An observational study on monoclonal antibodies against calcitonin-gene-related peptide and its receptor.

BACKGROUND AND PURPOSE: Based on their pharmacological target, two classes of calcitonin-gene-related peptide (CGRP) monoclonal antibodies (mAbs) have been identified: antibodies against the CGRP ligand-galcanezumab, fremanezumab, eptinezumab-and antibodies against the CGRP receptor (CGRP-R), erenumab. The aim of the present study was to compare anti-CGRP versus anti-CGRP-R mAbs in patients with high frequency episodic and chronic migraine. METHODS: All patients on monthly treatment with anti-CGRP mAbs with an available 6 months' follow-up at January 2022 were included. Data on efficacy outcome were collected following one (T1), three (T3) and six (T6) months of treatment, and included monthly headache/migraine days, the Migraine Disability Assessment Scale (MIDAS) and Headache Impact Test 6 (HIT-6) scores, pain intensity, analgesics consumption and response rates (>50% headache days reduction compared to baseline). RESULTS: In all, 152 patients were enrolled, of whom 68 were in treatment with anti-CGRP mAbs (49 galcanezumab, 19 fremanezumab) and 84 with the anti-CGRP-R (erenumab). MIDAS scores were significantly lower in the anti-CGRP group at T1 and T3 (respectively p < 0.02 and p < 0.03) as well as the number of mean migraine days at T3 (p < 0.01). At T3 and T6 outcome measures were comparable, although a significantly higher percentage of super-responders was found in the anti-CGRP group (respectively p < 0.04 and p < 0.05), with a similar overall percentage of responders. CONCLUSIONS: The present study on a real-world sample confirms the beneficial effect of both anti-CGRP and anti-CGRP-R mAbs, with a more favorable outcome for anti-CGRP antibodies.

Migraine Disability and Severity Improvement during Long-Term Treatment with Erenumab.

The aim of the present study was to assess erenumab efficacy in migraine disability and intensity throughout the first treatment cycle, discontinuation, and the first 6 months of re-treatment in patients with high-frequency episodic migraine. The study design was retrospective and observational. Inclusion criteria were the following: diagnosis of high-frequency episodic migraine and ongoing treatment with erenumab 140 mg currently at their second treatment cycle. Data regarding migraine frequency, disability (MIDAS score), and severity of attacks (NRS score) were collected quarterly. Twenty-five patients were enrolled. At the end of the first treatment cycle, compared to baseline, a significant improvement of MIDAS scores was found (13.5 ± 11.1 vs. 72.5 ± 32.1; p = 0.005), with a subsequent worsening during treatment suspension (30.1 ± 26.9; p = 0.03). Pain intensity remained unmodified during the first treatment cycle (NRS score baseline: 7.6 ± 0.9 vs. 12 months: 7.5 ± 0.7; p = 0.13). During re-treatment, MIDAS scores documented a new significant improvement, reaching the same level at 6 months of re-treatment as at the end of the first cycle (30.1 ± 26.9 vs. 12.9 ± 5.4; p = 0.03). A significant improvement, compared to baseline, was observed for pain intensity during re-treatment (6.8 ± 2.2 vs. 5.6 ± 0.9 at RT3 vs. 5.2 ± 1.4 at RT6; p = 0.05). In conclusion, during re-treatment with erenumab 140 mg, migraine pain intensity and disability documented a significant and progressive improvement. Our data confirm the long-term efficacy, although in a very limited case series, of monoclonal antibodies targeting CGRP beyond headache frequency reduction.

Migraine Monitoring in the Time of COVID-19: Triggers and Protectors During a Pandemic.

OBJECTIVE: Aim of the present observational study was to assess the impact of coronavirus disease 2019 (COVID-19) quarantine on migraine and evaluate potential influencing factors. Previous studies reported mixed results regarding clinical outcome during quarantine in patients with migraine. In particular, data from areas strongly affected by COVID-19 pandemic are missing. METHODS: One hundred and seventy patients, previously assessed at the Headache Centre-ASST Spedali Civili Brescia, underwent a telephonic interview regarding migraine features and clinical, occupational, and lifestyle variables. RESULTS: Compared to baseline, during quarantine, we found a significant overall reduction in migraine days (14.7 ± 0.6 vs 12.3 ± 0.7, P < .001), with 47.1% patients reporting a clinical improvement. Outdoor living spaces (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.7-3.07, P = .009), a positive attitude throughout quarantine (OR 4.12, 95% CI 2.3-7.1, P = 0.03), working full-time (OR 1.03, 95% CI 0.5-1.9, P < .001) and a baseline diagnosis of chronic migraine (OR 1.4, 95% CI 1.1-2.02, P = 0.002) were associated with an increased chance of migraine improvement. Being single (OR 1.5, 95% CI 1.1-2.01, P = .05) and physical inactivity (OR 1.3, 95% CI 1.1-1.6, P = .02) were associated with an increased risk of worsening. CONCLUSIONS: Quarantine had an overall positive impact on migraine. Based on our results, we hypothesize the reduction of daily hassles and challenges might be the main reason for such improvement.

Diaphragmatic myoclonus due to SARS-CoV-2 infection.

A wide range of neurological signs and symptoms have been associated with SARS-CoV-2 infection. In the present report, we described two Italian patients diagnosed with diaphragmatic myoclonus after COVID-19. In both cases, mild lymphocytosis at cerebrospinal fluid analysis and no structural brain changes were reported. The pathophysiological origin of the myoclonus in the two cases was different. In case 1, electroencephalogram did not reveal any cortical correlates and brain imaging of the spine was unremarkable, while in case 2, cortical origin of myoclonus was demonstrated. With the present two cases, we confirm and extend the neurological manifestations of SARS-CoV-2 infection.

Functional Connectivity Networks in Asymptomatic and Symptomatic DYT1 Carriers.

BACKGROUND: DYT1 mutation is characterized by focal to generalized dystonia and incomplete penetrance. To explore the complex perturbations in the different neural networks and the mutual interactions among them, we studied symptomatic and asymptomatic DTY1 mutation carriers by resting-state functional MRI. METHODS: A total of 7 symptomatic DYT1, 10 asymptomatic DYT1, and 26 healthy controls were considered. Resting-state functional MRI (Oxford Centre for Functional MRI of the Brain) [FMRIB] Software Library) (FSL) MELODIC, dual regression, (as a toolbox of FSL, with Nets is referred to "networks") (FSLNets) (http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FSLNets) was performed on 9 resting-state neural networks. RESULTS: DYT1 mutation signature (symptomatic DYT1 and asymptomatic DYT1) was characterized by increased connectivity in the dorsal attention network and in the left fronto-parietal network. Functional correlates of symptomatic DYT1 patients (symptomatic DYT1 vs healthy controls) showed increased connectivity in the sensorimotor network. DISCUSSION: This study argues that DYT1 dystonia is a network disorder, with crucial nodes in sensory-motor integration of posterior parietal structures. A better characterization of cortical networks involved in dystonia is crucial for possible neurophysiological therapeutic interventions. © 2016 International Parkinson and Movement Disorder Society.

Management of headache disorders in the Emergency Department setting.

Headache is a common presenting complaint in the Emergency Department. The aim of this study was to delineate the demographic profile of patients presenting a chief complaint of headache and to assess the application of diagnostic algorithms for the management of these patients. We examined patients admitted to the Spedali Civili Hospital ED between January 2005 and December 2009 who complained of headache not related to trauma and all patients hospitalized for headache in Neurological Clinic, from ED, between January 2008 and December 2009. 7495 patients were examined at ED for headaches. 72 % of patients were discharged, 22 % were admitted. From 2005 to 2009, there was a definite decrease in the rate of hospitalization due to headache (15 vs 9.9 % in Department of Neurology and 26 vs 18.9 % in all Departments). Considering the decrease year by year, this reduction was significant from 2007 to 2008, when the algorithms were adopted. The most common diagnosis in the ED was "Non-specific headache" (41 %), followed by "Primary headaches and complications of primary headaches" (20.8 %), "Secondary headaches not associated with risk of serious disease" (20.4 %) and "Secondary headache associated with risk of serious disease" (5 %). Over 2-year period (2008-2009) we found an increase in the diagnosis of "Primary headaches and complications of primary headaches" and "Secondary headaches associated with risk of serious disease" compared with a decrease of "nonspecific headache" and "secondary headaches not associated with risk of serious disease". The use of the diagnostic algorithms and collaborative network between the ED and the Headache Center can improve the management of patients with headache in ED.

Where SUNCT contacts TN: a case report.

BACKGROUND: Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) and trigeminal neuralgia (TN) are unilateral painful conditions that can share the same triggering factors, autonomic features and the main location, as well as the cyclically recurrent crises. Both these syndromes are associated with a high percentage of findings of vascular malformation touching the trigeminal nerve, suggesting a pathophysiological relationship. CASE: In this paper, we report a new case with the main purpose to shine a light on the pathophysiology of these conditions. CONCLUSION: Many authors described a SUNCT case deriving from TN or vice versa, suggesting that these conditions are strongly related. Every case of transformed TN or SUNCT should therefore be reported to gather and compare further information.

Reduction in retinal nerve fiber layer thickness in migraine patients.

Migraine is a common disorder and its pathogenesis remains still unclear. Several hypotheses about the mechanisms involved in the pathogenesis of migraine have been proposed, but the issue is still far from being fully clarified. Neurovascular system remains one of the most important mechanisms involved in the pathogenesis of migraine and it could be possible that hypoperfusion might involve other areas besides brain, including the retina. This is, for example, of particular interest in a form of migraine, the retinal migraine, which has been associated with hypoperfusion and vasoconstriction of the retinal vasculature. Although vasoconstriction of cerebral and retinal blood vessels is a transient phenomenon, the chronic nature of the migraine might cause permanent structural abnormalities of the brain and also of the retina. On this basis, a few studies have evaluated whether retina is involved in migraine patients: Tan et al. have not found differences in retinal nerve fiber layer (RNFL) thickness between migraine patients and healthy subjects, while Martinez et al. have shown that RNFL in the temporal retinic quadrant of migraineurs is thinner than in normal people. The aim of our study was to analyze if there are differences in retinal nerve fiber layer thickness between migraine patients and normal subjects by studying 24 consecutive migraine patients who presented at the Headache Center of our Neurological Department. Migraine diagnosis has been made according to the International Classification of Headache disorder (ICHD-II). Patients have been recruited according to strict inclusion criteria; then patients have undergone a complete ophthalmological examination at the Ophthalmological Department. All patients and controls who met the ophthalmological criteria have been examined with ocular coherence tomography spectral domain (OCT-SD) after pupillary dilation. OCT-SD is an optical system designed to acquire the retinal layer images simultaneously with fundus confocal images. The statistical analysis has been performed using the Statistical Package for Social Sciences program. The Student's t test has been used to compare numeric variables between migraine and control groups. p value >0.05 has been considered not significant. We have analyzed 40 female subjects, 24 included in the study group and 16 included in the control group. Two migraine patients have been excluded. No differences have been found in the visual acuity between the two groups. Comparing RNFLs of a single eye per person in the two groups, we have found that migraine patients showed significant reduction in the superior quadrants (p < 0.005). Also evaluating both eyes per person there was a significant difference in the same quadrant between the two groups (p < 0.05). The result of this present study show that migraine patients have RNFL thickness reduction in the superior retinal quadrant compared with normal subjects. It is important to underline that RNFL thickness measurement could be a new interesting technique to evaluate the evolution of migraine and perhaps to study if prophylactic treatment could reduce retinal abnormalities seen in migraine patients. OCT-SD is a simple exam that could be repeated and then used for evaluation of headache progression during the time. Our study shows that RNFLs thickness does not depend on illness duration and frequency.

Migraine Disability Improvement during Treatment with Galcanezumab in Patients with Chronic and High Frequency Episodic Migraine.

BACKGROUND: The aim of the present study was to assess the migraine outcome, in particular migraine disability, in chronic (CM) and high frequency episodic migraine (HFEM) patients in treatment with galcanezumab. METHODS: The present study was conducted at the Headache Centre of Spedali Civili of Brescia. Patients were treated with galcanezumab 120 mg monthly. Clinical and demographical information were collected at the baseline (T0). Data about outcome, analgesics consumption and disability (MIDAS and HIT-6 scores) were collected quarterly. RESULTS: Fifty-four consecutive patients were enrolled. Thirty-seven patients had a diagnosis of CM, 17 of HFEM. During treatment, patients reported a significant reduction in terms of mean headache/migraine days (p < 0.001), the attacks' pain intensity (p = 0.001) and monthly consumed analgesics (p < 0.001). The MIDAS and HIT-6 scores also documented a significant improvement (p < 0.001). At the baseline, all patients documented a severe degree of disability (MIDAS score ≥ 21). Following six months of treatment, only 29.2% of patients still documented a MIDAS score ≥ 21, with one third of patients documenting little or no disability. A > 50% MIDAS reduction, compared to baseline, was observed in up to 94.6% of patients, following the first three months of treatment. A similar outcome was found for HIT-6 scores. A significant positive correlation was found between headache days and MIDAS at T3 and T6 (T6 > T3), but not baseline. DISCUSSION: Monthly prophylactic treatment with galcanezumab was found to be effective in both CM and HFEM, especially in reducing migraine burden and disability.

Immigration and neurological diseases: a longitudinal study in an acute neurological care.

Very few data exist on causes and outcomes of hospitalization of immigrants in Italy. Even though immigration is a real challenge for the western countries, we are still unaware of how it reflects on the costs and the management of an acute care department. This study was aimed to compare the patterns of hospital use by immigrants incoming to the Acute Care Department of Neurology in Brescia, Italy, with those of the resident Italian people. The study was based on the hospital discharge data. Discharges of immigrants were compared to those of a random selection of Italian patients matched by age and sex. The length of the study period was of 2.5 years. A similar pattern of hospital use by age was observed between foreigners and Italian patients; however, average length of hospitalization was significantly longer in immigrant population.

Photophobia and migraine outcome during treatment with galcanezumab.

Background: Calcitonin gene-related peptide (CGRP) plays a pivotal role in migraine physiology, not only regarding migraine pain but also associated symptoms such as photophobia. The aim of the present study was to assess monoclonal antibodies targeting CGRP efficacy not only in terms of headache and migraine frequency and disability but also in reducing ictal photophobia. Material and methods: This is a retrospective observational study, conducted at the Headache Center-ASST Spedali Civili Brescia. All patients in monthly treatment with galcanezumab with at least a 6-month follow-up in September 2022 with reported severe photophobia during migraine attacks were included. Data regarding headache frequency, analgesics consumption, and migraine disability were collected quarterly. Moreover, patients were asked the following information regarding photophobia: (1) whether they noticed an improvement in photophobia during migraine attacks since galcanezumab introduction; (2) the degree of photophobia improvement (low, moderate, and high); and (3) timing photophobia improvement. Results: Forty-seven patients were enrolled in the present study as they met the inclusion criteria. Seventeen patients had a diagnosis of high-frequency episodic migraine and 30 of chronic migraine. From baseline to T3 and T6, a significant improvement in terms of headache days (19.2 ± 7.6 vs. 8.6 ± 6.8 vs. 7.7 ± 5.7; p < 0.0001), migraine days (10.4 ± 6.7 vs. 2.9 ± 4.3 vs. 3.6 ± 2.8; p < 0.0001), analgesics consumption (25.1 ± 28.2 vs. 7.6 ± 7.5 vs. 7.6 ± 8.1; p < 0.0001), MIDAS score (82.1 ± 48.4 vs. 21.6 ± 17.6 vs. 18.1 ± 20.5; p < 0.0001), and HIT-6 score (66.2 ± 6.2 vs. 57.2 ± 8.6 vs. 56.6 ± 7.6; p < 0.0001) was found. Thirty-two patients (68.1%) reported a significant improvement in ictal photophobia, with over half of the patients reporting it within the first month of treatment. Photophobia improvement was more frequent in patients with episodic migraine (p = 0.02) and triptans responders (p = 0.03). Conclusions: The present study confirms previous reports regarding galcanezumab efficacy beyond migraine frequency. In particular, over 60% of patients, in our cohort, documented a significant improvement also in reducing ictal photophobia. This improvement was, in most patients, moderate to high, and within the first 6 months of treatment, regardless of the clinical response on migraine frequency.

Post COVID-19 vaccination headache: A clinical and epidemiological evaluation.

Introduction: This study aimed to assess the prevalence and clinical characteristics of headaches, in particular secondary headaches. Materials and Methods: This observational study was performed at the ASST Spedali Civili of Brescia, Italy. Visits to the Emergency Department (ED) and subsequent hospitalizations regarding a new or worsening headache in the 16 days following the administration of the COVID-19 vaccine between January 2021 and January 2022 were recorded and compared with those of January 2019-January 2020. Results: The ratio between ED admissions due to headaches and total ED admissions was significantly higher in 2021 compared with 2019 (4.84% vs. 4.27%; p < 0.0001). Two-hundred and eighty-nine ED headache admissions (10.8% of all ED headache admissions) were time-correlated to the COVID-19 vaccination, of which 40 were hospitalized in order to exclude a symptomatic etiology. At discharge, 32 patients had a diagnosis of benign headache not attributed to any cranial/extracranial disorder and eight patients of secondary headache, whose diagnoses were the following: Headache attributed to cranial and/or cervical vascular disorder (n = 4); headache attributed to nonvascular intracranial disorder (n = 2); headache or facial pain attributed to disorder of the cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cervical structure (n = 1); and painful lesions of the cranial nerves (n = 1). The headache most frequently reported by patients had migraine-like characteristics: the localization was predominantly frontal or temporal, the pain was described as throbbing and severe in intensity and it was frequently accompanied by nausea/vomit, and photo-phonophobia. Over half-regardless of the final diagnosis-of hospitalized patients had a history of primary headaches. Conclusions: Following the spread of COVID-19 vaccination, the number of ED admissions due to headaches significantly increased. However, less than 14% of all the ED visits due to a headache time-correlated to the COVID-19 vaccination were actually hospitalized, with most patients documenting a benign headache, possibly related to the generic side effects of the vaccination. Only 8/40 hospitalized patients were diagnosed with a secondary headache. These benign headaches would actually fulfill diagnostic criteria for 8.1 Headaches attributed to the use of or exposure to a substance (ICHD-3), although, at the time being, it does not include vaccines as possible substances.The headache migraine-like characteristics' reported by most patients could suggest activation of the trigeminovascular pathway by all the cytokines and other pro-inflammatory molecules released following the vaccination.

Erenumab Discontinuation After 12-Month Treatment: A Multicentric, Observational Real-Life Study.

OBJECTIVE: To assess migraine outcome after 12-month treatment with erenumab and compare patients who underwent 3-month erenumab discontinuation following the first treatment cycle with those who continued monthly administrations. METHODS: This is a multicentric observational study in patients with migraine in treatment with erenumab. After a full 12-month treatment cycle (T12), patients could either continue or discontinue erenumab for at least 3 months. Patients who underwent treatment discontinuation were assessed after 3 months (T15) to decide whether to start retreatment. Patients were then assessed following at T16 and T18. RESULTS: Thirty consecutive patients were enrolled. Nineteen patients underwent treatment suspension at T12 up to T15, whereas 11 continued prophylaxis. At T15, patients who discontinued treatment documented significantly more migraine days (17.06 ± 6.5 vs 4.8 ± 2.5; p < 0.0001) and analgesics consumption (14.8 ± 9.2 vs 4.6 ± 2.5; p = 0.002), compared with those who continued treatment. After retreatment, at T16, patients who had previously undergone discontinuation documented a significant improvement in terms of migraine days (9.01 ± 4.4 vs 17.06 ± 6.5; p < 0.0001) and analgesics consumption (9.6 ± 7.3 vs 14.8 ± 9.2; p = 0.004). Such improvement was even greater at T18, comparable with T12. CONCLUSION: After treatment discontinuation, a rapid migraine worsening was found, despite the high clinical response during treatment and at retreatment, which might be secondary to an untimely interruption of a potentially disease-modifying pharmacologic intervention. Although clinical improvement was documented after retreatment, given the high frequency and degree of worsening during discontinuation, it seems plausible-even ethical-to re-evaluate current timing of discontinuation. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that people with migraine discontinuing erenumab migraine prophylaxis after 12 months were more likely to have an increase in nonresponder status and migraine days than those who continued treatment.

Clinical characteristics and outcomes of inpatients with neurologic disease and COVID-19 in Brescia, Lombardy, Italy.

OBJECTIVE: To report clinical and laboratory characteristics, treatment, and clinical outcomes of patients admitted for neurologic diseases with and without coronavirus disease 2019 (COVID-19). METHODS: In this retrospective, single-center cohort study, we included all adult inpatients with confirmed COVID-19 admitted to a neuro-COVID unit beginning February 21, 2020, who had been discharged or died by April 5, 2020. Demographic, clinical, treatment, and laboratory data were extracted from medical records and compared (false discovery rate corrected) to those of neurologic patients without COVID-19 admitted in the same period. RESULTS: One hundred seventy-three patients were included in this study, of whom 56 were positive and 117 were negative for COVID-19. Patients with COVID-19 were older (77.0 years, interquartile range [IQR] 67.0-83.8 years vs 70.1 years, IQR 52.9-78.6 years, p = 0.006), had a different distribution regarding admission diagnoses, including cerebrovascular disorders (n = 43, 76.8% vs n = 68, 58.1%), and had a higher quick Sequential Organ Failure Assessment (qSOFA) score on admission (0.9, IQR 0.7-1.1 vs 0.5, IQR 0.4-0.6, p = 0.006). In-hospital mortality rates (n = 21, 37.5% vs n = 5, 4.3%, p < 0.001) and incident delirium (n = 15, 26.8% vs n = 9, 7.7%, p = 0.003) were significantly higher in the COVID-19 group. Patients with COVID-19 and without COVID with stroke had similar baseline characteristics, but patients with COVID-19 had higher modified Rankin Scale scores at discharge (5.0, IQR 2.0-6.0 vs 2.0, IQR 1.0-3.0, p < 0.001), with a significantly lower number of patients with a good outcome (n = 11, 25.6% vs n = 48, 70.6%, p < 0.001). In patients with COVID-19, multivariable regressions showed increasing odds of in-hospital death associated with higher qSOFA scores (odds ratio [OR] 4.47, 95% confidence interval [CI] 1.21-16.5, p = 0.025), lower platelet count (OR 0.98, 95% CI 0.97-0.99, p = 0.005), and higher lactate dehydrogenase (OR 1.01, 95% CI 1.00-1.03, p = 0.009) on admission. CONCLUSIONS: Patients with COVID-19 admitted with neurologic disease, including stroke, have a significantly higher in-hospital mortality and incident delirium and higher disability than patients without COVID-19.

Response Predictors in Chronic Migraine: Medication Overuse and Depressive Symptoms Negatively Impact Onabotulinumtoxin-A Treatment.

Background: Despite numerous studies that have investigated clinical, radiological, and biochemical response predictors, the clinical profile of those patients who might benefit from OnabotulinumtoxinA is still missing. The aim of the present study was to identify potential OnabotulinumtoxinA response predictors among several clinical characteristics and confirm OnabotulinumtoxinA efficacy and safety in chronic migraine (CM) prevention. Methods: The study was conducted at the Headache Center-Neurology Clinic-Spedali Civili Hospital of Brescia. Eighty-four consecutive CM patients were enrolled, with a mean age of 48 years (SD 9.7) and a mean disease duration of 10.1 years (SD 6.6). The mean reported headache-days frequency was 22.5 (SD 5.9) per month, while the mean number of severe headache-days was 15.2 (SD 8.9) with a mean monthly medication intake of 33.2 (SD 5.6). The clinical characteristics analyzed as potential response predictors were: gender, disease duration, migraine characteristics (location, side constancy, unilateral autonomic and neurovegetative symptoms), previous prophylactic treatments, add-on therapies, withdrawal therapies, psychiatric (anxiety and depression symptoms) comorbidities and medication overuse. Results: A significant reduction from baseline to 3, 6, 9, and 12 month treatment cycles in total headache days, high intensity headache days and triptans consumption per month was found. Depressive symptoms and medication overuse negatively predicted OnabotulinumtoxinA outcome. Conclusions: Our results confirm the efficacy and safety of OnabotulinumtoxinA in CM. Depressive comorbidity and medication overuse, among all clinical variables, were the only significant response predictors. Such findings provide interesting insights regarding patients selection for OnabotulinumtoxinA treatment as, with the introduction of anti calcitonin gene-related (CGRP) monoclonal antibodies, clinicians will have to thoroughly judge and tailor among the many available therapeutic options now available. Future research might be needed to confirm our findings, in particular for its therapeutic implications.