Long-term effectiveness and tolerability of galcanezumab in patients with migraine excluded from clinical trials: real world evidence of 1055 patients with 1 year follow-up from the Galca-Only registry.

BACKGROUND: Galcanezumab has shown efficacy and effectiveness in the treatment of episodic and chronic migraine (CM), however, the population represented in randomized clinical trials (RCTs) differs from the population observed in real-world setting. To describe the long-term effectiveness and tolerability of galcanezumab in clinical practice in patients excluded from RCTs. METHODS: Multicenter prospective cohort study of consecutive patients with chronic and high-frequency episodic migraine (HFEM) with prior failure to three or more migraine preventive drugs, treated with galcanezumab and followed up for 12 months. RESULTS: We enrolled 1055 patients, aged 50 (IQR: 42-58), 82.9% female, 76.4% chronic migraine, 69% with at least one exclusion criteria for RCTs, including age > 65 (n = 121), concomitant use of onabotulinumtoxinA (n = 185), daily headache at baseline (n = 347), chronic painful syndromes (n = 206), fibromyalgia (n = 101) or treatment resistance (n = 957). The median number of prior preventive treatments was 4 (IQR: 3-5). The retention rate was 90.8%, 76.8% and 71.4% at 3, 6 and 12 months. The main reasons for treatment discontinuation were lack of effectiveness (21.1%) and inadequate tolerability (6.6%). The 30%, 50% and 75% responder rates were 62.6%, 49.8% and 24.2% between weeks 8-12; 60.9%, 48.8% and 24.6% between weeks 20-24; and 59.7%, 48.3% and 24.6% between weeks 44-48. Daily headache at baseline (OR: 0.619; 95%CI: 0.469-0.817) and patient's age (OR: 1.016; 95%CI: 1.005-1.026) were associated with 50% response at weeks 20-24. The variables that were associated with a higher reduction of headache days between weeks 20-24 were patient's age (0.068; 95% CI: 0.018-0.119) and headache days per month at baseline (0.451; 95% CI: 0.319-0.583), while psychiatric comorbidity (-1.587; 95% CI: -2.626-0.538) and daily headache at baseline (-2.718; 95% CI: -4.58-0.869) were associated with fewer reduction in the number of headache days between weeks 20-24. CONCLUSION: This study provides class III evidence of effectiveness and tolerability of galcanezumab in patients with HFEM and CM with comorbidities that would result in exclusion of the pivotal RCTs. Nonetheless, the clinical results over a 12-month period were similar to the efficacy observed in randomized controlled trials. Few patients discontinued the drug due to inadequate tolerability.

A novel PSEN1 gene mutation (L235R) associated with familial early-onset Alzheimer's disease.

Mutations in the presenilin 1 (PSEN1) gene are the most frequent cause of familial Alzheimer's disease (AD), with at least 182 different mutations published to date. We report a 48-year-old woman (age at onset 47 years) who presented a progressive alteration of episodic memory, spatial disorientation, apathy, language disturbances and neglect of personal care. Her MMSE score was 20/30. The patient presented an unusually rapid deterioration and at 6 months follow-up her cognitive and functional status had worsened considerably (MMSE score of 11). Cranial MRI showed a bilateral atrophy with temporal and parietal predominance and the quantification of AD CSF biomarkers showed the typical AD signature. Family history evidenced an autosomal dominant pattern of inheritance. Mutational screening was performed by direct sequencing of exons 3-12 of PSEN1. The patient presented the 3/3 APOE genotype. Genetic analysis revealed a nucleotide substitution in exon 7 of PSEN1 gene, producing a missense mutation in codon 235 from leucine amino acid to arginine (L235R). This amino acid is conserved between presenilin-1 and presenilin-2 proteins. The L235R mutation had not been previously reported, although other mutations in the same residue have also been associated with familial early-onset AD, providing support for the importance of this residue for the presenilin-1 function.

[Effects of kidney and pancreas transplantation on neurophysiological rates of polyneuropathy and autonomous cardiac function in diabetic patients with end-stage renal disease]. / Efectos del trasplante de riñón y páncreas en los índices neurofisiológicos de polineuropatía y función autonómica cardiorreguladora en pacientes diabéticos con insuficiencia renal terminal.

BACKGROUND: Patients with type 1 diabetes mellitus (DM1) and end-stage renal disease (ESRD) usually exhibit a severe polyneuropathy (PNP) whose progression can be halted after kidney and pancreas transplantation (KPT). We studied the evolution of both PNP and autonomous cardioregulatory function (ACF) in patients with DM1 and ESRD within the first year after KPT. PATIENTS AND MEHTOD: The study was carried out in 26 patients who underwent KPT and whose organs were functioning normally at least during one year after KPT. They were examined neurophysiologically in three different periods: a) before KPT; b) 1-3 months after KPT, and c) 12 months after KPT. We evaluated PNP by measuring the conduction velocity (CV) and the amplitude of the compound action potentials (ACAP) of common peroneal, posterior tibial and sural nerves. ACF was evaluated by measuring the change in the interval separating two consecutive QRS complexes in the electrocardiogram during quiet breathing and Valsalva manoeuvre. RESULTS: All patients had a severe PNP before KPT. Ten patients (38.4%) showed a significant reduction in ACAP and ACF in the exam carried out within 1 to 3 months after KPT, whereas all patients showed an increase in the CV, ACAP and ACF at 1 year after KPT. CONCLUSIONS: KPT induces a significant improvement of neurophysiological signs of PNP and of ACF, which is statistically significant at 1 year after KPT. In some patients, the improvement is heralded by an increase in the axonal damage, occurring in the first months after KPT, which may be due the aggression from the surgical treatment and related events.

Efectos del trasplante de riñón y páncreas en los índices neurofisiológicos de polineuropatía y función autonómica cardiorreguladora en pacientes diabéticos con insuficiencia renal terminal / Effects of kidney and pancreas transplantation on neurophysiological rates of polyneuropathy and autonomous cardiac function in diabetic patients with end-stage renal disease

FUNDAMENTO: Los pacientes con diabetes mellitus tipo 1 (DM1) e insuficiencia renal crónica terminal (IRCT) suelen presentar polineuropatía (PNP) grave, cuya progresión puede detenerse tras el trasplante de riñón y páncreas (TRP). Hemos analizado la modificación de los índices neurofisiológicos de PNP y de función autónoma cardiorreguladora (FAC) en los pacientes con DM1 e IRCT en el curso del primer año después de TRP. PACIENTES Y MÉTODO: Se estudió a 26 pacientes sometidos a TRP que mantuvieron los órganos normofuncionantes durante al menos un año después del trasplante. Se realizaron exámenes neurofisiológicos en tres períodos: a) antes del TRP; b) 1-3 meses post-TRP, y c) 12 meses post-TRP. Se midieron la velocidad de conducción (VC) y la amplitud de los potenciales de acción (APA) de los nervios peroneal común, tibial posterior y sural, así como la variación observada en el intervalo entre complejos QRS del electrocardiograma durante la respiración tranquila y la maniobra de Valsalva. RESULTADOS: Todos los pacientes presentaban PNP grave pre-TRP. Diez pacientes (38,4 por ciento) presentaron una reducción significativa de la APA y de la FAC en el examen realizado entre uno y tres meses post-TRP, mientras que todos los pacientes presentaron un aumento en la VC, APA y FAC al año del TRP. CONCLUSIÓN: El TRP induce una mejoría estadísticamente significativa de los signos neurofisiológicos de PNP y de FAC al año del trasplante. En algunos pacientes, la mejoría va precedida de un incremento en la afección axonopática, que sucede en los primeros meses después del trasplante y podría estar relacionado con la agresión periquirúrgica. (AU)