Unraveling the Spectrum of Migraine Resistant to Treatments: Searching for Novel Biological PHEnotypes and theRApeutic Approaches (SPHERA Project)
Unraveling the Spectrum of Migraine Resistant to Treatments: Searching for Novel Biological PHEnotypes and theRApeutic Approaches (SPHERA Project)
Primary working hypothesis is that NON-responders to mAbs bear a dysfunction of the endocannabidiome system (eCBome), as suggested by pre-clinical and clinical data by our group.
They will be identified as patients showing a reduction of monthly migraine days < 50% after three months of treatment.
The clinical, biochemical and neurofunctional impact of novel therapeutic approaches expected to interfere with eCBome will be evaluated in NON-responder patients
Monoclonal antibodies directed against the calcitonin gene related peptide pathway (mAbs) have recently become available as the first targeted-therapy for migraine prevention. Despite their revolution in migraine therapy, clinical evidence demonstrated that nearly one-third of patients do not respond to mAbs. Even among Responders (namely those with a reduction in monthly migraine days - MMDs, of at least 50%), almost half still suffers from 8 residual MMDs or more.
There is therefore room for improvement, and understanding the pathophysiological mechanisms involved in these processes is mandatory to develop novel therapies and optimize treatment outcome.
Among several non-CGRP pathways, the eCBome may play a major role in migraine as it interacts with multiple pathways to modulate inflammation and pain.
Previous evidence showed that genes expression of eCBome system is altered in migraine patients.
Interestingly, it seems possible to normalize eCBome dysfunction in migraineurs, as demonstrated by the decrease of FAAH levels in chronic migraineurs with medication overuse who underwent a successful detoxification.
From a therapeutic point of view, a potential role for PEA in the termination of experimentally-induced migraine attack in humans and in the acute treatment of spontaneous attacks were published.
Polyunsaturated fatty acids (PUFAs) are other eCBome precursors involved in neuronal processes and anti-inflammatory properties. Data supports an interconnection between dietary n-3 PUFAs intake, also showing a protective action of high PUFAs intake in inflammation and neurodegenerative disease.
Another therapeutic weapon is represented by the ketogenic diet (KD), a "fat" diet that induces an increase in PUFAs. In migraine, KD reduced the frequency of migraine attacks when compared to a standard mediterranean diet in episodic migraine.
It may interfere with the eCBome at multiple levels (gut and brain) and via multiple mechanisms: i) increase in substrate availability; ii) improvement of cortical metabolism and hyperexcitability enhancing glutamate clearing from astrocytes; ii) modulation of neuro-inflammation.
Preliminary evidence also support a role for KD in treatment-resistant migraine, and in a small number of CM patients resistant to approved therapies, with preliminary data suggest a positive response. Its efficacy in patients who failed mAbs treatment is yet to be elucidated, though.
As intriguing data suggests the possibility to interfere with the eCBome via multiple modalities, ranging from PEA administration to dietary adaptations, it seems extremely interesting to identify an eCBome-dependent migraine phenotype and to test its performance in proof-of-concept therapeutic challenges.
The investigators intend to act on the alteration of microbiota through the ketogenic diet (KD) and on the alteration in endocannabinoids related lipids with PEA or PUFA supplementation. These therapeutic modalities are already available for clinical use and have a highly safe profile, easily ready to be used for improving health in a group of highly disabled patients.
The investigators will also try a concomitant therapy (mAbs + PEA / PUFA) in order to provide insights on the effect of a concomitant dual modulation (CGRP and eCBome system) in patients undergoing mAbs treatment.
Furthermore, a comprehensive biochemical set of potential biomarkers will be evaluated, including neuropeptides, microRNAs, inflammatory cytokines, kynurenine metabolites and brain cortical connectivity trough recording of HD- EEG and rs-fMRI. The biochemical and functional phenotyping will allow the identification of a multibiomarkers panel signature of migraine patients resisting to specifically targeted preventive treatments, potentially associated to the clinical response to treatments that targets different pathways.
Study design:
Patients will be enrolled among those receiving treatment with monoclonal antibodies against the calcitonin gene receptor peptide pathway (mAbs) at the clinic of IRCCS Mondino Institute (Pavia) and Neurology Department of the University of L'Aquila (Avezzano).
The following groups will be identified:
NON-responders will stop mAbs treatment and will receive one of the following:
Partial responders will be assigned to add-on to mAbs:
- PEA (600mg twice a day for three months)
Clinical data will be collected and biochemical and neurofunctional profiling of migraine patients will be performed before starting novel treatment (PEA or KD) (V0) and after three months of treatment (V1). Clinical data will be collected up to 6 months from treatment starting (V2).
Methods:
BIOCHEMICAL PROFILING
All patients will undergo a biochemical profiling that will include analysis of:
The following collection methods will be adopted:
NEUROFUNCTIONAL PROFILING All patients will undergo high density-EEG and subset of 40 patients will also be studied in parallel with resting state- functional MRI at T0.
- HD-EEG: the investigators will randomly acquire 4 recordings (6 minutes each) in resting-state condition, 2 with opened eyes, and 2 with closed eyes. The following frequency bands will be considered: delta (1-4 Hz), theta (4-8 Hz), alfa (8-13 Hz), beta (13-30 Hz), gamma (30-80 Hz).
Acquisition parameters will be: High-Pass: 0.5 Hz; Low-Pass: 100 Hz; Notch: 50 Hz. For analysis of HD-EEG data, a previously developed and validated tailored analysis pipe-line will be used to reconstruct neural sources from cortical/subcortical gray matter. EEG signals will be band-pass filtered (1-80 Hz) and down-sampled at 250 Hz. Biological artifacts will be rejected using Independent Component Analysis (ICA). EEG signals will be referenced with a customized version of the Reference Electrode Standardization Technique (REST). A matrix will estimate the relationship between the measured scalp potentials and the dipoles corresponding to brain sources. Sources reconstruction will be performed with the exact low-resolution brain electromagnetic tomography (eLORETA) algorithm
Statistical analysis As a pilot study, sample size is not calculated and our data will provide the fundament for further confirmatory randomized controlled studies.
The investigators will separately evaluate the clinical effects of Ketogenic Diet and PEA supplementation in NON-responders and PEA supplementation in partial responders.
As statistical test, ANOVA for repeated measure test, with a within-subject TIME factor (T0 vs. T3 vs. T6) will be used. The primary outcome will be the reduction in MMDs at T3 compared with baseline. As secondary outcome the investigators will analyze: modification of monthly headache days, monthly days of acute drug intake, monthly doses of acute drugs, percentage of patients with a 30-50% reduction of MMDs, migraine related disability (MIDAS, HIT-6), and quality of life (MSQ).
Inclusion Criteria:
Exclusion Criteria:
roberto.deicco@mondino.it00390382380425
cinzia.fattore@mondino.it00390382380385