SUNCT syndrome: prolonged attacks, refractoriness and response to topiramate.
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Central Nervous System Vascular Malformations↗
Biomedical subjects
P J Goadsby
Publications and source records attributed to P J Goadsby.
Neurovascular headache and a midbrain vascular malformation: evidence for a role of the brainstem in chronic migraine.
Migraine is a common, disabling form of primary headache that has been linked by functional imaging studies to activation in the rostral brainstem. In specialty clinics migraine is most commonly seen in association with frequent less feature full headache that has been called transformed migraine or more recently termed chronic migraine. A patient is described with frequent migraine, 3 days per week, and less feature full headaches on other days. The patient has a cavernoma in the midbrain that has bled. She was previously headache free and now has contralateral daily headache. The patient supports the functional imaging observations from positron emission tomography (PET) that the rostral brainstem is pivotal in migraine pathophysiology, particularly the contralateral midbrain periaqueductal grey matter. Moreover, the patient's lesion provides biologically plausible support that a single entity causes her clinical presentation: chronic migraine, not two-disorders, migraine and tension-type headache.
Blood Vessels↗
Raeder's syndrome [corrected]: paratrigeminal paralysis of the oculopupillary sympathetic system.
Raeder described five patients with mixed features of trigeminal nerve pathology and oculosympathetic impairment, with or without other cranial nerve lesions. This constellation of clinical features drew the original author's attention to the paratrigeminal region as a likely site for the causative lesion in this syndrome. An analysis of the anatomy of the oculosympathetic innervation supports the view that a restricted lesion in the middle cranial fossa might cause the syndrome of trigeminal nerve involvement, neuralgic pain or sensory change, with ptosis or miosis, or both, but no anhidrosis. Such a paratrigeminal oculosympathetic syndrome (POSS) usefully reminds clinicians to pursue vigorously possible lesions of the middle cranial fossa with careful, and possibly repeated, imaging studies. Attaching the eponym Raeder's syndrome or Raeder's paratrigeminal neuralgia to this syndrome adds nothing valuable to the anatomical description (POSS), which might be preferred for clarity.
Adolescent↗
Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials.
BACKGROUND: The triptans, selective serotonin 5-HT(1B/1D) agonists, are very effective acute migraine drugs with a well- developed scientific rationale. Seven different triptans will soon be clinically available, making evidence-based selection guidelines necessary. Triptan trials have similar designs, facilitating meta-analysis; this will provide a foundation for using triptans in clinical practice. METHOD: We asked pharmaceutical companies and the principal investigators of company-independent trials for raw patient data of all double-blind, randomised, controlled, clinical trials of oral triptans in migraine. We calculated summary estimates across studies for important efficacy and tolerability parameters, and separately summarised direct comparator trials. RESULTS: 53 clinical trials (12 unpublished) involving 24089 patients, met the criteria for inclusion. Mean results for 100 mg sumatriptan were 59% (95% CI 57-60) for 2 h headache response (improvement from moderate or severe to mild or no pain); 29% (27-30) for 2 h pain free (improvement to no pain); 20% (18-21) for sustained pain free (pain free by 2 h and no headache recurrence or use of rescue medication 2-24 h post dose); and 67% (63-70) for consistency (response in at least two of three treated attacks); placebo-subtracted proportions for patients with at least one adverse event (AE) were 13% (8-18), for at least one central nervous system AE 6% (3-9), and for at least one chest AE 1.9% (1.0-2.7). Compared with these data, 10 mg rizatriptan showed better efficacy and consistency, and similar tolerability; 80 mg eletriptan showed better efficacy, similar consistency, but lower tolerability; 12.5 mg almotriptan showed similar efficacy at 2 h but better other results; 2.5 mg naratriptan and 20 mg eletriptan showed lower efficacy and (the first two) better tolerability; 2.5 mg and 5 mg zolmitriptan, 40 mg eletriptan, and 5 mg rizatriptan showed very similar results. The results of the 22 trials that directly compared triptans show the same overall pattern. We received no data on frovatriptan, but publicly available data suggest lower efficacy. INTERPRETATION: At marketed doses, all oral triptans were effective and well tolerated. 10 mg rizatriptan, 80 mg eletriptan, and 12.5 mg almotriptan provide the highest likelihood of consistent success.
Acute Disease↗
The NMDA receptor antagonist MK-801 reduces Fos-like immunoreactivity within the trigeminocervical complex following superior sagittal sinus stimulation in the cat.
Expression of Fos protein is an indicator of neuronal perturbation and is readily observed in the caudal medulla and the spinal cord following trigeminovascular nociceptive activation by electrical stimulation of the superior sagittal sinus (SSS) in the cat. It has been shown in the rat that N-methyl-D-aspartate (NMDA) receptor blockade causes a reduction in Fos protein expression after generalised meningeal irritation. We wished to examine if the same relationship was true in the cat, using the same non-competitive NMDA receptor antagonist MK-801, and a trigeminovascular-specific stimulus. A group of experimental animals underwent stimulation following blinded administration of MK-801 (4 mg/kg i.v.); control animals underwent stimulation minus MK-801, and a non-stimulated control animal underwent surgery alone. The regions examined for Fos-like immunoreactivity were the trigeminal nucleus caudalis (TNC) and its caudal extension into the C(1) and C(2) levels of the upper cervical spinal cord. The Fos-positive cell counts for the three regions (TNC, C(1) and C(2)) were grouped together for analysis. In the control stimulated group a median of 78 (56-99, quartile range, n=4) cells were Fos-positive. In the group treated with MK-801 the median number of Fos-positive cells was reduced to 40 (30-48; P<0.03, n=7). The large reduction that was observed in SSS stimulation-evoked Fos protein expression following the administration of MK-801, taken together with electrophysiological data, indicates a role for glutamate in neurotransmission within the trigeminocervical complex. Understanding glutamatergic mechanisms in the trigeminocervical complex offers mechanistic insight and therapeutic possibilities for primary neurovascular headaches, such as migraine.
Animals↗
The effect of adrenergic compounds on neurogenic dural vasodilatation.
The pharmacology of neurogenic trigeminovascular vasodilator responses in the dura mater is of interest for understanding the pathophysiology of migraine and to develop new therapies for this disabling common condition. Aminergic mechanisms have been implicated in migraine through direct study of amines in patients, and by inference from the pharmacology of many effective anti-migraine compounds, particularly preventative agents. This study used intravital microscopy to assess the role of aminergic transmission in neurogenic dural vasodilatation (NDV) by measuring directly the diameter of dural arteries in sodium pentobarbitone anaesthetised rats. Electrical stimulation of a closed cranial window produces, by local depolarisation of nerves, dural vessel dilation that is monitored continuously on-line using video-microscopy and a video dimension analyser. This dural vasodilatation was not affected by pre-treatment with an alpha1-adrenoceptor agonist (phenylephrine, 1 and 5 microg/kg), or antagonist (corynanthine, 1 and 2 mg/kg), nor by an alpha2-adrenoceptor agonist (UK14,304, 5 microg/kg) or antagonist (yohimbine, 1 and 3 mg/kg). Similarly, we saw no effect of beta-adrenoceptor blockade (propranolol, 1 and 3 mg/kg). The lack of an inhibitory effect of UK14,304 the model of neurogenic dural vasodilation contrasts with its effect in neurogenic dural plasma protein extravasation model. The lack of inhibition of beta-adrenoceptor antagonists in the neurogenic vasodilatation model contrasts with their usefulness as migraine prophylactics, and suggests that their mechanism of action in migraine is unlikely to be through sensory trigeminal fibre terminals at the neurovascular junction. Moreover, the data indicate that the adrenergic system does not play a significant role in neurogenic dural vasodilation.
Adrenergic Agents↗
Neuroimaging in headache.
Neuroimaging of primary headache syndromes, such as cluster headache and migraine, has begun to provide a glimpse of the neuroanatomical and physiological basis of the conditions. Although these headache types have been widely described as vascular, there is now considerable imaging and clinical evidence to suggest that they are primarily driven from the brain. The shared anatomical and physiological substrate for both of these clinical problems is the neural innervation of the cranial circulation. Functional imaging with positron emission tomography (PET) has shed light on the genesis of both syndromes, documenting activation in the midbrain and pons in migraine, and in the hypothalamic grey in cluster headache. These areas are involved not simply as a response to first division nociceptive pain impulses but specifically in each syndrome, probably in some permissive or dysfunctional role. In a recent PET study in cluster headache, as well as brain activation, tracer pooled in the region of the major basal arteries. This is likely to be due to vasodilatation of these vessels during the acute pain-attack and represents the first convincing activation of neural vasodilator mechanisms in humans. The author takes the view that the known physiology and pathophysiology of the systems involved dictate that these disorders should be collectively regarded as neurovascular headaches to place emphasis on the interaction between nerves and vessels, which is the underlying characteristic of these syndromes. Understanding this neurovascular relationship facilitates an understanding of the pain mechanisms, while characterising the CNS dysfunction will ultimately allow us to dissect out the basic pathogenesis of these disorders.
Capsaicin↗
Brainstem activation specific to migraine headache.
Findings from functional imaging studies have shown activation of the brainstem during migraine without aura (MWOA) and activation of the hypothalamus during cluster headache. We assessed a patient with cluster headache and migraine by positron emission tomography during an active cluster headache after he had taken 1.2 glyceryl trinitate. The patient developed a typical MWOA, during which we saw activation in the dorsal rostral brainstem. There was no activation in the region of the hypothalamus. Our findings provide evidence that migraine involves the brainstem, and show several areas involved in cluster headaches. Our data show the potential for objective distinction between primary headache syndromes with functional imaging, in disorders hitherto distinguished on clinical grounds.
Adult↗
Post-traumatic chronic paroxysmal hemicrania (CPH) with aura.
The authors describe a patient who developed chronic paroxysmal hemicrania (CPH) in close temporal relationship to a head injury. The subsequent attacks of CPH were associated with a typical migrainous sensory and motor aura. Administration of indomethacin 75 mg daily resulted in isolated occurrence of autonomic and aura symptoms in the absence of pain symptoms. The patient became completely asymptomatic on indomethacin 100 mg daily. Migrainous aura may be seen with trigeminal-autonomic headaches and may represent the expression of an aura-susceptibility gene rather than typical migraine headache biology.
Brain Injuries↗
Migraine, aura, and cortical spreading depression: why are we still talking about it?
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Cortical Spreading Depression↗
Evidence for postjunctional serotonin (5-HT1) receptors in the trigeminocervical complex.
Units linked to stimulation of the superior sagittal sinus were identified and recorded from in the trigeminocervical complex of the anesthetized cat. Iontophoresis of glutamate NMDA receptor agonists increased the baseline-firing rate of these neurons. Coejection of sumatriptan, 4991W93, or ergometrine resulted in a significant reduction in NMDA agonist-induced increases in firing. These data establish the existence of triptan-sensitive (5-HT1) receptors on postsynaptic central trigeminal neurones.
Animals↗
Hypothalamic involvement and activation in cluster headache.
Cluster headache is an episodic form of primary neurovascular headache that is both severe and relatively rare. It is characterized by episodes of headache with cranial parasympathetic activation and sympathetic impairment that come in bouts, or clusters. Its pathophysiology can be divided into understanding the attack phenotype and the biotype of the periodicity. Acute attacks of cluster headache are marked by trigeminal nerve-mediated pain and with cranial autonomic activation, trigeminal-autonomic cephalalgia; an activation that characterizes the phenotype of a group of headaches. The signature feature of cluster headache is its periodicity, the daily cycle of attacks when the patient is in an active bout, or the circumannual, or other period, cycling that distinguishes the on period from the off period. Functional brain imaging with positron emission tomography and structural imaging with voxel-based morphometry have identified an area in the posterior hypothalamic gray as key in understanding cluster headache. This area is subtly enlarged in its gray matter volume, active during an acute cluster headache but inactive when patients are challenged between bouts. Cluster headache is likely to be a form of primary neurovascular pain whose phenotypic expression relies on the trigeminal-autonomic reflex, with a biotype determined by the brain area, the posterior hypothalamus, in which the lesion seems to be located. Understanding both the phenotypic expression and the biotype will, respectively, enable better acute attack treatments and better preventative management of this horrible form of headache.
Biological Clocks↗
4991W93 inhibits release of calcitonin gene-related peptide in the cat but only at doses with 5HT(1B/1D) receptor agonist activity?
Calcitonin gene-related peptide (CGRP) is a marker for trigeminovascular activation and is released during the headache phase of migraine and cluster headache. CGRP may have a role in migraine through its potent cranial vasodilator effects, or by an action on trigeminal nerve activity, both of which are targeted by 5HT(1B/1D) agonist drugs. CP122,288, a conformationally restricted analogue of sumatriptan that is a potent inhibitor of neurogenic plasma protein extravasation (PPE), was ineffective at inhibiting CGRP release at a single low dose; and is also ineffective as an acute anti-migraine compound. However, it remained unclear as to whether, as a class, the conformationally-restricted triptan analogues could have inhibitory effects on CGRP in higher doses. 4991W93, a conformationally restricted analogue of zolmitriptan, is also a potent inhibitor of PPE at doses without 5HT(1B/1D)-mediated effects, that was developed as an anti-migraine drug, and thus was suitable to test whether higher doses of such conformationally restricted triptan analogues could inhibit trigeminal-evoked CGRP release. The superior sagittal sinus (SSS) was stimulated in 14 anaesthetised cats and external jugular vein blood samples were analysed by radioimmunoassay for CGRP levels before, 1 min after SSS stimulation, and 1 min after SSS stimulation in the presence of 4991W93. Stimulation of the SSS resulted in release of CGRP from the external jugular vein. 4991W93 at a dose of 0.1 and 10 microg/kg, selected for maximal PPE blocking effects in rodents, was ineffective at inhibiting CGRP release, with an SSS stimulation level of 78+/-4 pmol/l compared to a post-4991W93 level of 79+/-3 pmol/l (n=4). In comparison CGRP release was inhibited after a dose of 100 microg/kg 4991W93 from 64+/-6 to 36+/-3 pmol/l (n=5). Given that 4991W93 is inactive clinically at non-vascular doses, it seems clear that the 5HT(1B/1D) agonist effects of the compound are necessary for blockade of CGRP release and thus any anti-migraine action. Taken with the clinical results, these data emphasise the importance of CGRP release in migraine, and suggest that other non-5HT-based pharmacological targets may account for PPE blockade in animal studies.
Animals↗
4991W93, a potent blocker of neurogenic plasma protein extravasation, inhibits trigeminal neurons at 5-hydroxytryptamine (5-HT1B/1D) agonist doses.
Triptans share the pharmacological profile of being 5-hydroxytryptamine (5-HT1B/1D) agonists and having potent anti-migraine activity. The conformationally restricted zolmitriptan analogue 4991W93 was developed as a potent, and at low doses, specific, non-vasconstrictor inhibitor of neurogenic dural plasma protein extravasation. Here, we sought to study the effect of 4991W93 at plasma protein extravasation blocking and at 5-HT(1B/1D) agonist doses. Nociceptive cells with firing latencies consistent with Adelta fibres were recorded in the dorsal horn region of the trigeminal nucleus caudalis after electrical stimulation of the sagittal sinus. Both evoked (13 units) and free running (6 units) activity in cells linked to sagittal sinus stimulation were inhibited by 4991W93 delivered microiontophoretically or by intravenous administration at 10 microg/kg or 100 microg/kg, but not 0.1 microg/kg. When applied iontophoretically, 4991W93 did not appear to have an additive effect over a 5-HT(1B/1D) agonist effective concentration of zolmitriptan. These data suggest that 4991W93 is only effective at modulating the trigeminocervical complex at 5-HT(1B/1D) agonist doses. To account for neurogenic dural plasma protein extravasation blockade in animal studies, 4991W93 might have non-5-HT(1B/1D)-based pharmacological targets that are yet to be described.
Animals↗
The periaqueductal grey matter modulates trigeminovascular input: a role in migraine?
The periaqueductal grey (PAG) region of the brainstem is a known modulator of somatic pain transmission. Migraine is likely to be due to episodic brain dysfunction in pathways involved in the control of pain and other sensory modalities, such as light and sound. To investigate the influence of the PAG on pain transmission from intracranial structures, we examined spinal trigeminal neuronal activity in response to PAG stimulation in a model of trigeminovascular nociception in the cat. Evoked trigeminal neuronal activity in the spinal cord was reversibly inhibited by stimulation of the PAG. The effect was robust with a mean reduction in evoked activity of -61+/-21%. This effect could be seen both ipsilateral and contralateral to the side of PAG stimulation and was well localised to the ventrolateral PAG. These data demonstrate that a role of the PAG is to inhibit afferent trigeminal nociceptive traffic. Considered with neurosurgical and human functional imaging studies, these data support the notion that brainstem dysfunction might lead to disinhibition of trigeminal afferents and be important in the pain process of migraines.
Action Potentials↗
GABA receptors modulate trigeminovascular nociceptive neurotransmission in the trigeminocervical complex.
1. GABA (gamma-aminobutyric acid) receptors involved in craniovascular nociceptive pathways were characterised by in vivo microiontophoresis of GABA receptor agonists and antagonists onto neurones in the trigeminocervical complex of the cat. 2. Extracellular recordings were made from neurones in the trigeminocervical complex activated by supramaximal electrical stimulation of superior sagittal sinus, which were subsequently stimulated with L-glutamate. 3. Cell firing evoked by microiontophoretic application of L-glutamate (n=30) was reversibly inhibited by GABA in every cell tested (n=19), the GABA(A) agonist muscimol (n=10) in all cells tested, or both where tested, but not by iontophoresis of either sodium or chloride ions at comparable ejection currents. Inhibited cells received wide dynamic range (WDR) or nociceptive specific input from cutaneous receptive fields on the face or forepaws. 4. The inhibition of trigeminal neurones by GABA or muscimol could be antagonized by the GABA(A) antagonist N-methylbicuculline, 1(S),9(R) in all but two cells tested (n=16), but not by the GABA(B) antagonist 2-hydroxysaclofen (n=11). 5. R(-)-baclofen, a GABA(B) agonist, inhibited the firing of three out of seven cells activated by L-glutamate. Where tested, this inhibition could be antagonized by 2-hydroxysaclofen. These baclofen-inhibited cells were characterized as having low threshold mechanoreceptor/WDR input. 6. GABA thus appears to modulate nociceptive input to the trigeminocervical complex mainly through GABA(A) receptors. GABA(A) receptors may therefore provide a target for the development of new therapeutic agents for primary headache disorders.
Animals↗
SUNCT syndrome or trigeminal neuralgia with lacrimation.
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Autonomic Nervous System↗
Fos expression in the midbrain periaqueductal grey after trigeminovascular stimulation.
There is an accumulating body of evidence suggesting that the periaqueductal grey (PAG) is involved in the pathophysiology of migraine. Positron emission tomography (PET) studies in humans have shown that the caudal ventrolateral midbrain, encompassing the ventrolateral PAG, has activations during migraine attacks. The PAG may well be involved not only through the descending modulation of nociceptive afferent information, but also by its ascending projections to the pain processing centres of the thalamus. In this study the intranuclear oncogene protein Fos was used to mark cell activation in the PAG following stimulation of the trigeminally-innervated superior sagittal sinus (SSS) in both cats and in nonhuman primates (Macaca nemestrina). Fos expression in the PAG increased following stimulation to a median of 242 cells (interquartile range 236-272) in the cat and 155 cells (range 104-203) in the monkey, compared with control levels of 35 cells (21-50) and 26 cells (18-33), respectively. Activation was predominantly in the ventrolateral area of the caudal PAG suggesting that the PAG is involved following trigeminally-evoked craniovascular pain.
Animals↗