Posterior Hypothalamic and Brainstem Activation In Hemicrania
Posterior Hypothalamic and Brainstem Activation In Hemicrania
Objective: To determine the brain structures involved in mediating the pain of hemicrania continua using positron emission tomography.
Background: Hemicrania continua is a strictly unilateral, continuous headache of moderate intensity, with superimposed exacerbations of severe intensity that are accompanied by trigeminal autonomic features and migrainous symptoms. The syndrome is exquisitely responsive to indomethacin. Its clinical phenotype overlaps with that of the trigeminal autonomic headaches and migraine in which the hypothalamus and the brainstem, respectively, have been postulated to play central pathophysiologic roles. We hypothesized, based on the clinical phenotype, that hemicrania continua may involve activations in the hypothalamus, or dorsal rostral pons, or both.
Methods: Seven patients with hemicrania continua were studied in two sessions each. In one session, the patients were scanned during baseline pain and when rendered completely pain free after being administered indomethacin 100 mg intramuscularly. In the other session, the patients were scanned during baseline pain and when still in pain after being administered placebo intramuscularly. Seven age- and sex-matched nonheadache subjects acted as the control group. The scan images were processed and analyzed using SPM99.
Results: There was a significant activation of the contralateral posterior hypothalamus and ipsilateral dorsal rostral pons in association with the headache of hemicrania continua. In addition, there was activation of the ipsilateral ventrolateral midbrain, which extended over the red nucleus and the substantia nigra, and bilateral pontomedullary junction. No intracranial vessel dilatation was obvious.
Conclusions: This study demonstrated activations of various subcortical structures, in particular the posterior hypothalamus and the dorsal rostral pons. If posterior hypothalamic and brainstem activation are considered as markers of trigeminal autonomic headaches and migrainous syndromes, respectively, then the activation pattern demonstrated in hemicrania continua mirrors the clinical phenotype, with its overlap with trigeminal autonomic headaches and migraine.
Hemicrania continua (HC) is a strictly unilateral, continuous headache of moderate intensity, with superimposed exacerbations of severe intensity that are accompanied, ipsilateral to the pain, by at least one of conjunctival injection, lacrimation, nasal congestion, rhinorrhea, ptosis, or myosis. A complete response to indomethacin is a prerequisite for diagnosis by the classification criteria of the International Headache Society (IHS).
The clinical description and exquisite response to indomethacin of HC was first described by Medina and Diamond as "a cluster headache variant." Interestingly, Boghan and Desaulniers described the problem as a "background vascular headache." Sjaastad and Spierings coined the term "hemicrania continua" in 1984 when they described two further cases. Over 130 cases have been described in the literature. The incidence and prevalence of HC is not known and there is probably now a negative publication bias since the disorder is itself well recognized. It was thought to be a very rare syndrome; however, headache clinics which have systematically sought this entity have rapidly identified significant number of patients thereby suggesting that the condition is underdiagnosed.
The pathophysiology of HC is poorly understood. The possible involvement of the cranial vasculature has been investigated using orbital phlebography in six patients. An abnormality was detected in only one patient who had bilateral narrowing of the ophthalmic vein and therefore this finding is unlikely to be specific for the unilateral pain. The role of the pain-control system has been studied by measuring pressure pain thresholds. The pain pressure thresholds were reported to be reduced in patients with HC, as they are in paroxysmal hemicrania and cluster headache. Pupillometric studies have shown no clear abnormality in HC and studies of facial sweating have shown modest changes similar to those seen in PH.
The nosological status of HC is unclear. Attempts have been made to classify HC on the basis of its clinical features. Goadsby and Lipton have proposed the term "trigeminal autonomic cephalgias" to describe a group of primary headache disorders characterized by unilateral trigeminal distribution pain that occurs in association with prominent ipsilateral cranial autonomic features. HC was then considered as a trigeminal autonomic cephalgia (TAC) in view of the strictly unilateral pain and the association of the autonomic features with the painful exacerbations, though the autonomic features are less prominent than in the other TACs, such as cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) syndrome. Furthermore, both HC and paroxysmal hemicrania exhibit exquisite indomethacin-responsiveness thereby raising the possibility of a common biological basis.
Conversely, it has been proposed that HC is a migraine variant. This has been suggested on the basis of the observation that migraine-related symptoms occur commonly in this disorder, especially during the painful exacerbations. Furthermore, in one series 74.5% of the patients had either episodic migraine or a migrainous disorder before HC developed and 67.5% had a family history of migraine. Hence, the clinical phenotype of HC has features that overlap with both migraine and TACs.
Developments in functional brain imaging are beginning to provide new insights into the pathophysiology of primary headaches. Positron-emission tomography (PET) and functional magnetic resonance imaging (fMRI) in primary headaches, such as migraine, cluster headache, and SUNCT syndrome, have demonstrated activations in brain areas associated with pain, such as the cingulate cortex, insulae, frontal cortex, thalamus, basal ganglia, and the cerebellum. These areas are similarly activated when head pain is induced by the injection of capsaicin into the forehead of volunteers. In addition to these generic pain areas, activations in specific brain regions can be seen in migraine that are not observed when the first (ophthalmic) division pain pathways are activated by the capsaicin injections. Specifically, brainstem areas are activated in migraine, which has recently been refined in localization to the dorsal pons. In contrast the posterior hypothalamic gray matter seems to be uniquely activated in cluster headache and SUNCT syndrome. These data raise the possibility that hypothalamic and brainstem activities are markers of TACs and migraine, respectively.
In this study, we sought to determine the brain structures active in HC with regional cerebral blood flow (rCBF) PET as an index for neuronal activity. We hypothesized, based on the clinical phenotype, that the pain of HC would involve the hypothalamus or the dorsal rostral pons, or both.
Objective: To determine the brain structures involved in mediating the pain of hemicrania continua using positron emission tomography.
Background: Hemicrania continua is a strictly unilateral, continuous headache of moderate intensity, with superimposed exacerbations of severe intensity that are accompanied by trigeminal autonomic features and migrainous symptoms. The syndrome is exquisitely responsive to indomethacin. Its clinical phenotype overlaps with that of the trigeminal autonomic headaches and migraine in which the hypothalamus and the brainstem, respectively, have been postulated to play central pathophysiologic roles. We hypothesized, based on the clinical phenotype, that hemicrania continua may involve activations in the hypothalamus, or dorsal rostral pons, or both.
Methods: Seven patients with hemicrania continua were studied in two sessions each. In one session, the patients were scanned during baseline pain and when rendered completely pain free after being administered indomethacin 100 mg intramuscularly. In the other session, the patients were scanned during baseline pain and when still in pain after being administered placebo intramuscularly. Seven age- and sex-matched nonheadache subjects acted as the control group. The scan images were processed and analyzed using SPM99.
Results: There was a significant activation of the contralateral posterior hypothalamus and ipsilateral dorsal rostral pons in association with the headache of hemicrania continua. In addition, there was activation of the ipsilateral ventrolateral midbrain, which extended over the red nucleus and the substantia nigra, and bilateral pontomedullary junction. No intracranial vessel dilatation was obvious.
Conclusions: This study demonstrated activations of various subcortical structures, in particular the posterior hypothalamus and the dorsal rostral pons. If posterior hypothalamic and brainstem activation are considered as markers of trigeminal autonomic headaches and migrainous syndromes, respectively, then the activation pattern demonstrated in hemicrania continua mirrors the clinical phenotype, with its overlap with trigeminal autonomic headaches and migraine.
Hemicrania continua (HC) is a strictly unilateral, continuous headache of moderate intensity, with superimposed exacerbations of severe intensity that are accompanied, ipsilateral to the pain, by at least one of conjunctival injection, lacrimation, nasal congestion, rhinorrhea, ptosis, or myosis. A complete response to indomethacin is a prerequisite for diagnosis by the classification criteria of the International Headache Society (IHS).
The clinical description and exquisite response to indomethacin of HC was first described by Medina and Diamond as "a cluster headache variant." Interestingly, Boghan and Desaulniers described the problem as a "background vascular headache." Sjaastad and Spierings coined the term "hemicrania continua" in 1984 when they described two further cases. Over 130 cases have been described in the literature. The incidence and prevalence of HC is not known and there is probably now a negative publication bias since the disorder is itself well recognized. It was thought to be a very rare syndrome; however, headache clinics which have systematically sought this entity have rapidly identified significant number of patients thereby suggesting that the condition is underdiagnosed.
The pathophysiology of HC is poorly understood. The possible involvement of the cranial vasculature has been investigated using orbital phlebography in six patients. An abnormality was detected in only one patient who had bilateral narrowing of the ophthalmic vein and therefore this finding is unlikely to be specific for the unilateral pain. The role of the pain-control system has been studied by measuring pressure pain thresholds. The pain pressure thresholds were reported to be reduced in patients with HC, as they are in paroxysmal hemicrania and cluster headache. Pupillometric studies have shown no clear abnormality in HC and studies of facial sweating have shown modest changes similar to those seen in PH.
The nosological status of HC is unclear. Attempts have been made to classify HC on the basis of its clinical features. Goadsby and Lipton have proposed the term "trigeminal autonomic cephalgias" to describe a group of primary headache disorders characterized by unilateral trigeminal distribution pain that occurs in association with prominent ipsilateral cranial autonomic features. HC was then considered as a trigeminal autonomic cephalgia (TAC) in view of the strictly unilateral pain and the association of the autonomic features with the painful exacerbations, though the autonomic features are less prominent than in the other TACs, such as cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) syndrome. Furthermore, both HC and paroxysmal hemicrania exhibit exquisite indomethacin-responsiveness thereby raising the possibility of a common biological basis.
Conversely, it has been proposed that HC is a migraine variant. This has been suggested on the basis of the observation that migraine-related symptoms occur commonly in this disorder, especially during the painful exacerbations. Furthermore, in one series 74.5% of the patients had either episodic migraine or a migrainous disorder before HC developed and 67.5% had a family history of migraine. Hence, the clinical phenotype of HC has features that overlap with both migraine and TACs.
Developments in functional brain imaging are beginning to provide new insights into the pathophysiology of primary headaches. Positron-emission tomography (PET) and functional magnetic resonance imaging (fMRI) in primary headaches, such as migraine, cluster headache, and SUNCT syndrome, have demonstrated activations in brain areas associated with pain, such as the cingulate cortex, insulae, frontal cortex, thalamus, basal ganglia, and the cerebellum. These areas are similarly activated when head pain is induced by the injection of capsaicin into the forehead of volunteers. In addition to these generic pain areas, activations in specific brain regions can be seen in migraine that are not observed when the first (ophthalmic) division pain pathways are activated by the capsaicin injections. Specifically, brainstem areas are activated in migraine, which has recently been refined in localization to the dorsal pons. In contrast the posterior hypothalamic gray matter seems to be uniquely activated in cluster headache and SUNCT syndrome. These data raise the possibility that hypothalamic and brainstem activities are markers of TACs and migraine, respectively.
In this study, we sought to determine the brain structures active in HC with regional cerebral blood flow (rCBF) PET as an index for neuronal activity. We hypothesized, based on the clinical phenotype, that the pain of HC would involve the hypothalamus or the dorsal rostral pons, or both.
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