RE-START: Exploring the effectiveness of anti-calcitonin gene-related peptide resumption after discontinuation in migraine.

BACKGROUND AND PURPOSE: According to the latest European guidelines, discontinuation of monoclonal antibodies against calcitonin gene-related peptide (anti-CGRP MAb) may be considered after 12-18 months of treatment. However, some patients may worsen after discontinuation. In this study, we assessed the response following treatment resumption. METHODS: This was a prospective study conducted in 14 Headache Units in Spain. We included patients with response to anti-CGRP MAb with clinical worsening after withdrawal and resumption of treatment. Numbers of monthly migraine days (MMD) and monthly headache days (MHD) were obtained at four time points: before starting anti-CGRP MAb (T-baseline); last month of first treatment period (T-suspension); month of restart due to worsening (T-worsening); and 3 months after resumption (T-reintroduction). The response rate to resumption was calculated. Possible differences among periods were analysed according to MMD and MHD. RESULTS: A total of 360 patients, 82% women, with a median (interquartile range [IQR]) age at migraine onset of 18 (12) years. The median (IQR) MHD at T-baseline was 20 (13) and MMD was 5 (6); at T-suspension, the median (IQR) MHD was 5 (6) and MMD was 4 (5); at T-worsening, the median (IQR) MHD was 16 (13) and MMD was 12 (6); and at T-reintroduction, the median (IQR) MHD was 8 (8) and MHD was 5 (5). In the second period of treatment, a 50% response rate was achieved by 57.4% of patients in MHD and 65.8% in MMD. Multivariate models showed significant differences in MHD between the third month after reintroduction and last month before suspension of first treatment period (p < 0.001). CONCLUSION: The results suggest that anti-CGRP MAb therapy is effective after reintroduction. However, 3 months after resumption, one third of the sample reached the same improvement as after the first treatment period.

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.

C9ORF72 Gene GGGGCC Hexanucleotide Expansion: A High Clinical Variability from Amyotrophic Lateral Sclerosis to Frontotemporal Dementia.

The expanded GGGGCC hexanucleotide repeat (HRE) in the non-coding region of the C9ORF72 gene (C9ORF72-HRE) is the most common genetic cause of familial forms of amyotrophic lateral sclerosis (ALS), FTD, and concurrent ALS and FTD (ALS-FTD), in addition to contributing to the sporadic forms of these diseases. Both syndromes overlap not only genetically, but also sharing similar clinical and neuropathological findings, being considered as a spectrum. In this paper we describe the clinical-genetic findings in a Basque family with different manifestations within the spectrum, our difficulties in reaching the diagnosis, and a narrative review, carried out as a consequence, of the main features associated with C9ORF72-HRE. Family members underwent a detailed clinical assessment, neurological examination, and genetic analysis by repeat-primed PCR. We studied 10 relatives of a symptomatic carrier of the C9ORF72-HRE expansion. Two of them presented the expansion in the pathological range, one of them was symptomatic whereas the other one remained asymptomatic at 72 years. Given the great intrafamilial clinical variability of C9ORF72-HRE, the characterization of patients and family members with particular clinical and genetic subgroups within ALS and FTD becomes a bottleneck for medication development, in particular for genetically focused medicines for ALS and FTD.

Analysis of a large case series of fatal familial insomnia to determine tests with the highest diagnostic value.

Fatal familial insomnia (FFI) is a rare prionopathy with unusually high incidence in the Basque Country. We report detailed data on clinical, diagnostic, histopathological, and biochemical characteristics of a recent FFI case series. The Basque Brain Bank database was screened for patients diagnosed from 2010 to 2021 with standard genetic and/or neuropathological criteria. This series includes 16 patients, 25% without family history, with 12 cases from 9 unrelated (but geographically-linked, Basque country) kindreds, onset ranging from 36 to 70 years, and disease course from 7 to 11.5 months. Insomnia was the initial symptom in most cases, with consistent polysomnography in 92% of the cases. In contrast, 14-3-3 and RT-QuIC from cerebrospinal fluid were negative. Most patients were homozygous for methionine. Gliosis and neuronal loss in basal ganglia and thalamus were the main histopathological findings; Western blotting identified preferentially the protease-resistant prion protein (PrPres) type 2, although detection of the scrapie isoform of the prion protein (PrPSc) identified using brain tissue RT-QuIC was more successful. This is one of the largest current studies on FFI patients performed to provide improvements in diagnostic reliability. Among the analyzed tests, polysomnography and the genetic study show the highest diagnostic value in FFI.

Blood ß-Synuclein and Neurofilament Light Chain During the Course of Prion Disease.

BACKGROUND AND OBJECTIVES: For early diagnosis and disease monitoring of neurodegenerative diseases (NDs), reliable blood biomarkers are needed. Elevated levels of neurofilament light chain protein (NfL), an axonal damage marker, have been described across different NDs, with highest values in prion diseases and amyotrophic lateral sclerosis (ALS). Synaptic degeneration is a common early feature in most NDs and seems to precede neuronal degeneration in prion disease. However, synaptic markers in blood are still missing. Here, we investigated whether the brain-specific protein ß-synuclein might be a suitable blood biomarker for early diagnosis and evaluation of synaptic integrity in prion disease. METHODS: We analyzed blood ß-synuclein with a newly established digital ELISA and NfL with a single-molecule array in samples obtained from human participants and prion and ALS animal models. Furthermore, ß-synuclein was investigated in brain tissue of individuals with Creutzfeldt-Jakob disease (CJD) and controls. RESULTS: We investigated 308 patients, including 129 cases with prion disease, 8 presymptomatic PRNP variation carriers, 60 with ALS, 68 with other ND, and 43 control patients. In CJD symptomatic cases, ß-synuclein and NfL were markedly increased compared to all other diagnostic groups (p < 0.001). In the large majority of presymptomatic PRNP variation carriers, ß-synuclein and NfL levels were within normal ranges. In prion disease animal models, ß-synuclein and NfL displayed normal levels in the presymptomatic phase with a sudden elevation at disease onset and a plateau in the symptomatic phase. In contrast to NfL, ß-synuclein was not elevated in either symptomatic patients with ALS or an ALS animal model. In the discrimination between prion disease and all other groups, ß-synuclein (area under the curve 0.97, 95% CI 0.94-0.99, p < 0.001) was superior to NfL (area under the curve 0.91, 95% CI 0.88-0.94, p < 0.001). In addition, brain tissue ß-synuclein showed significantly reduced levels in patients with CJD compared to control patients (p < 0.001). DISCUSSION: Blood ß-synuclein was significantly elevated in patients with CJD, reflecting ongoing synaptic damage, and showed good discriminative characteristics. We therefore propose it as a candidate blood marker for early diagnosis and monitoring of synaptic integrity in prion disease. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that serum ß-synuclein concentration accurately distinguishes patients with symptomatic CJD from controls.

Sporadic Creutzfeldt-Jakob disease with extremely long 14-year survival period.

BACKGROUND AND PURPOSE: Sporadic Creutzfeldt-Jakob disease is a rapidly progressing and highly variable neurodegenerative disease with heterogeneous clinical presentation and a median survival time from diagnosis to death of 4-6 months. METHODS: We report a rare case of a 61-year-old woman with a history of initially rapidly progressive dementia, with subsequent development of pyramidal and extrapyramidal signs and with an unusually long survival period of 14 years. Initial magnetic resonance imaging evaluation, single-photon emission computed tomography, and electroencephalogram did not show relevant alterations. RESULTS: The postmortem examination of the brain showed diffuse spongiform change, gliosis, and neuronal loss along with abnormal immunostaining of prion protein in the grey matter, especially in the cerebellum. Indirect PRNP genetic analysis was negative. CONCLUSIONS: This case is, to our knowledge, the sporadic Creutzfeldt-Jakob disease patient with the longest survival period ever documented. This surprisingly long duration highlights the importance of histopathological confirmation with brain autopsies for suspected cases, as the disease can easily be misdiagnosed in such slowly progressing cases.

MRI findings in cervical spondylotic myelopathy with gadolinium enhancement: Review of seven cases.

Cervical spondylotic myelopathy (CSM) is a clinical syndrome secondary to a spinal cord compression due to cervical spondylosis. In some cases, conventional MRI typically shows an intramedullary hyperintense signal on T2W imaging and contrast enhancement on post-gadolinium T1W imaging. We report a series of seven patients with CSM who had typical clinical presentation and imaging findings on T2W and contrast-enhanced T1W sequences. The imaging findings included degenerative changes of the cervical spine, intramedullary T2-signal hyperintensity, and an intramedullary enhancement on post-gadolinium T1W images. Our results support the statement that the presence of an intramedullary gadolinium-enhancement with a flat transverse pancake-like pattern (on sagittal images) and a circumferential pattern (on axial images), located within a T2-signal abnormality, in patients with cervical spondylosis and clinical myelopathy is indicative of spondylosis as the cause of the myelopathy.

Predictors of in-hospital mortality after ischemic stroke: A prospective, single-center study.

BACKGROUND AND AIMS: Stroke is the second leading cause of death around the globe. Studies examining the predictors of in-hospital mortality and the impact of complications on early outcome of acute ischemic stroke are scant. The aim of this study was to identify predictors of in-hospital mortality in patients with acute ischemic stroke. METHODS: This was a prospective, single-center study of patients with acute ischemic stroke consecutively admitted to the Neurology Department of a general hospital during a 2-year period (from January 1, 2010 to December 31, 2011). Prospective data from this single-center study included variables related to sociodemographics, comorbidities, and medical complications, together with in-hospital mortality. Since stroke mortality may impact differently by sex and is also influenced by hospital length of stay, we proceeded to stratify by these variables. RESULTS: Six-hundred and seventy-three patients were included. Overall, in-hospital mortality rate was 7.13%. Stratifying by length of stay in-hospital (< 7 days and ≥ 7 days), we observed that within the first week, overall mortality was related to a history of previous stroke, higher stroke severity, and to cardiovascular and respiratory complications. After 7 days, the main factor independently associated with overall in-hospital mortality was stroke severity (National Institutes of Health Stroke Scale (NIHSS) ≥ 14, odds ratio (OR): 17.15; 95% CI, 3.06-96.07).Stratifying by sex, we observed that females had a worse outcome if there was a history of prior stroke (OR: 3.29; 95% CI, 1.19-9.10), higher stroke severity (NIHSS ≥ 14, OR: 16.63; 95% CI, 4.66-59.31), and cardiovascular complications (OR: 29.70; 95% CI, 5.70-154.8). Among men, stroke severity (NIHSS ≥ 14, OR: 23.19; 95% CI, 5.69-94.56), respiratory infections (OR: 3.84; 95% CI, 1.32-11.20), and older age had significant negative impact. CONCLUSIONS: Stroke severity and potentially modifiable complications (respiratory infections and cardiovascular complications) confer an increased risk of in-hospital death in both women and men, particularly during the first week of admission.