Alessandro Capuano

Topiramate in migraine prophylaxis: A randomised double-blind versus placebo study

The objectives of this paper are to evaluate the efficacy and tolerability of topiramate, given at the dose of 100 mg/day, in the prophylactic treatment of migraine. The hypothesis that migraine is the result of a condition of neuronal hyperexcitability and the quest for drugs that are able to limit the number of crises justifies the attempt to utilise the new antiepileptic drugs in the prophylaxis of this pathology, which is so important due to its high prevalence and due to the high disability it causes. The study was randomised double-blind versus placebo, lasting 16 weeks, and was preceded by a run-in period of 4 weeks. One hundred and fifteen patients were randomly allocated to treatment with topiramate (TPM) or placebo: 35 patients completed the study in the TPM group and 37 patients in the placebo group. At the end of the double-blind phase of study, in the TPM group, we recorded a significant reduction in the frequency of migraine crises (from 5.26 at baseline to 2.60 in the last 4 weeks), a significant reduction in the quantity of symptomatic drugs taken as compared to the placebo control group (from 6.17±1.80 SD to 2.57±0.80) and a significant downward trend in the number of days of disability over the 16-week period of therapy. In the TPM group, side effects were transient and well tolerated. TPM has thus proven its efficacy and tolerability in the prophylaxis of migraine.

Topiramate and triptans revert chronic migraine with medication overuse to episodic migraine

Objective: This is a randomized, double-blind versus placebo study aimed at evaluating the efficacy of topiramate (TPM) in reducing the number of days with headache and the amount of acute medication taken monthly in patients with chronic migraine with medication overuse. We also studied the efficacy of single triptans available in Italy in interrupting headache crises during preventive treatment. Methods: The studied sample was made up of 50 subjects: 30 patients were randomized for treatment with TPM, 100 mg/d, and 20 for placebo. Subjects treated with TPM were further randomized to evaluate, in double-blind versus placebo, the efficacy of single triptans available in Italy. The double-blind phase consisted of a titration phase (4 weeks) and of a maintenance phase (8 weeks). Outcome Measures: The reduction in the number of days with headache per 28 days and the reduction in the amount of acute medication taken per 28 days throughout the clinical trial in the TPM group were compared with those of the placebo group; the number of patients who were pain-free at 2 hours after the triptan intake and the headache recurrence rate in the 22 hours after the pain-free condition in the triptan group were compared with those of the placebo group. We also looked at tolerability profile. Results: The group treated with TPM had a significant reduction in the number of days with headache (P < 0.0001 vs placebo) and in the mean amount of acute medication taken (P < 0.0001 vs placebo); all triptans were superior to placebo; there were no significant differences between different triptans; the analgesic effect of triptans increased throughout the trial. Conclusions: Topiramate proved to be well tolerated and effective in reverting chronic migraine with medication overuse to episodic migraine.

Influence of cholinergic circuitries in generation of high-frequency somatosensory evoked potentials

OBJECTIVE High-frequency oscillations (HFOs) evoked by upper limb stimulation reflect highly synchronised spikes generated in the somatosensory human system. Since acetylcholine produces differential modulation in subgroups of neurons, we would determine whether cholinergic drive influences HFOs. METHODS We recorded somatosensory evoked potentials (SEPs) from 31 scalp electrodes in 7 healthy volunteers, before and after single administration of rivastigmine, an inhibitor of central acetylcholinesterase. Right median nerve SEPs have been analysed after digital narrow bandpass filtering (500-700 Hz). Raw data were further submitted to Brain Electrical Source analysis (BESA) to evaluate the respective contribution of lemniscal, thalamic and cortical sources. Lastly, we analysed by Fast Fourier transform spectral changes after drug administration in the 10-30 ms latency range. RESULTS Rivastigmine administration caused a significant increase of HFOs in the 18-28 ms latency range. Wavelets occurring before the onset latency of the conventional N20 SEP did not show any significant change. A similar increase concerned the strength of cortical dipolar sources in our BESA model. Lastly, we found a significant power increase of the frequency peak at about 600 Hz in P3-F3 traces after drug intake. CONCLUSIONS Our findings demonstrate that the cortical component of HFOs is significantly enhanced by cholinergic activation. Pyramidal chattering cells, which are capable to discharge high-frequency bursts, are mainly modulated by cholinergic inputs; by contrast, acetylcholine does not modify the firing rate of fast-spiking GABAergic interneurons. We thus discuss the hypothesis that cortical HFOs are mainly generated by specialised pyramidal cells.

Migraine equivalents as part of migraine syndrome in childhood

BACKGROUND Migraine equivalents are common clinical conditions without a headache component, occurring as repeated episodes with complete remission between episodes. They include abdominal migraine, cyclical vomiting, benign paroxysmal vertigo, and benign paroxysmal torticollis. Other clinical entities, such as motion sickness and limb pain have been associated with migraine. We aimed to investigate the prevalence of migraine equivalents in a large population of children referred to a pediatric headache center and to analyze the possible relationship between migraine equivalents and headache features. METHODS A total of 1134 of children/adolescents (73.2% with migraine and 26.8% with tension-type headache) were included. Patients were divided into two groups according to the episode frequency (high and low). Pain intensity was rated on a three-level graduate scale (mild, moderate, and severe pain). RESULTS Migraine equivalents were reported in 70.3% of patients. Abdominal migraine (48.9%), limb pain (43.9%), and motion sickness (40.5%) were the most common migraine equivalents. Although headache type (migraine or tension-type headache) did not correlate with migraine equivalents presence (χ(2) = 33.2; P = 0.27), high frequency of headache episodes correlated with the occurrence of migraine equivalents. Moreover, migraine equivalents indicated a protective role for some accompanying feature of the headache episode. CONCLUSIONS Our results suggest that migraine equivalents should not be considered merely as headache precursors, but they as part of the migrainous syndrome. Thus, their inclusion among the diagnostic criteria for pediatric migraine/tension-type headache is useful.

Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy

Microtubules are dynamic cytoskeletal elements coordinating and supporting a variety of neuronal processes, including cell division, migration, polarity, intracellular trafficking, and signal transduction. Mutations in genes encoding tubulins and microtubule-associated proteins are known to cause neurodevelopmental and neurodegenerative disorders. Growing evidence suggests that altered microtubule dynamics may also underlie or contribute to neurodevelopmental disorders and neurodegeneration. We report that biallelic mutations in TBCD, encoding one of the five co-chaperones required for assembly and disassembly of the αβ-tubulin heterodimer, the structural unit of microtubules, cause a disease with neurodevelopmental and neurodegenerative features characterized by early-onset cortical atrophy, secondary hypomyelination, microcephaly, thin corpus callosum, developmental delay, intellectual disability, seizures, optic atrophy, and spastic quadriplegia. Molecular dynamics simulations predicted long-range and/or local structural perturbations associated with the disease-causing mutations. Biochemical analyses documented variably reduced levels of TBCD, indicating relative instability of mutant proteins, and defective β-tubulin binding in a subset of the tested mutants. Reduced or defective TBCD function resulted in decreased soluble α/β-tubulin levels and accelerated microtubule polymerization in fibroblasts from affected subjects, demonstrating an overall shift toward a more rapidly growing and stable microtubule population. These cells displayed an aberrant mitotic spindle with disorganized, tangle-shaped microtubules and reduced aster formation, which however did not alter appreciably the rate of cell proliferation. Our findings establish that defective TBCD function underlies a recognizable encephalopathy and drives accelerated microtubule polymerization and enhanced microtubule stability, underscoring an additional cause of altered microtubule dynamics with impact on neuronal function and survival in the developing brain.

Trigeminal satellite cells express functional calcitonin gene-related peptide receptors, whose activation enhances interleukin-1β pro-inflammatory effects

Calcitonin gene-related peptide (CGRP) is the main mediator of trigeminal pain signal. Functional CGRP receptors were detected in trigeminal satellite cells, a specialized type of glia found within the sensory ganglia. CGRP displayed modest pro-inflammatory effects per se on trigeminal satellite cells, while it significantly enhanced IL-1β actions, increasing the expression and activity of cycloxygenase 2 as well as the expression of the inducible form of nitric oxide synthase and IL-1β. CGRP effects were reverted by a specific CGRP receptor antagonist and mimicked by elevation of intracellular cAMP levels. CGRP exerted also minor proinflammatory effects on cortical astrocytes.

Nociceptin (1–13)NH2 Inhibits Stimulated Calcitonin-Gene-Related-Peptide Release From Primary Cultures of Rat Trigeminal Ganglia Neurones

In this work we have developed and characterized primary cultures of neonatal rat trigeminal ganglia neurones; calcitonin-gene-related-peptide (CGRP) released from cells was taken as a marker of neuronal function. A significant and consistent increase in CGRP secretion was elicited by non-specific (56 mM KCl or veratridine) or specific (capsaicin) depolarizing stimuli. This paradigm was subsequently used to investigate the effects of nociceptin, an opioid-like peptide involved in central and peripheral control of nociception. We found that the nociceptin analogue nociceptin (1–13)NH2 (NOC) did not affect baseline CGRP release, but it reduced in a concentration-dependent manner CGRP release induced by all tested stimuli. NOC-induced reduction was statistically significant from 0.01 nM onward and achieved maximal effects at 10 nM. Such effects of NOC were seemingly mediated by the activation of specific ORL1 receptors, as a well-known nociceptin antagonist, N(Phe1)nociceptin (1–13)NH2, was able to completely revert NOC inhibition of capsaicin-stimulated CGRP release.

A sleep study in cluster headache

Cluster headache (CH) is a primary headache with a close relation to sleep. CH presents a circa-annual rhythmicity; attacks occur preferably during the night, in rapid eye movement (REM) sleep, and they are associated with autonomic and neuroendocrine modifications. The posterior hypothalamus is the key structure for the biological phenomenon of CH. Our aim is to describe a 55-year-old man presenting a typical episodic CH, in whom we performed a prolonged sleep study, consisting of a 9-week actigraphic recording and repeated polysomnography, with evaluation of both sleep macrostructure and microstructure. During the acute bout of the cluster we observed an irregular sleep-wake pattern and abnormalities of REM sleep. After the cluster phase these alterations remitted. We conclude that CH was associated, in this patient, with sleep dysregulation involving the biological clock and the arousal mechanisms, particularly in REM. All these abnormalities are consistent with posterior hypothalamic dysfunction.

Correlation between algogenic effects of calcitonin-gene-related peptide (CGRP) and activation of trigeminal vascular system, in an in vivo experimental model of nitroglycerin-induced sensitization

The neural mechanism(s) underlying migraine remain poorly defined at present; preclinical and clinical studies show an involvement of CGRP in this disorder. However current evidence pointed out that CGRP does not exert an algogenic action per se, but it is able to mediate migraine pain only if the trigeminal-vascular system is sensitized. The present study was addressed to investigate CGRP-evoked behavior in nitric oxide (NO) sensitized rats, using an experimental model of nitroglycerin induced sensitization of trigeminal system, looking at neuropeptide release from different cerebral areas after the intra-peritoneal (i.p.) administration of NO-donors. CGRP injected into the rat whisker pad did not induce significant changes in face rubbing behavior compared to controls. On the contrary, CGRP injected in animals pre-treated with 10mg/kg nitroglycerin significantly increased the time spent in face rubbing. Nitroglycerin pre-treated animals did not show any rubbing behavior after locally injected saline. Furthermore, the i.p. treatment with nitroglycerin produced an increase of CGRP levels in brainstem and trigeminal ganglia, but not in the hypothalamus and hippocampus. The absolute amounts of CGRP produced in the brainstem were lower compared to those in the trigeminal ganglion; however, after nitroglycerin stimulation the percentage increase was higher in the brainstem. In conclusion, findings presented in this study suggest that CGRP induces a painful behavior in rats only after sensitization of trigeminal system; thus supporting the concept that a genetic as well as acquired predisposition to trigemino- vascular activation represents the neurobiological basis of CGRP nociceptive effects in migraineurs.

Primary headache pathophysiology in children: The contribution of clinical neurophysiology

Although primary headaches are very prevalent also in pediatric age, most neurophysiologic studies in these diseases concerned only the adulthood. The neurophysiologic investigation of the pathophysiological mechanisms subtending migraine and tension-type headache in children and adolescents could be particularly interesting, since during the developmental age the migrainous phenotype is scarcely influenced by many environmental factors that can typically act on adult headache patients. The neurophysiologic abnormality most frequently found in adult migraineurs, that is the reduced habituation of evoked potentials, was confirmed also in migraine children, although it was shown to involve also children with tension-type headache. Some studies showed abnormalities in the maturation of brain functions in migraine children and adolescents. While the visual system maturation seems slowed in young migraineurs, the psychophysiological mechanisms subtending somatosensory spatial attention in migraine children are more similar to those of healthy adults than to those of age-matched controls. There are some still unexplored fields that will have to be subjects of future studies. The nociceptive modality, which has been investigated in adult patients with primary headaches, should be studied also in pediatric migraine. Moreover, the technique of transcranial magnetic stimulation, not yet used in young migraineurs, will possibly provide further elements about brain excitability in migraine children.