Ilenia Corbelli

Pathophysiological basis of migraine prophylaxis.

Several cellular and molecular mechanisms have been implicated in migraine pathophysiology including abnormal neuronal excitability and vascular events. Drugs from different pharmacological classes are used for migraine prophylaxis. These agents may normalize neuronal excitability by modulating distinct ionic channels and various neurotransmitter systems. They can also block cortical spreading depression, prevent peripheral and/or central pain sensitization, and normalize brainstem function. Most of the drugs recently used in migraine prophylaxis have been identified by serendipidy and they have been originally approved for other indications. Subsequently, their use has been extended to migraine prevention, according to their putative mechanisms of action. More recently, trials on adequate samples of migraine patients have been conducted for several drugs. In the present review, we will present and discuss the pathophysiological bases for the use of antidepressants, beta-adrenergic blockers, calcium channel blockers and antiepileptic drugs in migraine prevention. Currently, the major classes of conventional migraine preventive drugs include the antidepressant amitriptyline, the beta-adrenergic blocker propranolol, and the antiepileptic drugs topiramate and valproic acid. Promising results have recently been obtained for angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor blockers. Some limited clinical findings have also been reported for atypical antipsychotic agents, nutritional supplements and also botulinum toxin. Targets of migraine preventive treatment are to reduce frequency and intensity of attacks and to decrease disability related to chronic headache.

Levodopa-induced plasticity: a double- edged sword in Parkinson's disease?

The long-term replacement therapy with the dopamine (DA) precursor 3,4-dihydroxy-l-phenylalanine (L-DOPA) is a milestone in the treatment of Parkinsons disease (PD). Although this drug precursor can be metabolized into the active neurotransmitter DA throughout the brain, its therapeutic benefit is due to restoring extracellular DA levels within the dorsal striatum, which lacks endogenous DA as a consequence of the neurodegenerative process induced by the disease. In the early phases of PD, L-DOPA treatment is able to restore both long-term depression (LTD) and long-term potentiation (LTP), two major forms of corticostriatal synaptic plasticity that are altered by dopaminergic denervation. However, unlike physiological DA transmission, this therapeutic approach in the advanced phase of the disease leads to abnormal peaks of DA, non-synaptically released, which are supposed to trigger behavioural sensitization, namely L-DOPA-induced dyskinesia. This condition is characterized by a loss of synaptic depotentiation, an inability to reverse previously induced LTP. In the advanced stages of PD, L-DOPA can also induce non-motor fluctuations with cognitive dysfunction and neuropsychiatric symptoms such as compulsive behaviours and impulse control disorders. Although the mechanisms underlying the role of L-DOPA in both motor and behavioural symptoms are still incompletely understood, recent data from electrophysiological and imaging studies have increased our understanding of the function of the brain areas involved and of the mechanisms implicated in both therapeutic and adverse actions of L-DOPA in PD patients.

Palinopsia in patients with migraine: A case-control study

Objectives: This study was aimed at investigating the frequency of the visual phenomenon of palinopsia (visual perseveration) in patients with migraine. Methods: We interviewed 63 patients with migraine with aura (MwA), 137 patients with migraine without aura (MwoA) and 226 sex-age-matched healthy control subjects using an ad hoc structured interview/questionnaire. The interview was divided into four classes of variables for statistical testing. Results: Palinopsia occurred in 19/200 patients (9.5%); of them 10/63 had MwA and 9/137 MwoA (14.2% vs 6.6%, chi = 9.7, degrees of freedom = 1, p = 0.002). Patients with palinopsia had a significantly lower migraine attack frequency than those without this visual phenomenon (4.3 ± 0.3 vs 14.4 ± 0.2, z = 7.1, p < 0.0001). No healthy control subjects complained of palinopsia according to the structured interview/questionnaire. Discussion: Palinopsia is probably under-diagnosed in patients with migraine. Further investigations are needed to assess whether migraineurs are particularly susceptible to the development of recurrent episodes of visual perseveration.

Sodium valproate in migraine without aura and medication overuse headache: a randomized controlled trial.

OBJECTIVE To assess the efficacy, safety and tolerability of sodium valproate (800mg/die) compared with placebo in medication-overuse headache patients with a history of migraine without aura. METHODS This is a multicenter, randomized, double-blind, placebo-controlled study enrolled medication-overuse headache patients for a 3-month treatment period with sodium valproate (800mg/day) or placebo after a 6 day outpatient detoxification regimen, followed by a 3-month follow-up. Primary outcome was defined by the proportion of patients achieving ≥50% reduction in the number of days with headache per month (responders) from the baseline to the last 4 weeks of the 3-month treatment. Multivariate logistic regression models were used on the primary endpoint, adjusting for age, sex, disease duration, comorbidity and surgery. The last-observation-carried-forward method was used to adjust for missing values. RESULTS Nine sites enrolled 130 patients and, after a 6-day detoxification phase, randomized 88 eligible patients. The 3-month responder rate was higher in the sodium valproate (45.0%) than in the placebo arm (23.8%) with an absolute difference of about 20% (p=0.0431). Sodium valproate had safety and tolerability profiles comparable to placebo. CONCLUSIONS The present study supports the efficacy and safety of sodium valproate in the treatment of medication overuse headache with history of migraine after detoxification.

Psychopathological comorbidities in medication-overuse headache: a multicentre clinical study.

In medication‐overuse headache (MOH) patients, the presence of psychopathological disturbances may be a predictor of relapse and poor response to treatment. This multicentre study aimed to assess the occurrence of psychopathological disorders in MOH patients by comparing the incidence of psychopathological disturbances with episodic migraine (EM) patients and healthy controls (HC).

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.

Migraine preventive drug-induced weight gain may be mediated by effects on hypothalamic peptides: The results of a pilot study

Aims: This study was aimed to verify changes in the levels of hypothalamic neuropeptides in migraineurs under preventive treatment with amitryptiline and flunarizine. Thirty-nine migraine patients with a body mass index <25 kg/m2 and without endocrinological or metabolic diseases were assigned to two treatment groups, one receiving amitryptiline, the other flunarizine, for 3 months. Orexin-A, orexin-B and neuropeptide-Y plasma levels were measured at the basal time, at the 1st, 2nd and 3rd months of preventive treatment. Results: A statistically significant reduction in plasma orexin-A and orexin-B levels emerged in both groups. Conversely, plasma neuropeptide-Y levels were markedly increased, with the highest levels at the 2nd and 3rd months, in both patient groups. Orexin-A levels were also negatively correlated to weight gain in both groups during the treatment period. Conclusions: These results suggest that changes in the levels of hypothalamic orexinergic peptides may contribute to body weight increase occurring in migraineurs during amitryptiline or flunarizine prophylactic treatment.

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.

Application of ICHD 2nd edition criteria for primary headaches with the aid of a computerised, structured medical record for the specialist

We tested the computerised, structured medical record by entering and analysing the consecutive clinical sheets of primary headaches in the episodic forms (200) and chronic headache (200) and the corresponding output diagnoses of patients attending our Headache Centre. A diagnosis of one of the primary headache forms was obtained in 67.9% of cases. A certain diagnosis of primary headache plus that of a probable form was obtained in 24.4% of cases (12.7% represented by chronic migraine (CM) or chronic tension–type headache (CTTH)+probable medicationoveruse headache). Only probable forms were diagnosed in the remaining 7.3% (as single probable diagnosis in 5.8% of cases or multiple diagnoses of probable forms in the remaining ones). The percentage of certain diagnoses mainly in the chronic headache group (28.4%), and to a lesser extent tension–type headache (6.5%), were obtained in 34.9% of cases. A certain diagnosis of one chronic form plus that of a probable form was obtained in 50.8% of cases (26.9% represented by probable medication–overuse headache). Only probable forms were diagnosed in 13.46% (as single probable diagnosis in 8.73% of cases or multiple diagnoses of probable forms in the remaining ones). In the other cases, the ICHD–II classification does not allow the diagnoses of CM, CTTH or probable forms and medicationoveruse headache because the mandatory criteria for the diagnoses are too stringent and do not reflect modifications of the headache pattern in relation to its chronicity. These preliminary results underscore the usefulness of a computerised device based on the ICHD 2nd edition for diagnostic purposes in tertiary centres dedicated to headaches in clinical practice as well as its relevance for research. This computerised device may help to validate the new diagnostic criteria and to answer some emerging questions from the application of the new classification version, the relevance of which should be verified in clinical practice.

Stopping onabotulinum treatment after the first two cycles might not be justified: Results of a real-life monocentric prospective study in chronic migraine

Introduction Onabotulinum toxin A (OnabotA) cyclic treatment is approved for the prophylactic treatment of chronic migraine (CM), a highly disabling disorder. Although treatment response varies among patients, current guidelines suggest to stop treatment after cycle 2 if no response is achieved. This prospective study aimed to define, in real-life setting, the evolution of the response to OnabotA over five cycles of treatment among patients non-responding to cycle 1. The results of this study might help in decision-making, in particular whether prosecuting OnabotA further or not, when facing a patient not responding to cycle 1. Methods Patients failing to respond at cycle 1 were recruited to complete five cycles. Key outcomes were: (i) a ≥50% reduction in headache days, (ii) a ≥50% reduction in total cumulative hours of headache on headache days and (iii) a ≥5-point improvement in Headache Impact Test-6 (HIT-6) scores. Results Overall, 56 patients were included. Mean age was 45.7 years (female 83.9%). Severe (≥60) HIT-6 score was reported at baseline by 95.8% of patients. Responders (headache days reduction of more than 50%) progressively increased cycle after cycle, doubling from cycle 2 to cycle 5 (from 27 to 48%). In addition, patients regressed from CM to episodic migraine moving on with each cycle, with 78% of them reaching less than nine migraine days/month after cycle 5. The headache days per month decreased significantly from cycle 1 to cycle 5 (overall from 23.3 ± 5.7 to 9.2 ± 3.6; p < 0.001). During 12 months (5 cycles), migraine days per month progressively abated (from 18.5 to 8.7; p < 0.001), days with symptomatic medications intake/month consistently decreased (from 17.4 to 8.1; p < 0.001), and mean HIT-6 score lowered (from 72.4 ± 5.7 to 50.2 ± 4.3; p < 0.001). Conclusion The positive effect of OnabotA treatment spreads over the course of the treatment and might also manifest late in treatment course among patients with no benefit after the first two cycles. Thus, the results of this real-life study suggest to extend OnabotA treatment further, beyond cycle 2, to avoid premature withdrawal in patients who would have become responders at cycle 3, 4, or 5.