Lessons from 8 years' experience of hypothalamic stimulation in cluster headache.

Neuroimaging studies in cluster headache (CH) patients have increased understanding of attack-associated events and provided clues to the pathophysiology of the condition. They have also suggested stimulation of the ipsilateral posterior inferior hypothalamus as a treatment for chronic intractable CH. After 8 years of experience, stimulation has proved successful in controlling the pain attacks in almost 60% of chronic CH patients implanted at various centres. Although hypothalamic implant is not without risks, it has generally been performed safely. Implantation affords an opportunity to perform microrecordings of individual posterior hypothalamic neurons. These studies are at an early stage, but suggest the possibility of identifying precisely the target site by its electrophysiological characteristics. Autonomic studies of patients undergoing posterior hypothalamic stimulation provide further evidence that long-term stimulation is safe, revealing that it can cause altered modulation of the mechanisms of orthostatic adaptation without affecting the baroreflex, cardiorespiratory interactions or efferent sympathetic and vagal functions. Chronically stimulated patients have an increased threshold for cold pain at the site of the first trigeminal branch ipsilateral to the stimulated side; when the stimulator is switched off, changes in sensory and pain thresholds do not occur immediately, suggesting that long-term stimulation is required to induce sensory and nociceptive changes. Posterior inferior hypothalamic stimulation is now established as a treatment for many chronic CH patients. The technique is shedding further light on the pathophysiology of the disease, and is also providing clues to functioning of the hypothalamus itself.

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.

Functional connectivity between trigeminal and occipital nerves revealed by occipital nerve blockade and nociceptive blink reflexes.

Headache syndromes often suggest occipital and neck involvement, although it is still unknown to what extent branches of segment C1-C3 contribute actively to primary headache. Pain within the occipital area may be referred to the trigeminal territory. However, a modulation of trigeminal transmission by affecting cervical input in humans has not been elucidated so far. A convergence of cervical and trigeminal input at the level of the caudal part of the trigeminal nucleus in the brainstem has been suggested due to anatomical and neurophysiological studies in animals. We examined the R2 components of the nociceptive blink reflex responses in 15 healthy subjects before and after unilateral nerve blockade of the greater occipital nerve with 5 ml prilocain (1%). R2 response areas (AUC) decreased and the R2 latencies increased significantly after the nerve blockade only on the side of injection. AUC and latencies on the non-injection side remained stable. Thresholds for sensory or pain perception did not differ significantly between the repeated measurements on both sides. Our findings extend previous results related to anatomical and functional convergence of trigeminal and cervical afferent pathways in animals and suggest that the modulation of this pathway is of potential benefit in primary headache disorders.

Fructose-1,6-bisphosphate as a metabolic substrate in hog ileum smooth muscle during hypoxia.

Exogenously applied fructose-1,6-bisphosphate has been reported to be effective in preventing some damage to the small intestine during ischemia. To determine whether exogenously applied fructose-1,6-bisphosphate protects ileum smooth muscle from damage from hypoxia and from reoxygenation, we examined the effect of fructose-1,6-bisphosphate on the ability of hog ileum smooth muscle to maintain isometric force during hypoxia and to generate isometric force after reoxygenation in the presence of 5 mM glucose. After 180 min of hypoxia, tissues incubated with 20 mM fructose-1,6-bisphosphate maintained significantly greater levels of isometric force than tissues incubated in the absence of exogenous substrate (23% of pre-hypoxia force compared to 16%). During the first contraction following reoxygenation there was a significantly greater force generation in tissues incubated with 20 mM fructose-1,6-bisphosphate during the hypoxia period compared to tissues with no exogenous substrate included during the hypoxia period (29% of pre-hypoxia force compared to 19%). However, glucose always was a better metabolic substrate compared to fructose-1,6-bisphosphate under all experimental conditions. The presence of fructose-1,6-bisphosphate during hypoxia likely improved tissue function by fructose-1,6-bisphosphate entering the cells and acting as a glycolytic intermediate, since during a 120 min period of hypoxia, unmounted ileum smooth muscle metabolized 1,6-13C-fructose-1,6-bisphosphate to 3-13C-lactate. This conversion of 1,6-13C-fructose-1,6-bisphosphate to 3-13C-lactate was inhibited by the addition of 1 mM iodoacetic acid, a glycolytic inhibitor. We conclude that exogenously provided fructose-1,6-bisphosphate does provide modest protection of ileum smooth muscle from hypoxic damage by functioning as a glycolytic intermediate and improving the cellular energy state.