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Objective: To evaluate the long-term effectiveness, safety, and tolerability of erenumab in a real-world migraine population, looking for putative predictors of responsiveness. Background: Erenumab proved to be effective, safe, and well tolerated in the prevention of episodic migraine (EM) and chronic migraine (CM) in long-term extension studies of double-blind, placebo-controlled trials in patients with no more than two (EM) or three (CM) prior preventive treatment failures. Methods: A 48-week, multicenter, longitudinal cohort real-life study was conducted at 15headache centers across eight Italian regions between December 20, 2018 and July 31, 2020. We considered all consecutive patients with high-frequency episodic migraine (HFEM) or CM aged 18–65years. Each patient was treated with erenumab 70mg, administered monthly. The dose was switched to 140mg in nonresponders and in responders who had become nonresponders for at least 4weeks. Change in monthly migraine days (MMDs) or monthly headache days (MHDs) at Weeks 45–48 compared with baseline was the primary efficacy endpoint. Secondary endpoints encompassed variation in monthly analgesic intake, achievement of a ≥50%, ≥75%, or 100% reduction in migraine or headache days, and any change in the Visual Analogue Scale (VAS) and Headache Impact Test-6 scores (HIT-6) during the same time interval. Results: A total of 242 patients with migraine received at least one dose of erenumab 70mg and were considered for safety analysis, whereas 221 received a monthly erenumab dose for ≥48weeks and were included in the effectiveness and safety analysis set. All patients had previously been treated unsuccessfully with ≥3migraine-preventive medication classes. From baseline to Weeks 45–48, erenumab treatment reduced MMD by 4.3±5.3(mean±SD) in patients with HFEM, and MHD by 12.8±8.9 (mean±SD) in subjects with CM. VAS and HIT-6scores were decreased by 1.8±1.9 (mean±SD) and 12.3±11 (mean±SD) in HFEM, and by 3.0±2.2 (mean±SD) and 13.1±11.2 (mean±SD) in CM. Median monthly analgesic intake passed from 11.0 (interquartile range [IQR] 10.0–13.0) to 5 (IQR 2.0–8.0) in HFEM and from 20.0 (IQR 15.0–30.0) to 6.0 (IQR 3.8–10.0) in CM. The ≥50% responders were 56.1% (32/57) in HFEM and 75.6% (124/164) in CM; ≥75% responders were 31.6% (18/57) and 44.5% (73/164); and 100% responders were 8.8% (5/57) and 1.2% (2/164), respectively. At Week 48, 83.6% (137/164) of patients with CM had reverted to EM. Erenumab was safe and well tolerated. Responsiveness to erenumab was positively associated with cutaneous allodynia (OR: 5.44, 95% CI: 1.52–19.41; p=0.009) in HFEM. In patients with CM, ≥50% responsiveness was positively associated with male sex (OR: 2.99, 95% CI: 1.03–8.7; p=0.044) and baseline migraine frequency (OR: 1.12, 95% CI: 1.05–1.20; p=0.001) and negatively associated with psychiatric comorbidities (OR: 0.37, 95% CI: 0.15–0.87; p=0.023) and prior treatment failures (OR: 0.77, 95% CI: 0.64–0.92; p=0.004). Conclusions: Long-term (48-week) erenumab treatment provides sustained effectiveness, safety, and tolerability in real-life patients with HFEM or CM with ≥3 prior preventive treatment failures. The dose of 140mg was required in most patients along the study and should be taken into consideration as the starting dose. Allodynia (in HFEM), male sex, and baseline migraine frequency (in CM) might represent positive responsiveness predictors. Conversely, psychiatric comorbidities and multiple prior preventive treatment failures could be negative predictors in patients with CM.

Patients with upper limb dystonia have abnormal reciprocal inhibition between flexor and extensor forearm muscles. To see whether botulinum toxin treatment alters segmental motor system function, we studied reciprocal inhibition between forearm flexor and extensor muscles, before and after botulinum toxin injection in forearm muscles in 12 patients with upper limb dystonia. Reciprocal inhibition was studied by conditioning the H reflex in forearm flexors with a radial nerve stimulus delivered at a range of time intervals. Botulinum toxin injection improved upper limb dystonia. Before botulinum toxin injection, the dystonic patients had a decreased second phase of reciprocal inhibition. After botulinum toxin injections this second abnormal phase of reciprocal inhibition increased. Botulinum toxin did not change the first phase of reciprocal inhibition. Botulinum toxin treatment also reduced the M wave and the H reflex by a similar amount but left the Hmax:Mmax ratio unchanged. Ample evidence has shown that the therapeutic effects of botulinum toxin in dystonia depend mainly on its neuromuscular junction blocking action. Our data now suggest a concurrent indirect effect on spinal cord circuitry, probably through the action of botulinum toxin on the intrafusal neuromuscular junction.

Objective: To assess the effectiveness, safety, and tolerability of erenumab in a real-life migraine population, while trying to identify responsiveness predictors. Background: Erenumab is a fully human Ig-2 monoclonal antibody blocking the calcitonin gene-related peptide receptor, indicated for migraine prophylaxis. Phase II and III trials demonstrated that erenumab is effective, safe, and well tolerated in the prevention of episodic and chronic migraine (CM), showing an early onset of action. Methods: This is a multicenter, prospective, cohort, and real-life study. We considered for enrolment all consecutive patients aged 18–65 affected by high-frequency episodic migraine (HFEM) or CM, with or without medication overuse, visited at nine Italian Headache Centers from December 20, 2018 to September 30, 2019. Each patient was treated with erenumab 70mg, administered subcutaneously every 4weeks. Treatment duration was planned to last from 6 to 12months, depending on the patient's response. The primary endpoint was the change in monthly migraine days (MMDs) at weeks 9–12 compared to baseline. Secondary endpoints included changes in monthly analgesics intake, ≥50%, ≥75%, and 100% responder rates and any variation in the Visual Analog Scale (VAS) and Headache Impact Test scores (HIT). Results: In total, 372 migraine patients were treated with at least one dose of erenumab 70mg. At weeks 9–12, erenumab decreased MMDs by 4.5±4.1days (mean±SD) in patients with HFEM and by 9.3±9.1 (mean±SD) days in those with CM compared to baseline. At weeks 9–12 VAS score was reduced by 1.9±1.9 (mean±SD), HIT score by 10.7±8.8 (mean±SD), and median monthly analgesics intake passed from 12.0 (interquartile range [IQR] 10.0–14.0) to 5.0 (IQR 3.0–7.0) in HFEM. In CM patients, VAS was reduced by 1.7±2.0 (mean±SD), HIT by 9.7±10.4 (mean±SD), and median monthly analgesics intake passed from 20.0 (IQR 15.0–30.0) to 8.0 (IQR 5.0–15.0). At week 12, ≥50% responders were 60/101 (59.4%) for HFEM and 146/263 (55.5%) for CM, ≥75% responders were 17/101 (16.8%) and 59/263 (22.4%) and 100% responders 1/101 (1.0%) and 3/263 (1.1%), respectively. Erenumab responsiveness in HFEM was positively associated with unilateral pain localization (OR: 3.03, 95% CI: 1.24–7.40; p=0.015), whereas in CM responsiveness was positively associated with and baseline migraine frequency (OR: 1.06, 95% CI:1.02–1.11; p=0.031), dopaminergic symptoms (OR: 2.01, 95% CI: 1.14–3.52; p=0.015), and negatively associated with psychiatric comorbidities (OR: 0.43, 95% CI: 0.20–0.93; p=0.003). Conclusions: Erenumab 70mg is effective, safe, and well tolerated in real life. Easily obtainable clinical features might be of help in predicting patient's responsiveness.

Limited phenotypic variability has been reported in patients with Bartter syndrome type I, with mutations in the Na-K-2Cl cotransporter gene (BSC). The diagnosis of this hereditary renal tubular disorder is usually made in the antenatal-neonatal period, due to the presence of polyhydramnios, premature delivery, hypokalemia, metabolic alkalosis, hypercalciuria, and nephrocalcinosis. Among nine children with hypercalciuria and nephrocalcinosis, we identified new mutations consistent with a loss of function of the mutant allele of the BSC gene in five. Three of the five cases with BSC gene mutations were unusual due to the absence of hypokalemia and metabolic alkalosis in the first years of life. The diagnosis of incomplete distal renal tubular acidosis was considered before molecular evaluation. Three additional patients with hypokalemia and hypercalciuria. but without nephrocalcinosis in the first two and with metabolic acidosis instead of alkalosis in the third, were studied. Two demonstrated the same missense mutation A555T in the BSC gene as one patient of the previous group, suggesting a single common ancestor. The third patient presented with severe hypernatremia and hyperchloremia for about 2 months, and a diagnosis of nephrogenic diabetes insipidus was hypothesized until the diagnosis of Bartter syndrome type I was established by molecular evaluation. We conclude that in some patients with Bartter syndrome type I, hypokalemia and/or metabolic alkalosis may be absent in the first years of life and persistent metabolic acidosis or hypernatremia and hyperchloremia may also be present. Molecular evaluation can definitely establish the diagnosis of atypical cases of this complex hereditary tubular disorder, which, in our experience, may exhibit phenotypic variability.

F-waves are known to be highly sensitive to changes in the excitatory state of the spinal cord. This paper describes the effects of subthreshold transcranial magnetic stimulation on the F-waves evoked in hand and foot muscles. In the abductor pollicis brevis muscle, the F-wave was significantly enhanced when the cortical stimulus was given with a delay corresponding approximately to the expected time of collision, i.e., the difference between the mean latency of the F-wave and the mean latency of the motor evoked potential. A second, usually larger facilitatory phase follows the first phase after 2-3 msec, and later peaks of enhancement often occurred. After the enhancement periods, a significant inhibition of the F-wave was usually observed. In the extensor digitorum brevis muscle, the first facilitatory phase was observed some milliseconds earlier than expected in 4 of 5 subjects, and the inhibitory phase was less pronounced. We argue that the sequential arrival of I-waves at the spinal segment could be responsible for the changes observed in the F-wave recorded from the small hand muscle. In the foot muscle, anatomical and technical factors could contribute to the generation of a D-wave. The strong inhibition observed in the F-wave recorded from the hand muscle is likely to be due to the arrival on alpha-motoneurons of inhibitory postsynaptic potentials (IPSPs) generated by the cortical stimulus. Our data show that the F-wave ia a probe for changes in the spinal cord excitatory state.