Impact of COVID-19 pandemic on acute stroke care: facing an epidemiological paradox with a paradigm shift.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) outbreak, a decrease of stroke's hospital admissions and reperfusion therapy has been reported worldwide. This retrospective observational study assessed the volume of stroke cases managed in the Emergency Department (ED) and reperfusion therapies in an Italian stroke network with a high incidence of COVID-19, particularly to evaluate if the in-hospital rerouting and the switch from a drip-and-ship to a mothership model could assure an adequate volume of acute treatments. METHODS: We compared data from March 2020 with those from previous years and formulated five PICO questions regarding (1) incidence of stroke cases in the ED; (2) relation between stroke cases and COVID-19; (3) differences in the number of reperfusion therapies, (4) in the call-to-needle and door-to-needle times for intravenous thrombolysis, and (5) in the call-to-groin and door-to-groin times for thrombectomy. RESULTS: We found (1) a 28% decreased of confirmed stroke cases managed in the ED, (2) a negative correlation between stroke cases in ED and COVID-19 progression (rs = - .390, p = .030), and (3) a similar number of treatments in March 2020 and March 2019. The adoption of the mothership model (4) did not delay alteplase infusion (median call-to-needle p = .126, median door-to-needle p = .142) but led to (5) a significant reduction in median call-to-groin (p = .018) and door-to-groin times (p = .010). CONCLUSION: The "hospital avoidance" of stroke patients during the "stay-at-home" appeals needs to be considered for future public health campaigns. A prompt reorganization of the stroke network can guarantee optimal performances at times of crisis.

Analysis of Epigenetic Age Predictors in Pain-Related Conditions.

Chronic pain prevalence is high worldwide and increases at older ages. Signs of premature aging have been associated with chronic pain, but few studies have investigated aging biomarkers in pain-related conditions. A set of DNA methylation (DNAm)-based estimates of age, called "epigenetic clocks," has been proposed as biological measures of age-related adverse processes, morbidity, and mortality. The aim of this study is to assess if different pain-related phenotypes show alterations in DNAm age. In our analysis, we considered three cohorts for which whole-blood DNAm data were available: heat pain sensitivity (HPS), including 20 monozygotic twin pairs discordant for heat pain temperature threshold; fibromyalgia (FM), including 24 cases and 20 controls; and headache, including 22 chronic migraine and medication overuse headache patients (MOH), 18 episodic migraineurs (EM), and 13 healthy subjects. We used the Horvath's epigenetic age calculator to obtain DNAm-based estimates of epigenetic age, telomere length, levels of 7 proteins in plasma, number of smoked packs of cigarettes per year, and blood cell counts. We did not find differences in epigenetic age acceleration, calculated using five different epigenetic clocks, between subjects discordant for pain-related phenotypes. Twins with high HPS had increased CD8+ T cell counts (nominal p = 0.028). HPS thresholds were negatively associated with estimated levels of GDF15 (nominal p = 0.008). FM patients showed decreased naive CD4+ T cell counts compared with controls (nominal p = 0.015). The severity of FM manifestations expressed through various evaluation tests was associated with decreased levels of leptin, shorter length of telomeres, and reduced CD8+ T and natural killer cell counts (nominal p < 0.05), while the duration of painful symptoms was positively associated with telomere length (nominal p = 0.034). No differences in DNAm-based estimates were detected for MOH or EM compared with controls. In summary, our study suggests that HPS, FM, and MOH/EM do not show signs of epigenetic age acceleration in whole blood, while HPS and FM are associated with DNAm-based estimates of immunological parameters, plasma proteins, and telomere length. Future studies should extend these observations in larger cohorts.

Treatment of withdrawal headache in patients with medication overuse headache: a pilot study.

BACKGROUND: Drug withdrawal still remains the key element in the treatment of Medication Overuse Headache (MOH), but there is no consensus about the withdrawal procedure. Still debated is the role of the steroid therapy. The aim of this study was to evaluate the effectiveness of methylprednisolone or paracetamol in the treatment of withdrawal headache in MOH. METHODS: We performed a pilot, randomized, single-blinded, placebo controlled trial. MOH patients, unresponsive to a 3 months prophylaxis, underwent withdrawal therapy on an inpatient basis. Overused medications were abruptly stopped and methylprednisolone 500 mg i.v (A) or paracetamol 4 g i.v. (B) or placebo i.v. (C) were given daily for 5 days. Patients were monitored at 1 and 3 months. RESULTS: Eighty three consecutive MOH patients were enrolled. Fifty seven patients completed the study protocol. Nineteen patients were randomized to each group. Withdrawal headache on the 5th day was absent in 21.0% of group A, in 31.6% of group B and in 12.5% of group C without significant differences. Withdrawal headache intensity decreased significantly after withdrawal without differences among the groups. Rregardless of withdrawal treatment, 52% MOH patients reverted to an episodic migraine and 62% had no more medication overuse after 3 months. CONCLUSIONS: This study suggests that in a population of severe MOH patients, withdrawal headache decreased significantly in the first 5 days of withdrawal regardless of the treatment used. Methylprednisolone and paracetamol are not superior to placebo at the end of the detoxification program.

Precuneal Thickness and Depression in Parkinson Disease.

BACKGROUND: Depression-related gray matter changes in Parkinson disease (PD) patients have been reported, although studies investigating cortical thickness in early-stage disease are lacking. OBJECTIVE: We aimed to evaluate cortical changes related to depression in early-stage PD patients with an extensive neuropsychological evaluation. METHODS: 17 PD patients and 22 healthy controls underwent a 1.5-T brain MR protocol, and voxel-wise differences in cortical thickness among patients with (n = 6) and without (n = 11) depression and controls were evaluated using FreeSurfer software. RESULTS: Cortical thickness was increased in the precuneus bilaterally in PD patients with depression compared to the other groups (number of vertices >100; p < 0.001, uncorrected) with a direct correlation with the Beck Depression Inventory score (p < 0.001, uncorrected). CONCLUSION: Precuneal cortical thickening is evident in PD patients with mild-moderate depression even in the early stages of the disease. This finding may reflect the early involvement of this region in the development of PD-related depression.

A longitudinal study of a family with adult-onset autosomal dominant leukodystrophy: Clinical, autonomic and neuropsychological findings.

BACKGROUND AND PURPOSE: Adult-onset autosomal dominant leukodystrophy (ADLD) is a rare progressive neurological disorder caused by Lamin B1 duplication (LMNB1). Our aim was to investigate longitudinally the pattern of the autonomic dysfunction and the degree of neuropsychological involvement. METHODS: Three related ADLD patients and one asymptomatic carrier of LMNB1 duplication underwent a standardized evaluation of autonomic nervous system, including cardiovascular reflexes, pharmacological testing, microneurography, skin biopsy, Metaiodobenzylguanidine scintigraphy and a complete neuropsychological battery. RESULTS: An early neurogenic orthostatic hypotension was detected in all patients and confirmed by a low rise in noradrenaline levels on Tilt Test. However infusion of noradrenaline resulted in normal blood pressure rise as well as the infusion of clonidine. At the insulin tolerance test the increase in adrenaline resulted pathological in two out three patients. Microneurography failed to detect muscle sympathetic nerve activity bursts. Skin biopsy revealed a poor adrenergic innervation, while cardiac sympathetic nerves were normal. None of ADLD patients showed a global cognitive deficit but a selective impairment in the executive functions. CONCLUSION: Autonomic disorder in ADLD involves selectively the postganglionic sympathetic system including the sympatho-adrenal response. Cognitive involvement consisting in an early impairment of executive tasks that might precede brain MR abnormalities.

Brain magnetic resonance metabolic and microstructural changes in adult-onset autosomal dominant leukodystrophy.

INTRODUCTION: adult-onset autosomal dominant leukodystrophy (ADLD) is a rare inherited disorder due to a duplication of lamin-B1 (LMNB1) gene. The aim of this study was to investigate brain metabolic and microstructural alterations by using advanced MR techniques. METHODS: we performed brain MR scans including single-voxel proton-MR Spectroscopy ((1)H-MRS) of the lateral ventricles and parietal white matter and diffusion tensor imaging (DTI) in 4 subjects with LMNB1 gene duplication, 6 non-mutated relatives and 7 unrelated healthy controls. Cervical and thoracic spinal cord MR was performed in three symptomatic subjects with LMNB1 mutation. All participants underwent clinical and neuropsychological evaluation. RESULTS: all subjects with LMNB1 gene duplication presented pathological accumulation of lactate in lateral ventricles CSF and no alterations of brain white matter absolute metabolites concentrations or metabolites/Cr ratios. We found increased white matter intra- and extracellular water transverse relaxation times. Tract-based spatial statistics analysis detected a significantly reduced fractional anisotropy in the genu of the corpus callosum in mutated cases compared to unrelated healthy controls and non-mutated relatives. Moreover, we detected different degrees of the typical white matter signal intensity alterations and brain and spinal atrophy at conventional MRI in symptomatic subjects with LMNB1 mutation. A mild impairment of executive functions was found in subjects with LMNB1 gene mutation. CONCLUSION: in subjects with LMNB1 gene duplication, we found a pathological increase in CSF lactate, likely due to active demyelination along with glial activation, and microstructural changes in the genu of the corpus callosum possibly underpinning the mild neuropsychological deficits.

Messenger RNA processing is altered in autosomal dominant leukodystrophy.

Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurological disorder characterized by autonomic dysfunction, followed by cerebellar and pyramidal features. ADLD is caused by duplication of the lamin B1 gene (LMNB1), which leads to its increased expression. The molecular pathways involved in the disease are still poorly understood. Hence, we analyzed global gene expression in fibroblasts and whole blood of LMNB1 duplication carriers and used Gene Set Enrichment Analysis to explore their gene signatures. We found that LMNB1 duplication is associated with dysregulation of genes involved in the immune system, neuronal and skeletal development. Genes with an altered transcriptional profile clustered in specific genomic regions. Among the dysregulated genes, we further studied the role of RAVER2, which we found to be overexpressed at mRNA and protein level. RAVER2 encodes a putative trans regulator of the splicing repressor polypyrimidine tract binding protein (PTB) and is likely implicated in alternative splicing regulation. Functional studies demonstrated an abnormal splicing pattern of several PTB-target genes and of the myelin protein gene PLP1, previously demonstrated to be involved in ADLD. Mutant mice with different lamin B1 expression levels confirmed that Raver2 expression is dependent on lamin B1 in neural tissue and determines an altered splicing pattern of PTB-target genes and Plp1. Overall our results demonstrate that deregulation of lamin B1 expression induces modified splicing of several genes, likely driven by raver-2 overexpression, and suggest that an alteration of mRNA processing could be a pathogenic mechanism in ADLD.

Medication overuse headache in Europe and Latin America: general demographic and clinical characteristics, referral pathways and national distribution of painkillers in a descriptive, multinational, multicenter study.

BACKGROUND: Medication overuse headache (MOH) is a very disabling and costly disorder due to indirect costs, medication and healthcare utilization. The aim of the study was to describe general demographic and clinical characteristics of MOH, along with the national referral pathways and national painkillers distribution in several European and Latin American (LA) Countries. METHODS: This descriptive cross-sectional observational study included 669 patients with MOH referred to headache-centers in Europe and LA as a part of the COMOESTAS project. Information about acute medication and healthcare utilization were collected by extensive questionnaires, supplemented with structured patient interviews. RESULTS: Triptans were overused by 31 % European patients and by 6 % in LA (p < 0.001), whereas ergotamines were overused by 4 % in Europe and 72 % in LA (p < 0.001). Simple analgesics were overused by 54 % in Europe and by 33 % in LA (p < 0.001), while combination-analgesics were more equally overused (24 % in Europe and 29 % in LA). More European patients (57 %) compared with LA patients (27 %) visited general practitioners (p < 0.001), and 83 % of European patients compared to 38 % in LA consulted headache specialists (p < 0.001). A total of 20 % in Europe and 30 % in LA visited emergency rooms (p = 0.007). CONCLUSION: There are marked variations between LA and Europe in healthcare pathways and in acute medication overuse regarding patients with MOH. This should be considered when planning prevention campaigns against MOH.

Tilt-induced cardioinhibitory syncope: a follow-up study in 16 patients.

INTRODUCTION: The exact clinical and prognostic significance and the therapeutic implications of asystole induced by head-up tilt test are still a matter of debate. METHODS: We assessed, by means of a semi-structured interview, the long-term outcome of cardioinhibitory syncope in all the patients who presented a tilt-induced sinus arrest of more than 3 s in our Autonomic Unit between 1996 and 2010. CONCLUSIONS: Although syncopal recurrences were common, tilt-induced asystole did not imply a poor prognosis in terms of death or major therapeutic procedures.

Oneiric stupor: the peculiar behaviour of agrypnia excitata.

Agrypnia excitata (AE) is a syndrome characterized by the inability to sleep associated with a generalized motor and autonomic over-activation. AE is caused by a thalamo-limbic system dysfunction and comprises three different conditions: Fatal Familial Insomnia (FFI), Delirium Tremens (DT), and Morvan Syndrome (MS). Oneiric Stupor episodes (OS) are the peculiar motor behaviour of AE. During OS patients perform simple automatic gestures mimicking daily-life activities. This paper is the first description of the different characteristics of OS in two patients with MS and another with FFI, emphasizing the specific clinical features that reliably differentiate OS from REM sleep behaviour disorders.

A case of strictly unilateral migraine without aura transformed in an episodic hemicrania continua.

According to the diagnostic criteria of International Headache Society classification, hemicrania continua is a strictly unilateral continuous headache of moderate intensity with painful exacerbations associated with ipsilateral autonomic signs without pain-free periods. We report a case of a 42-year-old woman suffered of a remitting form of hemicrania continua evolved from a strictly unilateral migraine without aura.