The real-world effectiveness of intravenous brivaracetam as a second-line treatment in status epilepticus.

PURPOSE: Status epilepticus (SE) is defined by abnormally prolonged seizures that may lead to brain damage and death. Our aim was to evaluate the efficacy and tolerability (effectiveness) of intravenous brivaracetam (BRV) as a second-line treatment. METHODS: Twenty-one patients (median age 68 years ± 17.28) were prospectively recruited between June 2019 and December 2022. Patients were treated with BRV (50-200 mg) as a second-line add-on therapy for SE. We evaluated the response of SE to the administration of BRV in terms of SE termination and recurrence of epileptic seizures at 6, 12, and 24 h, also monitoring safety. The first-line therapy was represented by intravenous benzodiazepines (mainly diazepam). RESULTS: Almost a quarter of patients had generalized seizures, whereas the vast majority (76.2%) presented focal seizures. In 52.4% of patients, the underlying cause was cerebrovascular. Fourteen (66.7%) patients displayed a good early response in the subsequent 6 h. At 12 and 24 h, 8 (38%) and 11 (52.4%) patients, respectively, did not present seizures. CONCLUSION: The present study highlights the potential of BRV when used as an early add-on therapy in SE, further confirming its good safety profile.

Prevalence, clinical features, and radiological pattern of artery of Percheron infarction: a challenging diagnosis.

PURPOSE: Occlusion of artery of Percheron (AOP), a rare variant of paramedian branches of posterior cerebral artery, results in a characteristic pattern of ischemic lesions in bilateral paramedian thalami with or without midbrain and anterior thalami involvement. AIM: To evaluate the prevalence, the clinical, and the imaging features of AOP infarction in a single comprehensive stroke center experience. METHODS: We retrospectively search in our stroke center database, patients with ischemic lesions in the AOP distribution. We collected clinical features and time between hospital admission and diagnosis. Imaging findings were categorized following a pre-selected classification. RESULTS: Of 2830 ischemic stroke admitted in our center, we identified 15 patients with AOP infarction (0.53%). Clinical manifestations were variable, but oculomotor disturbances, particularly vertical gaze palsy, were the most observed, followed by consciousness impairment, varying from drowsiness to coma. The most frequent imaging pattern was bilateral paramedian thalamic infarction with midbrain infarction, and the V-sign was recognized in 6 cases from this group. In 8 patients a fetal origin of the PCA was observed. The average time from first hospital admission to diagnosis was 28.09 h. CONCLUSIONS: The prevalence of AOP infarction in our center was 0.53%. Diagnosis of AOP infarction can be challenging and should be suspected in case of sudden altered consciousness.

Fusion of magnetic resonance angiography and cisternography in acute ischemic stroke reveals the vessel anatomy ahead of the clot: a technical note to see beyond obstacles.

We describe how the fusion process between magnetic resonance angiography (MRA) and cisternography (MRC) promptly reveals vessel anatomy ahead of the clot, in patients affected by acute anterior circulation large vessel occlusion. This technique showed in 100% of subjects (n = 22) a clear tracing of vessel anatomy before and beyond the clot. The duration of the whole process is short and could be considered safe since no outcome differences have been found when compared with a control group (n = 23). This technique could play a relevant role in guiding endovascular therapy, especially in unexpected unfavorable anatomical arteries configurations.

Ultraviolet A phototest positivity is associated with higher free erythrocyte protoporphyrin IX concentration and lower transferrin saturation values in erythropoietic protoporphyria.

BACKGROUND: Erythropoietic protoporphyria (EPP) is a rare disorder of heme biosynthesis hallmarked by early-onset photosensitivity and mainly due to defective ferrochelatase activity leading to increased erythrocyte protoporphyrin IX (PPIX) levels. Evidence regarding the relationship between erythrocyte PPIX concentration and photosensitivity is limited. METHODS: To investigate the relationship between free erythrocyte PPIX (FEP) concentration; routine laboratory tests, particularly iron metabolism biomarkers; and ultraviolet (UV) A/visible light phototesting findings, 20 genetically confirmed EPP and one XLPP treatment-naive patients were included in our study. They underwent UVA and visible light phototesting. On the same day, blood samples were collected for measurement of FEP, serum iron, transferrin, transferrin saturation, and ferritin, 25-hydroxyvitamin D, and liver enzyme levels. RESULTS: Median FEP concentration at the time of phototesting was 57.50 (IQR: 34.58-102.70) µg/g of Hb. UVA and visible light phototesting were positive in 9 (42.9%) and 8 (38.1%) patients, respectively. Median FEP concentration was significantly higher in UVA phototest-positive patients than in those negative (64.37 [IQR: 57.45-121.82] vs 45.35 [IQR: 24.53-74.61] µg/g of Hb, respectively; P = .04486). Similarly, UVA photosensitive individuals had significantly lower median serum iron levels (61.5 [IQR: 33.5-84] µg/dL vs 109 [IQR: 63.25-154] µg/dL, respectively; P = .01862) and transferrin saturation values (15.005 [IQR: 7.0775-18.41] % vs 29.645 [IQR: 17.8225-34.3575] %; P = .0109) than those negative. CONCLUSIONS: Our study demonstrates that UVA phototest positivity is associated with higher FEP concentration and lower transferrin saturation and serum iron concentration in EPP.

PROMPT intervention for children with severe speech motor delay: a randomized control trial.

BACKGROUND: Currently, there is limited information on the intervention efficacy for children with speech motor delay (SMD). This randomized control trial (RCT) study examined the effectiveness of Prompts for Restructuring Oral Muscular Phonetic Targets (PROMPT) intervention to improve the outcomes in children with SMD. We hypothesized that children with SMD receiving PROMPT intervention would improve more in the measured outcomes than those waitlisted and receiving home training. METHODS: Using a two-arm, parallel group, RCT, 49 children with SMD were allocated to either an intervention group (N = 24) that received 45 min of PROMPT intervention two times a week for 10 weeks or were waitlisted for the same duration and received only home training instructions (N = 25). Outcome measures for speech motor control, articulation, speech intelligibility (word and sentence levels), and functional communication were assessed at baseline and at a 10-week follow-up. RESULTS: PROMPT intervention was associated with notable improvements in speech motor control, speech articulation, and word-level speech intelligibility. Intervention allocation yielded weak improvements in sentence-level speech intelligibility and functional communication. CONCLUSIONS: PROMPT intervention is a clinically effective intervention approach for children with SMD. IMPACT: Currently, there is limited information on the intervention efficacy for children with SMD. We report on the findings of a phase III intervention efficacy study on children with SMD using an RCT design. PROMPT intervention is a clinically effective intervention approach for children with SMD. Results of the study will be fundamental to the delivery of effective services for this population. These findings may facilitate the development of an evidence-based care pathway for children with severe speech sound disorders.

Intracranial aneurysm management in patients with late-onset Pompe disease (LOPD).

Pompe disease is a rare hereditary metabolic disorder caused by α-glucosidase (GAA) deficiency. The late-onset form of the disease (LOPD) is considered a multisystemic disorder which could involve vascular system with cerebrovascular abnormalities such as intracranial aneurysms or dolichoectasia. Intracranial aneurysm rupture may represent a life-threatening emergency. A possible treatment of unruptured intracranial aneurysms (UIAs) should consider both aneurysm-related (aneurysmal size, shape, localization, numbers and hemodynamic factors) and patient-related risk factors (patient's age and sex, hypertension, smoke exposure). Moreover, UIAs management of LOPD patients needs also to take into account the altered blood vessels integrity and elasticity, whose consistency is likely weakened by the deficient GAA activity as a further potential risk factor. We herein present our approach for of UIAs management in three patients with LOPD. Among them, only one patient with a left saccular UIA of the anterior communicating artery, after careful consideration of risk factors, underwent the endovascular treatment. The other two patients were scheduled for a 1-year follow-up, according to radiological, clinical, and risk evaluation features. Finally, we would like to suggest some general recommendations for UIAs management. In particular, if no risk factors are identified, a cautious yearly follow-up is suggested; otherwise, if risk factors are present, endovascular treatment should be considered.

Targeted resequencing of FECH locus reveals that a novel deep intronic pathogenic variant and eQTLs may cause erythropoietic protoporphyria (EPP) through a methylation-dependent mechanism.

PURPOSE: Existing data do not explain the reason why some individuals homozygous for the hypomorphic FECH allele develop erythropoietic protoporphyria (EPP) while the majority are completely asymptomatic. This study aims to identify novel possible genetic variants contributing to this variable phenotype. METHODS: High-throughput resequencing of the FECH gene, qualitative analysis of RNA, and quantitative DNA methylation examination were performed on a cohort of 72 subjects. RESULTS: A novel deep intronic variant was found in four homozygous carriers developing a clinically overt disease. We demonstrate that this genetic variant leads to the insertion of a pseudo-exon containing a stop codon in the mature FECH transcript by the abolition of an exonic splicing silencer site and the concurrent institution of a new methylated CpG dinucleotide. Moreover, we show that the hypomorphic FECH allele is linked to a single haplotype of about 20 kb in size that encompasses three noncoding variants that were previously associated with expression quantitative trait loci (eQTLs). CONCLUSION: This study confirms that intronic variants could explain the variability in the clinical manifestations of EPP. Moreover, it supports the hypothesis that the control of the FECH gene expression can be mediated through a methylation-dependent modulation of the precursor messenger RNA (pre-mRNA) splicing pattern.

Isolated Insular Stroke: Clinical Presentation.

The symptoms related to insular ischemia have been the object of several studies in patients affected by stroke, although they are often accompanied by other ischemic alteration of adjacent brain structures supplied by the middle cerebral artery (MCA). The insula is vulnerable because of an ischemia due to thromboembolic vascular occlusion of the M1 MCA segment and the 2 main MCA branches (M2), mainly when they abruptly arise from the principal stem at a right angle. This topographical and anatomical peculiarity could enable an embolic formation, especially due to atrial fibrillation (AF), to occlude the transition pathway between M1 and M2, while the proximal origin of vascular supply protects the insula from ischemia due to hemodynamic factors. The aim of the study is to characterize the clinical aspects of acute ischemic strokes as a first event in the insular territory with specific attention to atypical manifestation. We have considered 233 patients with a first event stroke involving the insular territory and 13 cases of isolated insular stroke (IIS), from the stroke registry of the Policlinico "G.Martino", University of Messina, between the February 10, 2014 and the February 7, 2018. IIS patients showed CT/MRI lesions restricted to the insular region. Exclusion criteria were coexisting neurological diseases, structural brain lesions, extension to the subinsular area >50% of the total infarct volume. We identified 13 IIS patients (mean age 74 years), with an isolated symptom or a combination of typical and atypical aspects. Furthermore, we observed high frequency detection of cardiac disturbances. To our knowledge, just a few previous studies have described IIS; their incidence is still not well defined. IIS manifested with a combination of deficits including motor, somatosensory, speaking, coordination, autonomic and cognitive disturbances. After an ischemic stroke, AF manifestation could follow briefly the major event and its duration could be very short, as an autonomic dysfunction due to an insular infarction. This clinical condition requires a continuous cardiac monitoring for this dangerous occurrence.

Nutrients and Porphyria: An Intriguing Crosstalk.

Porphyria refers to a group of fascinating diseases from a metabolic and nutritional standpoint as it provides an example of how metabolic manipulation can be used for therapeutic purposes. It is characterized by defects in heme synthesis, particularly in the erythrocytes and liver. Specific enzymes involved in heme biosynthesis directly depend on adequate levels of vitamins and minerals in the tissues. Moreover, micronutrients that are required for producing succinyl CoA and other intermediates in the Krebs (TCA) cycle are indirectly necessary for heme metabolism. This review summarizes articles that describe the nutritional status, supplements intake, and dietary practices of patients affected by porphyria, paying special attention to the therapeutic use of nutrients that may help or hinder this group of diseases.

Germline Mutation Enrichment in Pathways Controlling Endothelial Cell Homeostasis in Patients with Brain Arteriovenous Malformation: Implication for Molecular Diagnosis.

Brain arteriovenous malformation (bAVM) is a congenital defect affecting brain microvasculature, characterized by a direct shunt from arterioles to venules. Germline mutations in several genes related to transforming growth factor beta (TGF-ß)/BMP signaling are linked to both sporadic and hereditary phenotypes. However, the low incidence of inherited cases makes the genetic bases of the disease unclear. To increase this knowledge, we performed a whole exome sequencing on five patients, on DNA purified by peripheral blood. Variants were filtered based on frequency and functional class. Those selected were validated by Sanger sequencing. Genes carrying selected variants were prioritized to relate these genes with those already known to be linked to bAVM development. Most of the prioritized genes showed a correlation with the TGF-ßNotch signaling and vessel morphogenesis. However, two novel pathways related to cilia morphogenesis and ion homeostasis were enriched in mutated genes. These results suggest novel insights on sporadic bAVM onset and confirm its genetic heterogeneity. The high frequency of germline variants in genes related to TGF-ß signaling allows us to hypothesize bAVM as a complex trait resulting from the co-existence of low-penetrance loci. Deeper knowledge on bAVM genetics can improve personalized diagnosis and can be helpful with genotype-phenotype correlations.

Posterior reversible encephalopathy syndrome (PRES) and infection: a systematic review of the literature.

Posterior reversible encephalopathy syndrome (PRES) is an encephalopathy characterized by a rapid onset of symptoms including headache, seizures, confusion, blurred vision, and nausea associated with a typical magnetic resonance imaging appearance of reversible subcortical vasogenic edema prominent and not exclusive of parieto-occipital lobes. Vasogenic edema is caused by a blood-brain barrier leak induced by endothelial damage or a severe arterial hypertension exceeding the limits of cerebral blood flow autoregulation. Although the exact pathophysiological mechanism is still unclear, frequent conditions that may induce PRES include severe hypertension, eclampsia/pre-eclampsia, acute kidney diseases and failure, immunosuppressive therapy, solid organ, or bone marrow transplantation. Conversely to other conditions, which may induce PRES, the link between severe infection or sepsis and PRES, often associated with gram-positive bacteria, is still poorly understood and less well known. Clinicians from multiple disciplines, such as neurologists and internists, may encounter during their profession patients with severe infection or sepsis and should consider the possible association between PRES and these conditions. We systematically reviewed the literature about this association in order to provide a helpful clinical insight of such complex pathophysiological mechanism, highlighting the importance of recognizing PRES in such a complex clinical scenario.

Caffeine and blood pressure: a critical review perspective.

The WHO reported that high blood pressure (BP) is one of the primary causes of death worldwide. Hypertension (HPT) is a major risk factor for CVD and related diseases as well as for diseases, leading to a considerable increase in cardiovascular risk. Since BP response could also be influenced by caffeine, which is widely consumed with coffee and other items, it is important to define the possible effects associated with caffeine intake. The most recent findings aimed at clarifying the role of caffeine consumption on BP and HPT risk/incidence are conflicting and difficult to interpret. Therefore, in the present narrative review, we aimed to examine various methodological inaccuracies/aspects and factors that make studies difficult to be compared, in order to obtain a single consensus on the effects of caffeine intake on the risk of BP and HPT. We observed that this heterogeneity in results could be due to the presence of: (i) several variables affecting BP (such as age, sex, genetic and lifestyle aspects); (ii) different caffeine content of food and beverages; and (iii) caffeine metabolism. Moreover, different methodological aspects in the evaluation of daily dietary caffeine intake and in the BP measurement could add some other bias in the interpretation of results. Therefore, it is mandatory to consider all methodological aspects and confounding factors to generate a standardised methodology in order to increase cross-study consistency and minimise confounding effects of different variables on the relationship between BP response and HPT risk/incidence after caffeine intake.

Investigating intervention dose frequency for children with speech sound disorders and motor speech involvement.

BACKGROUND: Treatment outcome data for children with severe speech sound disorders with motor speech involvement (SSD-MSI) are derived from Phase I clinical research studies. These studies have demonstrated positive improvements in speech production. Currently there is no research examining the optimal treatment dose frequency for this population. The results of this study, which is the first of its kind, will inform the delivery of effective services for this population. AIMS: To investigate optimal treatment dose frequency for the Motor Speech Treatment Protocol (MSTP) for children with SSD-MSI. METHODS & PROCEDURES: A total of 48 children (aged 43-47 months) with SSD-MSI participated in the study. Participants received 45-min MSTP intervention sessions either once per week (lower dose frequency) or twice per week (higher dose frequency) for a 10-week period. Blinded outcome assessments were carried out at pre- and post-intervention. OUTCOMES & RESULTS: Treatment-related change was assessed at body structures, functions and activities participation level as per the World Health Organization's International Classification of Functioning framework: Children and Youth Version (ICF-CY) framework WHO (2007). These measures are related to articulation, functional communication and speech intelligibility. One-way analysis of variance (ANOVA) revealed that for all variables the baseline scores were not statistically different (p > 0.05) between the two dose-frequency groups. Overall, there was a significant main effect of Time (pre-post) across all variables (p < 0.01). However, repeated-measures ANOVA did not result in any statistical interactions (Time × Dose frequency) for any of the variables tested (p > 0.05). Only marginal clinical advantages (< 4% change in intelligibility) were noted with the 10 extra sessions. CONCLUSIONS & IMPLICATIONS: Overall, the MSTP intervention approach in conjunction with home practice led to significant positive changes for all measures in children with SSD-MSI. No statistical differences between high- and low-dose-frequency groups were observed for any of the variables. Clinical effects were examined using effect sizes, as well as changes in articulation, speech intelligibility and functional communication; these differed marginally between the two dose frequencies. This suggests limited benefits of 10 additional sessions per block. Thus, it is recommended that caregivers, speech-language therapists and policy-makers perform a cost-benefit analysis before determining the dose frequency, when considering additional sessions per block.

Eagle Syndrome: A Wide Spectrum of Clinical and Neuroradiological Findings From Cervico-Facial Pain to Cerebral Ischemia.

Eagle syndrome (ES) is a rare symptomatic condition generally caused by abnormal elongation of the styloid process or calcification of stylo-hyoid ligament.Patients with ES typically present a variety of symptoms, which range from mild discomfort to acute neurologic and referred pain in head-and-neck region.Eagle syndrome could be identified through physical examination but often goes undetected in the absence of imaging studies.Although uncommon, it should be considered in the differential diagnosis in patients with cervico-facial pain.The authors report 3 cases with clinical evidence of ES, including both neurologic and vascular patterns, with a clinical and radiological diagnosis.The authors also propose a brief review of its main clinical presentations, diagnostic studies, and part of treatment options of the syndrome.

Digital PCR (dPCR) analysis reveals that the homozygous c.315-48T>C variant in the FECH gene might cause erythropoietic protoporphyria (EPP).

Alterations in the ferrochelatase gene (FECH) are the basis of the phenotypic expressions in erythropoietic protoporphyria. The phenotype is due to the presence of a mutation in the FECH gene associated in trans to the c.315-48 T > C variant in the intron 3. The latter is able to increase the physiological quota of alternative splicing events in the intron 3. Other two variants in the FECH gene (c.1-252A > G and c.68-23C > T) have been found to be associated to the intron 3 variant in some populations and together, they constitute a haplotype (ACT/GTC), but eventually, their role in the alternative splicing event has never been elucidated. The absolute number of the aberrantly spliced FECH mRNA molecules and the absolute expression of the FECH gene were evaluated by digital PCR technique in a comprehensive cohort. The number of splicing events that rose in the presence of the c.315-48 T > C variant, both in the heterozygous and homozygous condition was reported for the first time. Also, the percentage of the inserted FECH mRNA increased, even doubled in the T/C cases, compared to T/T cases. The constant presence of variants in the promoter and intron 2 did not influence or modulate the aberrant splicing. The results of FECH gene expression suggested that the homozygosity for the c.315-48 T > C variant could be considered pathological. Thus, this study identified the homozygotes for the c.315-48 T > C variant as pathological. By extension, when the samples were categorised according to the haplotypes, the GTC haplotype in homozygosis was pathological.

Molecular characterization, by digital PCR analysis of four HMBS gene mutations affecting the ubiquitous isoform of Porphobilinogen Deaminase (PBGD) in patients with Acute Intermittent Porphyria (AIP).

Genetic variants in promoters and alternative-splicing lesions require to be experimentally tested in order to validate them as causatives of a disease. The digital PCR (dPCR) approach, which is an alternative to the classical qPCR, is an innovative and a more sensitive method for the detection and quantification of nucleic acids. In the present study, we identified four HMBS gene mutations affecting the ubiquitous isoform of porphobilinogen deaminase (PBGD) and established a dPCR protocol which would be able to detect the different transcripts of this gene. With the application of this method, we were able to characterize the functional roles of these four genetic variants, demonstrating that all these mutations were causatives of the non-erythroid variant of the acute intermittent porphyria (AIP) disease.

A novel SLC1A4 homozygous mutation causing congenital microcephaly, epileptic encephalopathy and spastic tetraparesis: a video-EEG and tractography - case study.

Biallelic mutations in the SLC1A4 gene have been identified as a very rare cause of neurodevelopmental disorders. l-serine transport deficiency has been regarded as the causal molecular mechanism underlying the neurological phenotype of SLC1A4 mutation patients. To date this genetic condition has been reported almost exclusively in a limited number of Ashkenazi-Jewish individuals and as a result the SLC1A4 gene is not routinely included in the majority of the genetic diagnostic panels for neurological diseases. We hereby report a 7-year-old boy from a Southern Italian family, presenting with epileptic encephalopathy, congenital microcephaly, global developmental delay, severe hypotonia, spasticity predominant at the lower limbs, and thin corpus callosum. Whole exome sequencing identified a novel segregating SLC1A4 gene homozygous mutation (c.1141G > A: p.Gly381Arg) as the likely cause of the disease in our family. In order to deeply characterize the electro-clinical and neurological phenotype in our index patient, long-term systematic video-electroencephalograms (EEG) as well as repeated brain imaging studies (which included tractographic reconstructions) were performed on a regular basis during a 7 years follow-up time. In conclusion, we suggest to carefully considering SLC1A4 biallelic mutations in individuals presenting an early onset severe neurodevelopmental disorder with variable spasticity and seizures, regardless the patients' ethnic background.

PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment.

PRUNE is a member of the DHH (Asp-His-His) phosphoesterase protein superfamily of molecules important for cell motility, and implicated in cancer progression. Here we investigated multiple families from Oman, India, Iran and Italy with individuals affected by a new autosomal recessive neurodevelopmental and degenerative disorder in which the cardinal features include primary microcephaly and profound global developmental delay. Our genetic studies identified biallelic mutations of PRUNE1 as responsible. Our functional assays of disease-associated variant alleles revealed impaired microtubule polymerization, as well as cell migration and proliferation properties, of mutant PRUNE. Additionally, our studies also highlight a potential new role for PRUNE during microtubule polymerization, which is essential for the cytoskeletal rearrangements that occur during cellular division and proliferation. Together these studies define PRUNE as a molecule fundamental for normal human cortical development and define cellular and clinical consequences associated with PRUNE mutation.