Francesca Coppola

Proinflammatory cytokines, adhesion molecules, and lymphocyte integrin expression in the internal jugular blood of migraine patients without aura assessed ictally.

Objective.—The aim of the present research was to verify the levels of the soluble adhesion molecules sL‐ and sE‐selectins, intercellular adhesion molecule (sICAM)‐1, and vascular cell adhesion molecule‐1 in serial samples of internal jugular venous blood taken from migraine patients without aura (MWoA) during attacks. The expression of leukocyte function antigen (LFA)‐1 and very late activation antigen (VLA)‐4 was also assessed on lymphocytes obtained from jugular venous blood. Levels of certain proinflammatory cytokines (tumor necrosis factor‐α[TNF‐α], interleukin‐1β[IL‐1β], IL‐4, and IL‐6) were also determined and correlated with those of adhesion molecules.

Endocannabinoids in Chronic Migraine: CSF Findings Suggest a System Failure

Based on experimental evidence of the antinociceptive action of endocannabinoids and their role in the modulation of trigeminovascular system activation, we hypothesized that the endocannabinoid system may be dysfunctional in chronic migraine (CM). We examined whether the concentrations of N-arachidonoylethanolamide (anandamide, AEA), palmitoylethanolamide (PEA), and 2-arachidonoylglycerol (2-AG) in the CSF of patients with CM and with probable CM and probable analgesic-overuse headache (PCM+PAOH) are altered compared with control subjects. The above endocannabinoids were measured by high-performance liquid chromatography (HPLC), and quantified by isotope dilution gas-chromatography/mass-spectrometry. Calcitonin gene-related peptide (CGRP) levels were also determined by RIA method and the end products of nitric oxide (NO), the nitrites, by HPLC. CSF concentrations of AEA were significantly lower and those of PEA slightly but significantly higher both in patients with CM and PCM+PAOH than in nonmigraineur controls (p<0.01 and p<0.02, respectively). A negative correlation was found between AEA and CGRP levels in CM and PCM+PAOH patients (r=0.59, p<0.01 and r=−0.65, p<0.007; respectively). A similar trend was observed between this endocannabinoid and nitrite levels. Reduced levels of AEA in the CSF of CM and PCM+PAOH patients may reflect an impairment of the endocannabinoid system in these patients, which may contribute to chronic head pain and seem to be related to increased CGRP and NO production. These findings support the potential role of the cannabinoid (CB)1 receptor as a possible therapeutic target in CM.

Involvement of corticotrophin-releasing factor and orexin-A in chronic migraine and medication-overuse headache: findings from cerebrospinal fluid.

The study set out to investigate the role of corticotrophin-releasing factor (CRF) and orexin-A in chronic migraine (CM) and medication-overuse headache (MOH). Twenty-seven patients affected by CM and 30 with MOH were enrolled. Control CSF specimens were obtained from 20 age-matched subjects who underwent lumbar puncture for diagnostic purposes, and in all of them CSF and blood tests excluded central nervous system or systemic diseases. Orexin-A and CRF were determined by radioimmunoassay methods. Significantly higher levels of orexin-A and CRF were found in the CSF of MOH and to a lesser extent in patients with CM compared with control subjects (orexin-A: P < 0.001 and P < 0.02; CRF: P < 0.002 and P < 0.0003). A significant positive correlation was also found between CSF orexin-A values and those of CRF (R = 0.71; P < 0.0008), monthly drug intake group (R = 0.39; P < 0.03) and scores of a self-completion 10-item instrument to measure dependence upon a variety of substances, the Leeds Dependence Questionnaire (LDQ) in the MOH group (R = 0.68; P < 0.0003). The significantly higher orexin-A levels found in CM and MOH can be interpreted as a compensatory response to chronic head pain or, alternatively, as an expression of hypothalamic response to stress due to chronic pain. A potential role for orexin-A in driving drug seeking in MOH patients through activation of stress pathways in the brain can also be hypothesized.

Glutamate and nitric oxide pathway in chronic daily headache: evidence from cerebrospinal fluid

A central sensitization has been advocated to explain chronic daily headache (CDH) due to sustained peripheral sensitization of algogenic structures responsible for sustained trigeminovascular system activation. Several mechanisms have been suggested to underlie central sensitization, but have been poorly investigated in CDH. They involve N-methyl-D-aspartate (NMDA) receptor activation and nitric oxide (NO) production and supersensitivity and increased and maintained production of sensory neuropeptides. The present study supports the above pathogenic mechanisms demonstrating a significant increase in glutamate and nitrite levels in the CSF of CDH patients, without a significant difference between patients without and those with analgesic overuse headache (P < 0.0001 and P < 0.002). The increase in CSF nitrites was accompanied by a significant rise in the CSF values of cyclic guanosine monophosphate (cGMP) in patients in comparison with controls (P < 0.0001). A statistically significant correlation emerged between visual analogic scale (VAS) values and glutamate, nitrites and cGMP. Although substance P (SP) and calcitonin gene-related peptide (CGRP), and to a lesser extent neurokinin A, were significantly increased in CSF compared with control subjects, their values did not correlate with glutamate, nitrites and cGMP levels in CSF in the patient group. The present study confirms the involvement of glutamate-NO-cGMP-mediated events underlying chronic head pain that could be the target of a new therapeutic approach which should be investigated.

NF‐κB activity and iNOS expression in monocytes from internal jugular blood of migraine without aura patients during attacks

This study investigated nuclear factor-kappa B (NF-κB) activity by electrophoresis mobility gel shift assay and IκBα expression by Western blot analysis in monocytes obtained from serial samples of internal jugular venous blood taken from seven migraine patients without aura during attacks. Inducible nitric oxide synthase (iNOS) expression was also assessed by reverse transcription-polymerase chain reaction. An increase in NF-κB activity peaked 2 h after attack onset. This was accompanied by a transient reduction in IκBα expression. Up-regulation of iNOS was evident at 4 h, maintained at 6 h and reduced at the end of the attack. These findings substantiate the hypothesis of transitory delayed inflammation, as suggested by the animal model, and suggest the possibility of using therapeutic approaches to target NF-κB transcription in the treatment of migraine.

Brain-derived neurotrophic factor in cerebrospinal fluid of patients with chronic daily headache: relationship with nerve growth factor and glutamate levels

Abstract Little has been done to investigate the biochemical basis of chronic daily headache (CDH). Our group has recently demonstrated an increase in the cerebrospinal fluid (CSF) levels of nerve growth factor (NGF) in CDH patients, supporting the involvement of this growth factor in the abnormal processing of head pain in this pathological condition. Other members of the neurotrophin family, especially brain-derived neurotrophic factor (BDNF), have been hypothesized as being involved in the development of chronic head pain in patients affected by CDH, but so far no data are available on this subject. BDNF, NGF and glutamate levels were determined in the CSF of 25 patients affected by CDH with a previous history of migraine. These levels were compared with those of a group of 20 control subjects, for whom the CSF examination and other instrumental investigations excluded diseases of the central and peripheral nervous systems. Significantly higher levels of BDNF, NGF and glutamate were found in CDH patients compared with control subjects (p<0.0001, p<0.0002 and p<0.001, respectively). A significant positive correlation emerged between CSF values of BDNF and those of NGF (r=0.61, p<0.001) and glutamate (r=0.44, p<0.025) in CDH patients. No significant differences were detected in BDNF, NGF and glutamate levels between CDH patients with analgesic overuse and those without. These results support the involvement of BDNF in CDH through the potentiation of glutamatergic transmission involved in the processing of head pain. The significant correlation between BDNF and NGF levels suggests that NGF-mediated up-regulation of BDNF in central sites involved in long-term sensitization plays a key role in persistent head pain in CDH patients.

Language disturbances as a side effect of prophylactic treatment of migraine.

Background.— Language disturbances have been previously described as word‐finding difficulties in epileptic patients. These disturbances have been recently reported in migraineurs in treatment with topiramate but they have never been defined and assessed in these patients with the aid of neuropsychological testing.

Characteristics of Migraine in an Out-Patient Population Over 60 Years of Age

One hundred and sixty-three consecutive patients (129 females and 34 males) over 60 years of age attending the Headache Centre of the University of Perugia in the period January 2000-December 2001 were included in the study. One hundred and fifty-two (93.3%) were affected by a primary headache disorder. According to the 1988 IHS Criteria, their prevailing attacks could be diagnosed as migraine without aura (MwoA) in 57.2% of cases (n = 87) and as migraine with aura (MwA) in 11.8% of cases (n = 18). Attacks both in MwoA and MwA were unilateral and of severe-to-moderate intensity in 45% and 50% of cases. Head pain was referred as pulsating by 56% and 38.9% of MwoA patients MwA patients, respectively. Aggravation with routine daily activities was present in 72.4% and 61.1% in MwoA and MwA patient groups. The most frequent accompanying symptoms were photophobia and phonophobia. Headache attacks were of shorter duration in MwA patients, but in 3.4% of MwoA patients attacks lasted between 2 and 4 h. Of patients affected by MwA, 55% referred, together with the typical attacks, symptoms of aura not followed by headache. A worsening of headache in the last 5 years was reported by 67.8% and 44.4% of MwoA and MwA patients, respectively. Of the patients with MwoA, 86.2% (n = 75), and 83.3% (n = 15) of those with MwA used symptomatic drugs for their attacks. In the majority of cases they took more than one analgesic or non steroidal anti-inflammatory drug. A total of 51.7% of patients with MwoA and 55.5% of patients with MwA were under prophylactic treatment. Preventive drugs included antidepressants, beta-blockers, calcium channel antagonists and antiepileptic drugs. The choice of symptomatic or prophylactic drugs was made, in the majority of cases, on the basis of concomitant diseases.

An open-label pilot study on the efficacy and tolerability of levetiracetam in the prophylaxis of migraine

AbstractA preliminary, open label study was conducted on 20 patients with migraine without aura and with high headache frequency to assess the efficacy and tolerability of the new antiepileptic drug levetiracetam. Patients were treated with levetiracetam for three months. The drug was started at a dose of 500 mg and slowly increased within 10 days to the target dose of 2000 mg/day. After 3 months of treatment, 11 (57.9%) of 19 patients who completed the study had a reduction of at least 50% in headache frequency. The intensity of migraine attacks was significantly reduced as was the use of symptomatic drugs. A 3-month carry-over effect was found in about two-thirds of the 11 patients reporting a positive treatment response. Levetiracetam was well tolerated and no patient discontinued the drug due to side effects. This preliminary study supports the potential role of levetiracetam as a new preventive treatment for migraine without aura. The promising results obtained should be confirmed by further research with a double-blind controlled design.

Application of the ICHD-II criteria to the diagnosis of primary chronic headaches via a computerized structured record.

Background.—The authors recently developed a software program designed to analyze clinical data from patients affected by primary headache. The program is based exclusively on the International Classification of Headache Disorders 2nd edition (ICHD‐II) criteria. This software examines all the diagnoses of primary headaches on the basis of the variables needed to fulfill these mandatory criteria.