Erenumab for Migraine Prevention in a 1-Year Compassionate Use Program: Efficacy, Tolerability, and Differences Between Clinical Phenotypes.

During a 1-year compassionate use program, 156 patients with migraine self-administered a monthly dose of erenumab 140 mg with a subcutaneous autoinjector. Main inclusion criteria were: ≥ 4 migraine days/month and ≥two prior prophylactic treatment failures. The patients covered the migraine severity spectrum from episodic migraine (EM) (n = 80) to chronic migraine (CM) (n = 76). During the 3rd month of treatment, monthly headache days decreased by 45.7% in EM and 35.5% in CM. The 50% responder rate for reduction in monthly headache days was significantly higher in EM (55%) than in CM (43%) (p = 0.05). In both the migraine subgroups, the clinical improvement vs. baseline was already significant during the 1st month of treatment (p < 0.001). There were also significant reductions in mean headache severity, duration, and monthly days with acute drug intake. The 30% responder rate at 3 months was 60% in CM and 54.1% of patients reversed from CM to EM. The therapeutic effect was maintained at 12 months when 50% responder rates, considering discontinuation for lack of efficacy or adverse effects as 0% response, still were 51% in EM and 41% in CM. A total of 10 patients with EM (12.5%) and 23 patients with CM (30.3%) had discontinued treatment, considering the treatment as ineffective. At 3 months, 48% of patients reported non-serious adverse events among which the most frequent was constipation (20.5%); corresponding figures at 12 months were 30 and 15%. Discontinuation due to an adverse effect for the entire 12 month period was rare (3.8%). The lower efficacy in CM than in EM was mainly due to a very low 50% responder rate in patients with CM with continuous pain (13%) as compared to CM with pain-free periods (58%) (p < 0.001). Similarly, the 50% responder rate was lower in patients with ≥two prior prophylactic treatment failures (40.5%) compared to those with two failures (70%) (p < 0.05). There was no significant efficacy difference between low (4-7 migraine days/month, n = 22) and high frequency (8-14 days, n = 59) EM nor between patients with CM with (n = 50) or without (n = 26) acute medication overuse. Erenumab had no effect on the frequency of auras. Taken together, erenumab 140 mg monthly was highly effective for migraine prophylaxis over the whole severity spectrum of the disease, except in patients with continuous headaches. Its effect is significant after the first injection, quasi-maximal after the second injection, and does not wear off after 12 months. The most frequent adverse effect was constipation. These results are compared to those published for erenumab in the pivotal randomized placebo-controlled trials and to those reported in several recent real-world studies.

Cerebral metabolism before and after external trigeminal nerve stimulation in episodic migraine.

Background and aim A recent sham-controlled trial showed that external trigeminal nerve stimulation (eTNS) is effective in episodic migraine (MO) prevention. However, its mechanism of action remains unknown. We performed 18-fluorodeoxyglucose positron emission tomography (FDG-PET) to evaluate brain metabolic changes before and after eTNS in episodic migraineurs. Methods Twenty-eight individuals were recruited: 14 with MO and 20 healthy volunteers (HVs). HVs underwent a single FDG-PET, whereas patients were scanned at baseline, directly after a first prolonged session of eTNS (Cefaly®) and after three months of treatment (uncontrolled study). Results The frequency of migraine attacks significantly decreased in compliant patients ( N = 10). Baseline FDG-PET revealed a significant hypometabolism in fronto-temporal areas, especially in the orbitofrontal (OFC) and rostral anterior cingulate cortices (rACC) in MO patients. This hypometabolism was reduced after three months of eTNS treatment. Conclusion Our study shows that metabolic activity of OFC and rACC, which are pivotal areas in central pain and behaviour control, is decreased in migraine. This hypometabolism is reduced after three months of eTNS. eTNS might thus exert its beneficial effects via slow neuromodulation of central pain-controlling areas, a mechanism also previously reported in chronic migraine and cluster headache after percutaneous occipital nerve stimulation. However, this finding needs to be confirmed by further studies using a sham condition.

Invasive occipital nerve stimulation for refractory chronic cluster headache: what evolution at long-term? Strengths and weaknesses of the method.

BACKGROUND: Invasive Occipital Nerve Stimulation (iONS) is a costly technique which appears effective in drug-refractory chronic cluster headache (drCCH) management. Available data on long-term effectiveness and safety of iONS in this indication are scarce, though they could be useful to neurologists and patients in daily practice. The purpose of this short report is to discuss the very long-term outcome of a drCCH cohort, including adverse events. FINDINGS: Previously, favourable results were obtained with iONS in 15 drCCH patients: 80 % were significantly improved and 60 % were pain free. We report here the very long-term follow-up (up to nine years) of 10 patients belonging to this cohort. Meanwhile 5 patients had to be definitively explanted because of device infection (3) or paresthesia intolerance (2). Four patients (40 %) evolved to an episodic form of CH. Six remained chronic but their attack frequency was decreased by 70 % on average. Intake of preventive drugs is still necessary in 80 % of patients. All patients needed at least one battery replacement. CONCLUSIONS: Up to nine years after implantation, iONS is still effective in most patients with drCCH. Concomitant preventive drugs remain often necessary. Forty percent of patients reverse to episodic CH, possibly by natural history. iONS is not a benign procedure but device-related complications appear similar to those reported with other invasive neurostimulators.

Prevalence of right-to-left shunts on transcranial Doppler in chronic migraine and medication-overuse headache.

BACKGROUND: It was suggested that right-to-left shunt (RLS) may be highly prevalent in chronic migraine (CM) patients, indicating that patent foramen ovale (PFO) might be an aggravating and chronifying factor of migraine. Since a high proportion of chronic migraineurs also have medication-overuse headache (MOH), one may wonder if they have a more severe form of the disorder and more frequently a PFO. OBJECTIVE: The objective of this study is to determine the prevalence and grade of RLS in patients suffering from CM and MOH. METHODS: A cross-sectional multicenter study of air-contrast transcranial Doppler was conducted in 159 patients with CM ( N = 57) or MOH ( N = 102) attending a tertiary headache clinic. RESULTS: The prevalence of RLS in CM was 37% (11% large shunts) and in MOH patients 31% (13% large shunts). There was no difference between the two groups ( P = 0.49). CONCLUSION: RLS prevalence in CM is within the upper range of those reported in episodic migraine without aura or in the general population, and not higher in MOH. PFO is thus unlikely to have a significant causal role in these chronic headaches.

Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial.

OBJECTIVE: To assess efficacy and safety of trigeminal neurostimulation with a supraorbital transcutaneous stimulator (Cefaly, STX-Med., Herstal, Belgium) in migraine prevention. METHODS: This was a double-blinded, randomized, sham-controlled trial conducted at 5 Belgian tertiary headache clinics. After a 1-month run-in, patients with at least 2 migraine attacks/month were randomized 1:1 to verum or sham stimulation, and applied the stimulator daily for 20 minutes during 3 months. Primary outcome measures were change in monthly migraine days and 50% responder rate. RESULTS: Sixty-seven patients were randomized and included in the intention-to-treat analysis. Between run-in and third month of treatment, the mean number of migraine days decreased significantly in the verum (6.94 vs 4.88; p = 0.023), but not in the sham group (6.54 vs 6.22; p = 0.608). The 50% responder rate was significantly greater (p = 0.023) in the verum (38.1%) than in the sham group (12.1%). Monthly migraine attacks (p = 0.044), monthly headache days (p = 0.041), and monthly acute antimigraine drug intake (p = 0.007) were also significantly reduced in the verum but not in the sham group. There were no adverse events in either group. CONCLUSIONS: Supraorbital transcutaneous stimulation with the device used in this trial is effective and safe as a preventive therapy for migraine. The therapeutic gain (26%) is within the range of those reported for other preventive drug and nondrug antimigraine treatments. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that treatment with a supraorbital transcutaneous stimulator is effective and safe as a preventive therapy for migraine.

Effects of light deprivation on visual evoked potentials in migraine without aura.

BACKGROUND: The mechanisms underlying the interictal habituation deficit of cortical visual evoked potentials (VEP) in migraine are not well understood. Abnormal long-term functional plasticity of the visual cortex may play a role and it can be assessed experimentally by light deprivation (LD). METHODS: We have compared the effects of LD on VEP in migraine patients without aura between attacks (MO, n = 17) and in healthy volunteers (HV, n = 17). Six sequential blocks of 100 averaged VEP at 3.1 Hz were recorded before and after 1 hour of LD. We measured VEP P100 amplitude of the 1st block of 100 sweeps and its change over 5 sequential blocks of 100 responses. RESULTS: In HV, the consequence of LD was a reduction of 1st block VEP amplitude and of the normal habituation pattern. By contrast, in MO patients, the interictal habituation deficit was not significantly modified, although 1st block VEP amplitude, already lower than in HV before LD, further decreased after LD. CONCLUSIONS: Light deprivation is thought to decrease both excitatory and subsequent inhibitory processes in visual cortex, which is in line with our findings in healthy volunteers. The VEP results in migraine patients suggest that early excitation was adequately suppressed, but not the inhibitory mechanisms occurring during long term stimulation and habituation. Accordingly, deficient intracortical inhibition is unlikely to be a primary factor in migraine pathophysiology and the habituation deficit.

Post-stroke reorganization of hand motor area: a 1-year prospective follow-up with focal transcranial magnetic stimulation.

OBJECTIVE: Focal transcranial magnetic stimulation was used to test prospectively corticospinal excitability changes and reorganization of first dorsal interosseous (FDI) motor cortical representation in 31 patients who experienced a first ischemic stroke in the middle cerebral artery territory. All had severe hand palsy at onset. METHODS: Patients were assessed clinically with the Medical Research Council, Rankin, the National Institutes of Health stroke scales and Barthel Index at days 1, 8, 30, 90, 180 and 360 after stroke. The following parameters of FDI motor evoked potential (MEPS) to focal transcranial magnetic stimulation were measured at the same delays: motor threshold, MEP amplitude, excitable cortical area, hot spot and center of gravity of FDI motor maps on affected and unaffected hemispheres. Correlations were sought between clinical and electrophysiological parameters. RESULTS: In patients whose affected motor cortex remained excitable at day 1, motor thresholds were not significantly different between sides and were similar to those of controls. Persistence of MEP on the affected side at day 1 was a strong predictor of good recovery. If present at day 1, MEPs recorded in affected FDI were significantly smaller than of the opposite side or in normals and progressively recovered up to day 360. In these patients, area of excitable cortex remained stable throughout the entire study. At day 1, amplitudes of MEPs obtained in unaffected FDI were significantly larger than later. Between days 1 and 360, we observed a significant displacement of center of gravity of motor maps towards more frontal regions on the affected side while no change was noted on the unaffected side. CONCLUSIONS: Our data confirm the early prognosis value of transcranial magnetic stimulation in stroke. They indicate that the brain insult induces a transient hyperexcitability of the unaffected motor cortex. The evolution of FDI motor maps along the course of recovery mostly reflect corticospinal excitability changes but might also reveal some degree of brain plasticity. Most modifications observed occurred within 3 months of stroke onset.

Single motor axon conduction velocities of human upper and lower limb motor units. A study with transcranial electrical stimulation.

OBJECTIVES: To calculate conduction velocities (CV) of single motor axons innervating hand, forearm and leg muscles, weak anodal electrical transcranial stimuli were used and single motor unit potentials were recorded in 17 normal subjects. METHODS: The central motor conduction time and neuromuscular transmission delay were subtracted from the latency of unit response to cortical stimulation and single motor axon CV were calculated. RESULTS: In extensor indicis proprius (EIP) units, CV ranged from 30.3 to 76.1m/s (mean: 51.3 +/- 7.1m/s, 139 units). In first dorsal interosseous (FDI), they ranged from 45.1 to 66.2m/s (mean: 54.6 +/- 2.6m/s, 88 units). In tibialis anterior (TA), velocities ranged from 27.8 to 55.9m/s (mean: 41.3 +/- 7.5m/s, 123 units). In FDI units, velocities were compared with those obtained with the F-wave method (range: 50.3-64.5m/s, mean: 58.1 +/- 2.0m/s). CONCLUSIONS: Compared with previously published values, the present method gives better access to slow-conducting units, first recruited by transcranial stimulation and voluntary effort. The spectrum of individual CV was much broader for EIP and TA than for FDI. A linear decline of maximal CV with age was observed, while minimal CV were not affected, suggesting that aging causes a selective loss of the fastest-conducting units.