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.     

Pupil responsiveness in cluster headache: A dynamic TV pupillometric evaluation

In this study the variations in pupil diameter induced by different stimuli (dark-light adaptation, light reflex, electric stimulation of the sural nerve) were investigated in episodic (in the active or remission phases) and in chronic cluster headache (CH) patients. Pupil size monitoring was performed with a monocular, infrared TV pupillometer, and sural nerve stimuli were applied after the pain threshold had been measured as the flexion reflex threshold of the biceps femoris muscle (RIII reflex). The results were compared with those obtained in patients with "peripheral" (third neuron) Horner's syndrome and in healthy sex- and age-matched controls. On the symptomatic side we found an impairment of pupil response to light flashes and nociceptive stimuli; similar findings were sometimes evident on the pain-free side, too. These results substantiate previous observations that in cluster headache a dysfunction of the integrative central nervous system pathways also exists intercritically and mostly bilaterally, involving both autonomic regulation and pain perception mechanisms.     

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.     

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.     

The Blink Reflex in Cluster Headache

To investigate the involvement of the trigeminal system in cluster headache, in twelve subjects the electrically-elicited blink reflex during a symptomatic period was examined. In eleven cases, the amplitude of the contralateral R2 response on the symptomatic side was significantly lower, at the same stimulus intensity, than on the asymptomatic side (p = 0.005). The blink reflex can be useful to evaluate biological and drug-induced phenomena in cluster headache.     

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.     

Electrophysiological evidence for trigeminal neuron sensitization in patients with migraine.

Neurosci Lett . 2002 Jan 14;317(3):135-138
The electrically elicited corneal reflex is a useful tool for exploring the trigeminal system in humans and it may provide additional evidence pointing to a dysfunction of this system in migrainous patients. Tactile perception, corneal reflex and pain thresholds were studied in 48 migraine without aura patients during pain-free periods and compared with those observed in 24 controls. Twenty-eight of the patients had strictly unilateral headache, while the other 20 had bilateral or side-shifting pain during attacks. Both migraine subgroups (bilateral and unilateral) showed significantly lower thresholds compared with controls. The lowest values were observed on the symptomatic side of unilateral migraine patients. These findings suggest that sensorimotor mechanisms and/or pain control systems at the trigeminal level are impaired in migraine. The bilateral location of these abnormalities seems to point to a centrally located dysfunction.
Comment: This is an important paper which describes a noninvasive method of studying sensorimotor/pain control mechanism in humans. This approach may help in the development of potential prophylactic agents, to establish likely clinically effective doses and duration of treatments in small-scale phase II trials, before exposing larger numbers of subjects to potentially ineffective doses in phase III trials. DSM     

Unilateral impairment of pupillary response to trigeminal nerve stimulation in cluster headache

The pupillary constriction induced ipsilaterally by transcutaneous electrical nerve stimulation (TENS) of the infratrochlear nerve was measured, using an electronic pupillometer, in 26 episodic cluster headache (CH) and 15 migraine sufferers tested during an attack-free period and in 16 healthy controls. In controls, TENS gave rise to a miosis which was slow in onset and long-lasting in duration, and which was comparable to that mediated by tachykinins in animals. A similar miotic response was bilaterally observed in migraine patients and in CH patients examined during the inactive phase. In CH sufferers during the cluster period, TENS only elicited a normal pupillary constriction in the asymptomatic eye, whereas the resulting response in the symptomatic eye was markedly decreased. Although the exact mechanism underlying the dysfunction remains to be clarified, these results seem to indicate that ocular trigeminal pathways are involved in CH.     

Trait- and Frequency-Dependent Dysfunctional Habituation to Trigeminal Nociceptive Stimulation in Trigeminal Autonomic Cephalalgias

We investigated whether the stimulation frequency (SF), the pain phases, and different diagnoses of trigeminal autonomic cephalalgias (TACs) may influence the habituation to pain. We studied the habituation of the nociceptive blink reflex R2 responses at different SFs (.05, .1, .2, .3, .5, and 1?Hz), in 28 episodic cluster headache (ECH) patients, 16 during and 12 outside the bout; they were compared with 16 episodic paroxysmal hemicrania (EPH) during the bout and 21 healthy subjects. We delivered 26 electrical stimuli and subdivided stimuli 2 to 26 in 5 blocks of 5 responses for each SF. Habituation values for each SF were expressed as the percentages of the mean area value of second through fifth blocks with respect to the first one. A significant lower mean percentage decrease of the R2 area across all blocks was found at .2 to 1?Hz SF during ECH, outside of the ECH, and EPH compared with healthy subjects. We showed a common frequency-dependent deficit of habituation of trigeminal nociceptive responses at higher SFs in ECH and EPH patients, independently from the disease phase. This abnormal temporal pattern of pain processing may suggest a trait-dependent dysfunction of some underlying pain-related subcortical structures, rather than a state-dependent functional abnormality due to the recurrence of the headache attacks during the active period.

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.     

Trigemino-cervical reflex abnormalities in patients with migraine and cluster headache

BACKGROUND: Head pain arises within the trigeminal nociceptive system. Current theories propose that the trigeminal system is intimately involved in the pathogenesis of migraine. Short-latency responses can be recorded in sternocleidomastoid muscles after stimulation of the trigeminal nerve (trigemino-cervical reflex). This brainstem reflex could be a suitable method to evaluate the trigeminal system in migraine and CH. OBJECTIVE: The aim of the present study was to further elucidate the pathophysiology of migraine and cluster headache (CH) with special reference to the involvement of the central trigeminal system in the different forms of primary headache. METHODS: The trigemino-cervical reflex was investigated in 15 healthy subjects, in 15 patients having migraine with aura, in 15 patients with migraine without aura, and in 10 patients with CH. RESULTS: Significant abnormalities were observed in a great number of patients with both types of migraine and CH during the headache attacks, but only in migraine patients during the interictal period. The alterations are bilateral in migraine, unilateral in CH. CONCLUSIONS: Our results further support the relevance of brainstem mechanisms in the pathogenesis of migraine rather than of CH. These data, taken together with that from experimental head pain and functional imaging studies, demonstrate that primary headache syndromes may be distinguished on a functional basis by areas of activation specific to the clinical syndrome.     

Exteroceptive suppression of activity of the temporal muscle in analysis of pain mechanisms

Stimulating afferent fibers of the trigeminal nerve usually causes two successive suppressions (ES1 and ES2) of the voluntary muscle activity of chewing muscles. The first phase of decreased voluntary activity is called the early exteroceptive suppression period (ES1); the second phase is called the late exteroceptive suppression period (ES2). Between these two suppression periods is a phase of increased muscle activity, the so-called facilitation period (FP). Usually, in healthy subjects this normal pattern of exteroceptive suppression can be elicited regularly. The reflex answer may occur at low non-painful stimulus intensities; however, typically it appears to be most pronounced with high-intensity stimuli. Because of the obvious relationship between stimulus intensity, pain perception and reflex answer, the reflex is regarded as an antinociceptive reaction. Chronic pain syndromes like chronic tension-type headache and migraine without aura cause changes within the normal ES recording pattern. Furthermore, some substances used in pain therapy such as serotoninagonists or antagonists, acetylsalicylic acid or naloxon may also alter the general appearance of the ES. In this review different parameters that influence the ES reflex answer are summarized. Above, the diagnostic value of the changes of the ES for pathophysiological procedures regarding pain perception and pain processing in certain pain diseases is discussed.     

Corneal Sensitivity in Cluster Headache

SYNOPSIS
Cluster headache pain is thought to arise from vasodilatation, but a neural origin of the pain has never been completely excluded. Some patients with cluster headache have complained of subjective diminution of sensation over the ipsilateral forehead. This is hard to quantitate and is often variable. Besides, ablation of trigeminal sensory pathways has been re sorted to for relief of pain in some intractable cases.
The present study was undertaken to quantitatively assess the sensitivity of the cornea in cluster patients. Fifteen cluster headache patients were the subjects of this study. Measurement of the corneal sensitivity was undertaken using a Cochet-Bonnet Aesthesiometer. There was no difference between the affected and the unaffected eye. There was no difference in the sensitivity when testing was done during the cluster period and later on when the patients were in remission. It is concluded from this study that there is no objective evidence for involvement of trigeminal sensory pathways in patients with cluster headache.     

Antiepileptic drugs in the management of cluster headache and trigeminal neuralgia

Cluster headache and trigeminal neuralgia are relatively rare but debilitating neurologic conditions. Although they are clinically and diagnostically distinct from migraine, many of the same pharmacologic agents are used in their management. For many patients, the attacks are so frequent and severe that abortive therapy is often ineffective; therefore, chronic preventive therapy is necessary for adequate pain control. Cluster headache and trigeminal neuralgia have several distinguishing clinical features. Cluster headache is predominantly a male disorder; trigeminal neuralgia is more prevalent in women. Individuals with cluster headaches often develop their first attack before age 25; most patients with trigeminal neuralgia are between age 50 and 70. Cluster headaches are strongly associated with tobacco smoking and triggered by alcohol consumption; trigeminal neuralgia can be triggered by such stimuli as shaving and toothbrushing. Although the pain in both disorders is excruciating, cluster headache pain is episodic and unilateral, typically surrounds the eye, and lasts 15 to 180 minutes; the pain of trigeminal neuralgia lasts just seconds and is usually limited to the tissues overlying the maxillary and mandibular divisions of the trigeminal nerve. Cluster headache is unique because of its associated autonomic symptoms. Although the pathophysiology of cluster headache and trigeminal neuralgia are not completely understood, both appear to have central primary processes, and these findings have prompted investigations of the effectiveness of the newer antiepileptic drugs for cluster headache prevention and for the treatment of trigeminal neuralgia. The traditional antiepileptic drugs phenytoin and carbamazepine have been used for the treatment of trigeminal neuralgia for a number of years, and while they are effective, they can sometimes cause central nervous system effects such as drowsiness, ataxia, somnolence, and diplopia. Reports of studies in small numbers of patients or individual case studies indicate that the newer antiepileptic drugs are effective in providing pain relief for trigeminal neuralgia and cluster headache sufferers, with fewer central nervous system side effects. Divalproex has been shown to provide effective pain control and to reduce cluster headache frequency by more than half in episodic and chronic cluster headache sufferers. Topiramate demonstrated efficacy in a study of 15 patients, with a mean time to induction of cluster headache remission of 1.4 weeks (range, 1 day to 3 weeks). In the treatment of trigeminal neuralgia, gabapentin has been shown to be effective in an open-label study. When added to an existing but ineffective regimen of carbamazepine or phenytoin, lamotrigine provided improved pain relief; it also may work as monotherapy. Topiramate provided a sustained analgesic effect when administered to patients with trigeminal neuralgia. The newer antiepileptic drugs show considerable promise in the management of cluster headache and trigeminal neuralgia.     

Sumatriptan and corneal reflexes in headache-free migraine patients: a randomized and placebo-controlled crossover study

A temporary sensitization of central trigeminal neurones in migraine patients during acute attacks has been described in previous studies using the electrically evoked nociceptive blink reflex. The cornea is innervated by small myelinated A-delta and unmyelinated C-fibres only. Stimulation with air puffs activates peripheral nociceptors and allows the investigation of peripheral trigeminal nerve structures. Our objective was to investigate whether corneal reflex examinations with air puff stimulation detect abnormalities in migraineurs during their pain-free interval and if the corneal reflex may be modulated by the administration of an oral triptan. After validation of the nociceptive air puff technique by investigating the corneal reflexes before and after a local anaesthesia of the cornea, we recorded corneal reflexes in 25 migraineurs during their pain-free period and 25 healthy controls before and after the oral administration of 100 mg sumatriptan in a randomized, placebo-controlled, crossover study. Baseline response areas under the curve (AUCs) and latencies of the R2 components of the corneal reflexes did not show any significant differences between patients and controls. Patients did not show any significant differences regarding their headache and non-headache side. The use of an oral triptan had no significant influence on latencies or AUCs in both patients and controls. Our data suggest that there is no facilitation of the trigeminal system in the headache-free interval among patients with migraine. The stable corneal reflexes after the oral administration of 100 mg sumatriptan suggest that there was no inhibition of the trigeminal system, both in patients during their headache-free period and in healthy controls.     

The Enhanced Ciliospinal Reflex in Asymptomatic Patients With Cluster Headache is Due to Preganglionic Sympathetic Mechanisms

An amplified ciliospinal reflex response has been documented in patients with cluster headache, lacking a Horner like syndrome. The mechanism is unknown, Tentatively, it may be due to an increased release of monoamines from post-ganglionic sympathetic nerve endings or an increased density of postsynaptic adrenergic receptors in the dilatator muscle of the iris.
The instillation of a 1% phenylephrine solution into the conjunctival sac induces mydriasis by stimulating postsynaptic adrenergic receptors in the dilatator muscle of the iris, while the instillation of a 2% tyramine solution causes mydriasis by releasing noradrenaline from the presynaptic sympathetic nerve terminals in the iris.
According to these premises, a positive correlation shouId be expected between the ciliospinal reflex response and the pupillary response to tyramine, if the enhanced ciliospinal so-flex response was due to an increased presynaptic release of monoamines. No such correlation was found. Nor was there any positive correlation between the ciliospinal reflex response and the pupillary response to phenylephrine, contradicting an increased density of postsynaptic monoaminergic receptors in the dilatator muscle of the iris as the explanation. However, there was a significant positive correlation between the pupillary responses to phenylephrine and tyramine, ruling out any functionally caused "denervation" hypersensitivity in the dilatator muscle of the iris.
It is concluded that the amplified ciliospinal reflex response in cluster headache patients (lacking a Horner-like syndrome) reflects compensatory pathophysiological mechanisms proximal to the third-order sympathetic neuron.     

Hypothalamic deep-brain stimulation modulates thermal sensitivity and pain thresholds in cluster headache

Deep-brain stimulation (DBS) of the posterior hypothalamus has been shown to be clinically effective for drug-resistant chronic cluster headache, but the underlying mechanism is still not understood. The hypothalamus as an important centre of homeostasis is connected among others to the trigeminal system via the trigeminohypothalamic tract. We aimed to elucidate whether hypothalamic stimulation affects thermal sensation and pain perception only in the clinically affected region (the first trigeminal branch) or in other regions as well. Thus, we examined three groups: chronic cluster headache patients with unilateral DBS of the posterior hypothalamus (n = 11), chronic cluster headache patients without DBS (n = 15) and healthy controls (n = 29). Perception and pain thresholds for hot and cold stimuli were determined bilaterally in all subjects supraorbitally, at the forearm, and in the lower leg. In DBS patients, thresholds were determined with the stimulator activated and inactivated. Cold pain thresholds at the first trigeminal branch were increased on the stimulated side in the DBS group compared to healthy subjects (p = .015). The DBS group also had higher cold detection thresholds compared to non-implanted cluster headache patients (p < .05). Short-term interruption of stimulation did not induce any changes in DBS patients. Clinically relevant differences were found neither between non-stimulated cluster headache patients and healthy controls nor between the affected and the non-affected sides in the chronic cluster headache patients without DBS. These results support the notion that neurostimulation of the posterior hypothalamus is specific for cluster headache and only affects certain aspects of pain sensation.     

Therapie und Prophylaxe von Cluster-Kopfschmerzen und anderen trigemino-autonomen Kopfschmerzen

Following the new IHS classification, cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT syndrome) are included in the classification as trigeminal autonomic cephalgias (TAC). The similarities of these syndromes suggest a considerable shared pathophysiology. These syndromes have in common that they involve activation of trigeminovascular nociceptive pathways with reflex cranial autonomic activation. Clinically, this physiology predicts pain with some combination of lacrimation, conjunctival injection, nasal congestion, or eyelid edema. Broadly the management of TAC comprises acute and prophylactic treatment. Some types of trigeminal autonomic headaches such as paroxysmal hemicrania and hemicrania continua have, unlike cluster headaches, a very robust response to indomethacin, leading to a consideration of indomethacin-sensitive headaches. This review covers the clinical picture and therapeutic options. Although studies following the criteria of evidence-based medicine (EBM) are rare, most patients can be treated sufficiently.     

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.     

Percutaneous Radiofrequency Trigeminal Gangliorhizolysis in Intractable Cluster Headache

SYNOPSIS
Recent interest in the possible role of substance P and other vaso-active polypeptides of the trigeminal vascular system, in the pathogenesis of vascular headache, has lad to a reconsideration of the value of ablative procedures on the trigeminal nerve in the control of chronic, medically intractable cluster headache. Twenty-seven patients with disabling intractable chronic cluster headache underwent radiofrequency trigeminal gangliorhizolysis. Indications included total resistance to prophylactic treatment, narcotic dependency, hypercorticism, and contra-indications to ergotamine and methysergide as a result of severe ischemic heart disease. The procedure had to be repeated in 6 patients, once in 4 and twice in 2. The average follow-up period was 28 months with a range of 6 to 63 months. Excellent results were obtained in 15 patients, very good in 2, good in 3, fair in 1 and poor in 6. Complications were anesthesia dolorosa, stabbing pain over the vertex, ice-pick like pain over the ipsilateral eye, transient corneal infection, transient diplopia, localized dermatosis, and recurrent stye. Complications were mild and transient in the majority of the patients, and the benefits from the surgery far outweighed the discomfort from the complications. The reasons for poor results in some patients were analyzed.
It is concluded that radiofrequency trigeminal gangliorhizolysis is a reasonable alternative in patients with chronic cluster headache 1) who are totally resistant to medical treatment, 2) with a history of strictly unilateral headache, and 3) with stable personality profile and low addiction proneness.