resulting from application of a constant-current either on the sural nerve or on the skin in its distal receptive field. Experiments were carried out on 15 normal volunteers.It was observed that: (1) Stimulation of the sural nerve (either on or through the skin) elicits two different reflex responses in the BF: the first (RII) is of short latency, low threshold and corresponds to a tactile reflex. The second (RIII) is of longer latency and higher threshold, and corresponds to a nociceptive reflex. The threshold of RIII was found to be the threshold of a pain sensation. (2) Stimulation of the skin elicits only a late nociceptive (RIII) response in the BF. The threshold of this response was also found to be that of pain. (3) The thresholds of both pain and RIII were found to be higher for sural nerve stimulation (10 mA) than for cutaneous stimulation (5 mA).It was suggested that the large diameter cutaneous fibers could have an inhibitory effect on both pain and the nociceptive reflex. This was supported by the results obtained during a selective ischemic block of the largest diameter fibers in the sural nerve, when a 10 mA stimulation was applied to the nerve. In this case, a decrease of the RII reflex was observed in BF, together with an increase of both RIII and pain sensation. Functional implications of these results are discussed.     

Ciliospinal Reflex Response in Cluster Headache

The ciliospinal reflex response is mainly mediated by second- and third-order sympathetic nerves to the dilatator muscle of the iris. As the pupillary response to various pharmacological agents indicates a sympathetic dysfunction in patients with cluster headache, the ciliospinal reflex was studied in 25 patients. Five of these patients with cluster headache exhibited a Horner-like syndrome (miosis, ptosis) on the symptomatic side. The pupillary responses to phenylephrine and tyramine showed that the Horner-like syndrome was due to postganglionic sympathetic nerve dysfunction. Their ciliospinal reflex response on the symptomatic side was significantly less than in controls and in other patients with cluster headache, lacking a Horner-like syndrome. This also applied to the nonsymptomatic side compared to the majority of cluster headache patients without any clinical evidence of sympathetic nerve dysfunction.
These findings seem to delineate those patients with a Horner-like syndrome as a subgroup, distinctly separated from the majority of cluster headache patients. Furthermore, the findings indicate that the Horner-like syndrome is not a consequence of repeated attacks of headache over many years, but is a manifestation of bilateral cephalic sympathetic dysfunction being more marked on the symptomatic side.
In 18 (72%) of our 25 patients, an asymmetric and lower ciliospinal reflex response on the symptomatic side was seen. In 3 (12%) patients, there was no difference in the response. In 4 patients (16%), the incorrect side was indicated by an asymmetric reflex response. Two of these patients (8%) had suffered from cluster headache on alternating sides.
In summary, the findings support the concept that dysfunction of the sympathetic nervous system, whether peripheral or central, is involved in the pathophysiology of cluster headache.     

Lateralisation of pain in cluster headache

In 27 patients with cluster headache a careful sensory examination of the entire body was performed. The exam included: the measurement of sensory thresholds with mechanical and electrical stimuli, the assessment of cutaneous and deep hyperalgesia and the ischaemic test of the upper limbs with limbs at rest. In most patients a lateralisation of the findings was observed: cutaneous and deep hyperalgesia were prevalent in the side of cluster headache attacks. The results indicate that in cluster headache, as in other pain syndromes, a lateralisation may be induced throughout the body, probably by phenomena of facilitation in the central nervous system and by activation of reflex arcs.     

Generalized expansion of nociceptive reflex receptive fields in chronic pain patients

Widespread central hypersensitivity is present in chronic pain and contributes to pain and disability. According to animal studies, expansion of receptive fields of spinal cord neurons is involved in central hypersensitivity. We recently developed a method to quantify nociceptive receptive fields in humans using spinal withdrawal reflexes. Here we hypothesized that patients with chronic pelvic pain display enlarged reflex receptive fields. Secondary endpoints were subjective pain thresholds and nociceptive withdrawal reflex thresholds after single and repeated (temporal summation) electrical stimulation. 20 patients and 25 pain-free subjects were tested. Electrical stimuli were applied to 10 sites on the foot sole for evoking reflexes in the tibialis anterior muscle. The reflex receptive field was defined as the area of the foot (fraction of the foot sole) from which a muscle contraction was evoked. For the secondary endpoints, the stimuli were applied to the cutaneous innervation area of the sural nerve. Medians (25-75 percentiles) of fraction of the foot sole in patients and controls were 0.48 (0.38-0.54) and 0.33 (0.27-0.39), respectively (P = 0.008). Pain and reflex thresholds after sural nerve stimulation were significantly lower in patients than in controls (P < 0.001 for all measurements). This study provides for the first time evidence for widespread expansion of reflex receptive fields in chronic pain patients. It thereby identifies a mechanism involved in central hypersensitivity in human chronic pain. Reverting the expansion of nociceptive receptive fields and exploring the prognostic meaning of this phenomenon may become future targets of clinical research.     

Evidence for spinal cord hypersensitivity in chronic pain after whiplash injury and in fibromyalgia

Patients with chronic pain after whiplash injury and fibromyalgia patients display exaggerated pain after sensory stimulation. Because evident tissue damage is usually lacking, this exaggerated pain perception could be explained by hyperexcitability of the central nervous system. The nociceptive withdrawal reflex (a spinal reflex) may be used to study the excitability state of spinal cord neurons. We tested the hypothesis that patients with chronic whiplash pain and fibromyalgia display facilitated withdrawal reflex and therefore spinal cord hypersensitivity. Three groups were studied: whiplash (n=27), fibromyalgia (n=22) and healthy controls (n=29). Two types of transcutaneous electrical stimulation of the sural nerve were applied: single stimulus and five repeated stimuli at 2 Hz. Electromyography was recorded from the biceps femoris muscle. The main outcome measurement was the minimum current intensity eliciting a spinal reflex (reflex threshold). Reflex thresholds were significantly lower in the whiplash compared with the control group, after both single (P=0.024) and repeated (P=0.035) stimulation. The same was observed for the fibromyalgia group, after both stimulation modalities (P=0.001 and 0.046, respectively). We provide evidence for spinal cord hyperexcitability in patients with chronic pain after whiplash injury and in fibromyalgia patients. This can cause exaggerated pain following low intensity nociceptive or innocuous peripheral stimulation. Spinal hypersensitivity may explain, at least in part, pain in the absence of detectable tissue damage.     

Impairment of corneal pain perception in cluster headache.

Despite many studies, the mechanisms underlying the pathogenesis of pain in cluster headache (CH) still remain obscure. An involvement of substance P (SP) containing neurons of the Gasserian ganglion and/or of the spinal trigeminal nucleus has recently been suggested, e.g., by impairment of inhibitory descending pathways on trigeminal nociceptive neurons. The electrically elicited corneal reflex was studied in 21 CH patients (15 in active phase, 6 in remission). This method allows simultaneous measurements of the trigemino-facial reflex and corneal pain perception. A significant reduction of pain thresholds (more evident on the pain side) was observed in CH during the active phase, while normal values were recorded during the remission phase. Ten out of 15 patients in the active phase showed a significantly reduced corneal pain threshold on the pain side, while tactile sensibility was normal. Moreover, latency, amplitude and duration of the corneal reflex were normal for both painful and painless stimulations during both phases. The threshold of the nociceptive muscular response in the active phase was significantly reduced, suggesting that the excitability of trigeminal nociceptive neurons or of the motor neurons is increased in CH. The results agree with the hypothesis that a reversible impairment of several integrative functions, including the activity of trigeminal pain control system, exists in CH during the active phase.     

The hypoalgesic effect of imipramine in different human experimental pain models

In a randomized, placebo-controlled, double-blind, cross-over study, the hypoalgesic effect of a single oral dose of 100 mg imipramine was investigated in 12 healthy volunteers. Test procedures performed before, 3, 6, and 9 h after medication included determination of (1) pain detection and tolerance thresholds to heat and pressure; (2) the thresholds of quadriceps femoris muscle withdrawal reflex to single and repeated electric stimulation of the sural nerve; (3) amplitude of the reflex evoked by 1.5 times the premedication reflex threshold; and (4) continuous pain rating during the cold pressor test.

Imipramine significantly increased pain tolerance thresholds to heat (P = 0.03) and pressure (P = 0.01), and both the psychophysical pain tolerance threshold and the reflex threshold to single electric stimulation (P = 0.02 and P = 0.03, respectively). On the repeated stimuli, which consisted of 4 pulses given at 3 Hz, imipramine induced a significant increase in the threshold at which the pain summated through the stimulation series (P = 0.03), whereas the increase in the threshold at which the reflex summated was not significant (P = 0.09). Pain detection thresholds to heat and pressure, the amplitude of the reflex to single suprathreshold stimulation, and pain ratings during the cold pressor test were unaltered by imipramine.

It is concluded that imipramine has a differential hypoalgesic effect on different human experimental pain tests. This provides new possibilities of assessing the differential effect of different tricyclic antidepressants on different pain modalities and intensities.     

Sensitivity to various stimuli in primary headaches: a questionnaire study

Questions about discomfort or pain produced by various stimuli (e.g., light, sound, exercise, neck movements) are currently used to differentiate between various primary headache disorders. In order to evaluate the usefulness of differences in sensitivity to physical stimuli in headache diagnosis, the answers to a questionnaire about sensitivity to various stimuli were compared in 68 patients with migraine, 45 with tension-type headache, 46 with cluster headache, and 23 patients with cervicogenic headache, and in 71 controls. Even among controls, a high proportion reported that many of these stimuli could elicit some degree of discomfort or pain. Without headache, migraineurs differed from the other patients with headache and controls mainly in their increased sensitivity to light. With headache, patients with tension-type headache were the least sensitive and migraineurs were the most sensitive to all stimuli, except for stimuli stemming from neck movements, to which patients with cervicogenic headache were most sensitive. Migraineurs also reported the highest degree of sensitivity regarding aggravation and provocation of headache. However, the most striking finding was that all patient groups, cluster headache in particular, became significantly more sensitive with headache than without headache to almost all stimulus categories. This may indicate that these headaches share important pathogenetic mechanisms. The fact that no headache had a very specific sensitivity profile may point to weaknesses of present headache classification systems.     

Cluster headache pathogenesis: A pupillometric study

Thirty-two cluster headache patients and healthy controls (n = 16-20 for the various tests) were examined by means of a Whitaker pupillometer during pain-free intervals. Eye drops of the sympathomimetic agents tyramine, hydroxyamphetamine, and phenylephrine were instilled into the conjunctival sacs on separate occasions, and pupillary diameters recorded at standard time intervals. The mydriatic responses of the two pupils were compared. A moderate, but statistically significant, basal relative miosis was found on the pain side in cluster headache. The symptomatic-side pupils were less responsive than their counterparts when stimulated with tyramine and hydroxyamphetamine, the difference being statistically significant for the OH-amphetamine test. With the phenylephrine test, however, the mydriasis on the symptomatic side significantly exceeded that of the contralateral pupil. This pattern of reactions does not quite correspond to those of "ordinary" Horner's syndrome (1st, 2nd, and 3rd neuron lesion). There are, however, gross similarities with the recently reported pattern in central sympathetic neuron dysfunction. In cluster headache there is probably a "Horner-like picture" rather than a proper Horner's syndrome.     

Occipital nerve blockade in chronic cluster headache patients and functional connectivity between trigeminal and occipital nerves

Headache syndromes often involve occipital and neck symptoms, suggesting a functional connectivity between nociceptive trigeminal and cervical afferents. Although reports regarding effective occipital nerve blockades in cluster headache exist, the reason for the improvement of the clinical symptoms is not known. Using occipital nerve blockade and nociceptive blink reflexes, we were able to demonstrate functional connectivity between trigeminal and occipital nerves in healthy volunteers. The R2 components of the nociceptive blink reflex and the clinical outcome in 15 chronic cluster headache patients were examined before and after unilateral nerve blockade of the greater occipital nerve with 5 ml prilocain (1%) on the headache side. In contrast to recent placebo-controlled studies, only nine of the 15 cluster patients reported some minor improvement in their headache. Six patients did not report any clinical change. Exclusively on the injection side, the R2 response areas decreased and R2 latencies increased significantly after the nerve blockade. These neurophysiological and clinical data provide further evidence for functional connectivity between cervical and trigeminal nerves in humans. The trigeminocervical complex does not seem to be primarily facilitated in cluster headache, suggesting a more centrally located pathology of the disease. However, the significant changes of trigeminal function as a consequence of inhibition of the greater occipital nerve were not mirrored by a significant clinical effect, suggesting that the clinical improvement of occipital nerve blockades is not due to a direct inhibitory effect on trigeminal transmission.     

Transcutaneous electrical stimulation applied to the infratrochlear nerve induces a homatropine-resistant miosis in humans

1. Both high- and low-intensity transcutaneous electrical stimuli were applied to the emergence of the infratrochlear nerve in 18 healthy subjects. The effect on the size of the homolateral pupil was investigated. The width of the pupil was also measured when high-intensity transcutaneous electrical stimulation was applied to the contralateral side. 2. The high-intensity pulse resulted in constriction of the pupil when the stimulation was homolateral. The miosis was slow in onset (120 s latency) and long-lasting (80 s). No pupillary changes were detected after either ipsilateral low-intensity or contralateral high-intensity stimuli. 3. In 11 healthy subjects, the pupillary response to transcutaneous electrical stimulation was evaluated during iris parasympathetic blockade induced by homatropine eyedrops. The disappearance of the light reflex due to homatropine was considered an index of the parasympathetic blockade. Afterwards, a high-intensity pulse was transcutaneously delivered to the emergence of the infratrochlear nerve and the ipsilateral pupil size was measured. 4. A reduction in the pupillary size followed the electrical stimulation, still under the effect of homatropine which abolished the light reflex. The time course of this pupillary constriction was similar to that seen without the influence of homatropine. 5. The findings suggest that homolateral miosis, observed after unilateral high-intensity stimulation of the infratrochlear nerve, does not stem from cholinergic activation. It has been suggested that miosis induced by transcutaneous electrical stimulation may be due to an antidromic activation of the iris sensory fibres.     

Acute intractable headache and oculomotor nerve palsy associated with nicorandil: A case report

Acute non-traumatic headaches with neurological deficits alarm emergency department (ED) physicians. Typically, a sudden headache with oculomotor nerve palsy involving a pupil indicates the possibility of a subarachnoid hemorrhage (SAH) due to an aneurysm originating from the posterior communicating artery. For the ED physician, thinking beyond the possibility of an SAH can be crucial. Here, we report on a 59-year-old woman who presented to the ED with an intractable headache and right ptosis. She had previously received nicorandil for paroxysmal atrial fibrillation in the cardiology clinic. Her vital signs were stable upon ED arrival. Neurological examination revealed a mild anisocoria with a sluggish response to light stimuli in the right eye. Adduction, supraduction, and infraduction were also limited in the right eye. Nuchal rigidity was not apparent. An urgent brain magnetic resonance image (MRI) with angiography was requested to assess for possible SAH, but revealed no aneurysm. Cerebrospinal fluid analysis was also unremarkable. The patient's headache and oculomotor nerve palsy improved completely after discontinuation of nicorandil for 3 days. To the best of our knowledge, this is the first case report on side effects of nicorandil presenting as a severe headache with reversible oculomotor nerve palsy involving a pupil, symptoms which mimicked a possible SAH due to aneurysm.     

Pupillary Reflexes in Complex Regional Pain Syndrome: Asymmetry to Arousal Stimuli Suggests an Ipsilateral Locus Coeruleus Deficit

Converging lines of evidence suggest that autonomic and nociceptive pathways linked with the locus coeruleus are disrupted in complex regional pain syndrome (CRPS). To investigate this, pupillary dilatation to arousal stimuli (which reflects neural activity in the locus coeruleus) and pupillary reflexes to light were assessed in a cross-sectional study of 33 patients with CRPS. Moderately painful electrical shocks were delivered to the affected or contralateral limb and unilateral 110 dB SPL acoustic startle stimuli were delivered via headphones. To determine whether the acoustic startle stimuli inhibited shock-induced pain, startle stimuli were also administered bilaterally 200 ms before or after the electric shock. The pupils constricted briskly and symmetrically to bright light (500 lux) and dilated symmetrically in dim light (5 lux). However, the pupil on the CRPS-affected side was smaller than the contralateral pupil before and after the delivery of painless and painful arousal stimuli. Auditory sensitivity was greater on the affected than unaffected side but acoustic startle stimuli failed to inhibit shock-induced pain. Together, these findings suggest that neural activity in pathways linked with the locus coeruleus is compromised on the affected side in patients with CRPS. This may contribute to autonomic disturbances, auditory discomfort and pain.PerspectiveThe locus coeruleus is involved not only in modulation of pain but also regulates sensory traffic more broadly. Hence, fatigue of neural activity in the ipsilateral locus coeruleus might not only exacerbate pain and hyperalgesia in CRPS but could also contribute more generally to hemilateral disturbances in sensory processing.     

Morphine blocks descending pain inhibitory controls in humans.

In man, heterotopic painful thermal conditioning stimuli induce parallel decreases in the spinal nociceptive flexion (RIII) reflex and the concurrent sensation of pain elicited by electrical stimulation of the sural nerve at the ankle. Such phenomena may be related to the diffuse noxious inhibitory controls (DNIC) which were initially described in the rat and subsequently documented in humans. In 9 subjects in the present study, a 2 min application of a moderately noxious temperature (46 degrees C) to the contralateral hand strongly depressed the RIII reflex elicited in the biceps femoris muscle by electrical stimulation of the sural nerve at 1.2 times the reflex threshold. These depressive effects were maximal during the second min of the conditioning period, showing a 80% inhibition of the RIII reflex which gradually recovered to its baseline value 7 min after the end of the conditioning period. Such inhibitory effects were completely blocked 15-26 min after administration of a low dose of morphine hydrochloride (0.05 mg/kg, i.v.). The lifting of the inhibitions was compatible with an action at the opioid receptors since the inhibitions were re-observed 5-16 min after naloxone injection (0.006 mg/kg, i.v.). During all the experimental sessions, heart and respiratory rates remained stable at their control levels. Since it has been shown previously that such a dose of morphine could not have a direct effect within the spinal cord (Willer 1985), it is concluded that this opiate blocks, in a naloxone-reversible fashion, those bulbo-spinal controls which are triggered by heterotopic nociceptive events. Possible implications for hypoalgesia based on the principles of counter-irritation are discussed.     

Cluster headache attacks and multiple sclerosis

We report the case of a patient who developed typical cluster headache attacks and was diagnosed as having multiple sclerosis (MS) at the same time. The headache attacks resolved after i.v. treatment with methylprednisolone. MR imaging showed a pontine demyelinating lesion involving the trigeminal nerve root inlet area, on the same side as the pain. The association between cluster headache and MS has been rarely described before. This case suggests that in patients with cluster headache neuroimaging is often useful in order to exclude structural lesions.     

Brain evoked potentials to noxious sural nerve stimulation in sciatalgic patients

In sciatalgic patients and before any treatment, the goal of this work was to compare the amplitude of the late component (N150-P220) of the brain evoked potential (BEP) between resting pain-free conditions and a neurological induced pain produced by the Lasègue manoeuvre. The study was carried out with 8 inpatients affected with a unilateral sciatica resulting from an X-ray identified dorsal root compression from discal origin. The sural nerve was electrically stimulated at the ankle level while BEPs were recorded monopolarly from the vertex. The stimulus intensity eliciting a liminal nociceptive reflex response in a knee-flexor muscle associated with a liminal pain was selected for this study. Both normal and affected side were alternatively stimulated during several conditions of controls and of Lasègue's manoeuvres performed on the normal and on the affected side. Results show that the Lasègue manoeuvre performed on the affected side induced a significant increase in the amplitude of N150-P220; performed on the normal side, this same manoeuvre resulted in a significant decrease of the N150-P220 amplitude. These variations were observed whatever was the side (normal or affected) under sural nerve stimulation. The possible neural mechanisms of these changes and clinical implications of these data are then discussed.