Comparative Targeted Metabolomics of Ischemic Stroke: Thrombi and Serum Profiling for the Identification of Stroke-Related Metabolites.

Ischemic stroke is one of the leading causes of death and permanent disability in the world. Rapid diagnosis and intervention are crucial for reducing its consequences on individuals and societies. Therefore, identifying reliable biomarkers for early detection, prognostics, and therapy can facilitate the early prediction and prevention of stroke. Metabolomics has been shown as a promising tool for biomarker discovery since many post-ischemic metabolites can be found in the plasma or serum of the patient. In this research, we performed a comparative targeted metabolomic analysis of stroke thrombi, stroke patient serums, and healthy control serums in order to determine the alteration in the patients' metabolomes, which might serve as biomarkers for early prediction or stroke prevention. The most statistically altered metabolites characterized in the patient serums compared with the control serums were glutamate and serotonin, followed by phospholipids and triacylglycerols. In stroke thrombi compared with the patients' serums, the most significantly altered metabolites were classified as lipids, with choline-containing phospholipids and sphingomyelins having the highest discriminatory score. The results of this preliminary study could help in understanding the roles of different metabolic changes that occur during thrombosis and cerebral ischemia and possibly suggest new metabolic biomarkers for ischemic stroke.

Diagnosis of Two Unrelated Syndromes of Prader-Willi and Calpainopathy: Insight from Trio Whole Genome Analysis and Isodisomy Mapping.

PURPOSE: An investigation for the co-occurrence of two unrelated genetic disorders of muscular dystrophy and Prader-Willi syndrome (PWS) (OMIM#176270) using joint whole genome sequencing (WGS). METHODS: Trio WGS joint analysis was performed to investigate the genetic etiology in a proband with PWS, prolonged muscular hypotonia associated hyperCKemia, and early-onset obesity. The parents were unaffected. RESULTS: Results showed maternal isodisomy uniparental disomy (UPD) in chromosome 15, expanding from 15q11.2 to 15q22.2, including PWS regions at 15q11.2-15q13. Maternal heterodisomy was detected from 15q22.2 to 15q26.3. A pathogenic variant, NM_000070.3(CAPN3):c.550del (p.Thr184fs), was identified at 15q15.1 in a heterozygous state in the mother that was homozygous in the proband due to maternal isodisomy. CONCLUSION: This is the first study of the concurrent molecular etiology of PWS and calpainopathy (OMIM#253600) in the same patient. This report highlights the utility of joint analysis and the need for the assessment of autosomal recessive disease in regions of isodisomy in patients with complex and unexplained phenotypes.

A 5-Year Follow-Up after Endovascular Treatment of 402 Intracranial Aneurysms-A Single-Centre Experience.

The aim of our study was to evaluate the early and long-term clinical and morphological outcomes of the endovascular treatment of ruptured and non-ruptured intracranial aneurysms in a cohort of patients from a single centre. We retrospectively analysed the treatment outcomes of 402 endovascularly treated intracranial aneurysms with an average follow-up of 5.5 years. All included patients were treated with endovascular techniques (coil, stent or both). We analysed patient demographics, risk factors for an aneurysm rupture, aneurysm characteristics, and clinical and angiographic complications and outcomes. We analysed and compared the data from the two groups, ruptured aneurysms (RAs) and unruptured aneurysms (UAs), separately. Out of the 318 patients included, a good early clinical outcome was achieved in 78.5% of RAs and in 95.3% of UAs. No complications occurred in 87.71% of patients with UAs and in 80.45% with RAs. The periprocedural rupture rate for UAs and RAs was 0.8% and 2.2%, respectively. The rate of thromboembolic events was 4.8 and 8% for UAs and RAs, respectively. A retreatment due to the recanalisation was required in 9.21% of patients with UAs and in 16.66% of patients with RAs. The results from our centre showed an overall favourable clinical outcome with acceptable periprocedural complications for both RAs and UR aneurysms and proved the endovascular method as safe and effective in the treatment of intracranial aneurysms.

Young stroke patient with patent foramen ovale and intracranial stenosis-a case report.

The prevalence of patent foramen ovale is approximately 20% in the global population. In patients under the age of 55 years, it has been proven as a cause of acute ischemic embolic stroke of otherwise undetermined source. We present a case of a 25-year-old patient who experienced an acute stroke of dominant hemisphere due to internal carotid artery occlusion.The patient underwent mechanical thrombectomy, followed by acute intracranial stenting due to persistent subocclusion of internal carotid artery. Further diagnostic investigations revealed a significant patent foramen ovale. During subsequent follow-up periods, the patient encountered multiple transient ischemic attacks despite receiving antithrombotic therapy. The indicated angiography examination revealed in-stent stenosis and thrombosis, which were resolved after optimal medical treatment. Following patent foramen ovale closure, the patient remained free from further neurological events during the subsequent two-year follow-up periods. This case emphasizes the necessity of comprehensive diagnostic evaluations in young individuals with stroke and underscores the importance of prudent slection of medical therapies.

Spinal dural arteriovenous fistulas: a report on outcomes in a single-center retrospective cohort treated surgically and/or endovascularly.

AIM: To report on the outcomes of spinal dural arteriovenous fistulas (sDAVFs) treatment in a single-center retrospective cohort. METHODS: Data were retrieved on sDAVF cases treated surgically and endovascularly between January 2009 and January 2020. Sociodemographic, clinical, imaging data, and outcomes were analyzed. RESULTS: Thirty-four patients were identified: 11 female, mean age 64.1 ± 11.5 years; mean time of symptom duration 12 (range 1-149) months. The sDAVF locations were the following: 18 (62.1%) thoracic, 4 (13.8%) lumbar, 4 (13.8%) sacral, and 3 (10%) with multiple location feeders. All patients had a motor deficit and affected walking, and the majority had a sensory deficit, bowel, and bladder dysfunction. Fifteen (44.1%) patients underwent surgical treatment, 7 (20.6%) underwent endovascular treatment, and 12 (35.3%) underwent both (crossover). Radiological myelopathy showed regression in 19 (55.9%) patients. Overall, clinical improvement (decrease in modified Rankin score) following treatment was observed in 14 patients (41.2%), worsening in 1 (2.9%), while other had unchanged status. The proportion of patients with initial treatment failure markedly differed between the before-2014 and after-2014 period. Patients who failed to improve had more extensive myelopathy. CONCLUSION: Patients who underwent surgery or endovascular treatment had on average significant clinical recovery, while those who underwent treatment crossover had negligible improvement. The extent of myelopathy seems to be associated with clinical improvement.

Transient acute hydrocephalus after aneurysmal subarachnoid hemorrhage and aneurysm embolization: a single-center experience.

PURPOSE: Acute hydrocephalus is a common complication after aneurysmal subarachnoid hemorrhage (aSAH). It can be self-limiting or require cerebrospinal fluid diversion. We aimed to determine the transient acute hydrocephalus (TAH) rate in patients with aSAH treated endovascularly and evaluate its predictive factors. METHODS: A retrospective review of 357 patients with aSAH who underwent endovascular treatment from March 2013 to December 2019 was performed. Clinical and radiographic data were analyzed and risk factors with potential significance for acute hydrocephalus were identified. We constructed a new risk score, the Drainage Or Transiency of Acute Hydrocephalus after Aneurysmal SAH (DOTAHAS) score, that may differentiate patients who would experience TAH from those needing surgical interventions. RESULTS: Acute hydrocephalus occurred in 129 patients (36%), out of whom in 66 patients (51%) it was self-limiting while 63 patients (49%) required external ventricular drainage placement. As independent risk factors for acute hydrocephalus, we identified older age, poor initial clinical condition, aSAH from posterior circulation, and the extent of cisternal and intraventricular hemorrhage. The following three factors were shown to predict acute hydrocephalus transiency and therefore included in the DOTAHAS score, ranging from 0 to 7 points: Hunt and Hess grade ≥ 3 (1 point), modified Fisher grade 4 (2 points), and Ventricular Hijdra Sum Score (vHSS) ≥ 6 (4 points). Patients scoring ≥ 3 points had significantly higher risk for EVD (P < 0.0001) than other patients. CONCLUSION: The newly developed DOTAHAS score can be useful in identifying patients with transient acute hydrocephalus. Further score evaluation is needed.

Early initiation of ambroxol treatment diminishes neurological manifestations of type 3 Gaucher disease: A long-term outcome of two siblings.

Gaucher disease type 3 (GD3) is a severely debilitating disorder characterized by multisystemic manifestations and neurodegeneration. Enzyme replacement therapy alleviates visceral signs and symptoms but has no effect on neurological features. Ambroxol has been suggested as an enzyme enhancement agent. Some studies have confirmed its effectiveness in preventing the progression of neurological manifestations of neuronopathic Gaucher disease. In this study, we report two GD3 siblings in whom ambroxol combined with enzyme replacement therapy was initiated at different stages of the disease. We demonstrate the enzyme enhancement effect of ambroxol on L444P/H225Q;D409H glucocerebrosidase activity through results of fibroblast studies and long-term clinical outcomes of the two patients. The sibling diagnosed at the age of four-and-a-half years with significant neurological involvement manifested relatively rapid improvement on ambroxol treatment, followed by stabilization of further course. The younger sibling, in whom the treatment was started at seven weeks, displayed attention deficit and low average cognitive functioning at the age of seven years, but did not manifest other neurological symptoms. The difference in neurological outcomes indicates that ambroxol delayed or even halted the evolution of neurological manifestations in the younger sibling. This observation suggests that early initiation of ambroxol treatment may arrest neurological involvement in some GD3 patients.

Decline in subarachnoid haemorrhage volumes associated with the first wave of the COVID-19 pandemic.

BACKGROUND: During the COVID-19 pandemic, decreased volumes of stroke admissions and mechanical thrombectomy were reported. The study's objective was to examine whether subarachnoid haemorrhage (SAH) hospitalisations and ruptured aneurysm coiling interventions demonstrated similar declines. METHODS: We conducted a cross-sectional, retrospective, observational study across 6 continents, 37 countries and 140 comprehensive stroke centres. Patients with the diagnosis of SAH, aneurysmal SAH, ruptured aneurysm coiling interventions and COVID-19 were identified by prospective aneurysm databases or by International Classification of Diseases, 10th Revision, codes. The 3-month cumulative volume, monthly volumes for SAH hospitalisations and ruptured aneurysm coiling procedures were compared for the period before (1 year and immediately before) and during the pandemic, defined as 1 March-31 May 2020. The prior 1-year control period (1 March-31 May 2019) was obtained to account for seasonal variation. FINDINGS: There was a significant decline in SAH hospitalisations, with 2044 admissions in the 3 months immediately before and 1585 admissions during the pandemic, representing a relative decline of 22.5% (95% CI -24.3% to -20.7%, p<0.0001). Embolisation of ruptured aneurysms declined with 1170-1035 procedures, respectively, representing an 11.5% (95%CI -13.5% to -9.8%, p=0.002) relative drop. Subgroup analysis was noted for aneurysmal SAH hospitalisation decline from 834 to 626 hospitalisations, a 24.9% relative decline (95% CI -28.0% to -22.1%, p<0.0001). A relative increase in ruptured aneurysm coiling was noted in low coiling volume hospitals of 41.1% (95% CI 32.3% to 50.6%, p=0.008) despite a decrease in SAH admissions in this tertile. INTERPRETATION: There was a relative decrease in the volume of SAH hospitalisations, aneurysmal SAH hospitalisations and ruptured aneurysm embolisations during the COVID-19 pandemic. These findings in SAH are consistent with a decrease in other emergencies, such as stroke and myocardial infarction.

Comparison between stenting and conservative management of posterior circulation perforator aneurysms: Systematic review and case series.

PURPOSE: Posterior circulation perforator aneurysms (PCPAs) are a rare type of intracranial aneurysms whose natural history and optimal clinical management are still largely unexplored. This study aims to report our experience with treating ruptured PCPAs and to provide a systematic review of the literature to compare the two most established treatment options, endovascular stenting, and conservative management including administration of antifibrinolytic drugs and watchful waiting. METHODS: We performed a systematic review of the literature following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Major databases were searched for case reports and case report series written in the English language between 1995 and 2020. Additionally, we retrospectively reviewed our stroke center database for cases of ruptured PCPAs between January 2014 and July 2020. Endovascular stenting and conservative treatment were compared using endpoints, including favorable outcome rate (mRS 0-2), occlusion rate, mortality rate, periinterventional complication rate, and re-hemorrhage rate. RESULTS: We identified 31 patients treated endovascularly using stents and 33 patients treated conservatively, with the administration of antifibrinolytic drugs in 3 of them. Our analysis showed no statistically significant difference between the groups, except for the occlusion rate. CONCLUSIONS: The optimal management strategy of PCPAs is still unknown, but stenting can be considered as an effective occlusion method with an acceptable complication rate. Preventive ventricular drainage may be necessary due to the high hydrocephalus rate encountered in ruptured PCPAs.

Choline elevation in amygdala region at recovery indicates longer survival without depressive episode: a magnetic resonance spectroscopy study.

RATIONALE: Depression, with variable longitudinal patterns, recurs in one third of patients. We lack useful predictors of its course/outcome, and proton magnetic resonance spectroscopy (1H-MRS) of brain metabolites is an underused research modality in finding outcome correlates. OBJECTIVES: To determine if brain metabolite levels/changes in the amygdala region observed early in the recovery phase indicate depression recurrence risk in patients receiving maintenance therapy. METHODS: Forty-eight patients on stable-dose antidepressant (AD) maintenance therapy were analyzed from recovery onset until (i) recurrence of depression or (ii) start of AD discontinuation. Two 1H-MRS scans (6 months apart) were performed with a focus on amygdala at the beginning of recovery. N-acetylaspartate (NAA), choline-containing metabolites (Cho), and Glx (glutamine/glutamate and GABA) were evaluated with regard to time without recurrence, and risks were assessed by Cox proportional hazard modeling. RESULTS: Twenty patients had depression recurrence, and 23 patients reached AD discontinuation. General linear model repeated measures analysis displayed three-way interaction of measurement time, metabolite level, and recurrence on maintenance therapy, in a multivariate test, Wilks' lambda = 0.857, F(2,40) = 3.348, p = 0.045. Cho levels at the beginning of recovery and subsequent changes convey the highest risk for earlier recurrence. Patients experiencing higher amygdala Cho after recovery are at a significantly lower risk for depression recurrence (hazard ratio = 0.32; 95% confidence interval 0.13-0.77). CONCLUSION: Cho levels/changes in the amygdala early in the recovery phase correlate with clinical outcome. In the absence of major NAA fluctuations, changes in Cho and Glx may suggest a shift towards reduction in (previously increased) glutamatergic neurotransmission. Investigation of a larger sample with greater sampling frequency is needed to confirm the possible predictive role of metabolite changes in the amygdala region early in the recovery phase.

Diffusion-weighted MRI: impact of the size of the ROI in detecting metastases in subcentimeter lymph nodes in head and neck squamous cell carcinoma.

PURPOSE: Our aim is to determine the impact of the size of ROI in detecting subcentimeter metastatic lymph nodes in patients with head and neck squamous cell carcinoma (HNSCC). Secondary aim is to determine the impact of the histopathologic grade of the primary cancer on the ADC value of the metastatic nodes. METHODS: The prospective study included 51 patients with histopathologically proven HNSCC at the primary site. Primary site includes oral cavity, oropharynx, larynx, and hypopharynx. ADC values of the lymph nodes were measured on ADC maps by placing two ROIs in the lymph nodes (0.2 cm2 in the center of the node and the whole node). Lymph nodes were dissected by levels, marked by the surgeon, and sent to the pathologist. RESULTS: By applying a smaller ROI, ADC values have greater sensitivity, specificity, NPV, PPV, and AUC in detecting metastasis compared to the ADC value of the entire node (88.0%, 80.73%, 90.7%, 75.9%, 0.912% versus 80.0%, 77.98%, 85% ,71.4%, and 0.819%, respectively) p < 0.001. Statistically significant negative correlation was established between the tumor grade and the ADC of lymph node at ROI 0.2 cm2and ROI of the whole lymph node (rho = - 0.425; p = 0.002, and rho = - 0.298; p = 0.038, respectively). CONCLUSION: ROI size affects the ADC value of the nodes. The higher histopathological grade of the primary tumor is inversely correlated with the ADC value of the lymph nodes.

Specific cognitive deficits in preschool age correlated with qualitative and quantitative MRI parameters in prematurely born children.

BACKGROUND: Cognitive deficits after perinatal brain lesion in preterm infants are among the most common neurodevelopmental disturbances. The relationship between structural changes on at term magnetic resonance imaging (MRI) and cognitive deficits in the preschool age should be a special focus due to timely intervention. The aim of this study was to correlate qualitative and quantitative MRI parameters of perinatal brain lesion in preterm children, on early neonatal MRI and follow up MRI, with general and specific cognitive functions in the preschool age. METHODS: Twenty-one preterm infants with verified perinatal lesions based on clinical and ultrasound data underwent a brain MRI at term-equivalent age and a second MRI between 3 and 5 years of age. Qualitative and quantitative MRI analyses were done. All subjects underwent cognitive assessment (3-5 years) using Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) and Developmental Neuropsychological Assessment (NEPSY-II). RESULTS: Results show that many structural changes on at term MRI and on follow up MRI in preterm born children moderately correlate with specific cognitive deficits in preschool age. At term equivalent MRI, white matter changes and cortical thickness correlate to general and specific cognitive functions in infants born preterm. By analyzing follow up MRI at preschool age, structural changes of different white matter segments, corpus callosum, cortical thickness and lobe volume correlate to some specific cognitive functions. CONCLUSION: Besides general cognitive delay, specific cognitive deficits in preterm children should be targeted in research and intervention, optimally combined with MRI scanning, providing timely and early intervention of cognitive deficits after perinatal brain lesion. Our results, as well as previously published results, suggest the importance of detailed preschool neuropsychological assessment, prior to enrolment in the school system. Although preliminary, our results expand our understanding of the relationship between early brain developmental lesions and cognitive outcome following premature birth.

Emergent Rescue Extracranial-Intracranial Bypass for Acute Carotid Stent Thrombosis Report.

BACKGROUND: Acute stent thrombosis is a rare adverse event following endovascular treatment of carotid artery. Experience on the topic is scarce, making the therapeutic approach a clinical challenge. In cases of intraprocedural acute carotid stent thrombosis, thromboaspiration, thrombectomy, and thrombolysis have been used as successful modalities for achieving recanalization. CASE DESCRIPTION: We describe a case of carotid artery dissection treated endovascularly and complicated by intraprocedural stent thrombosis, which was ultimately managed by emergent extracranial-intracranial bypass with radial artery graft connecting the external carotid artery to the ipsilateral middle cerebral artery. CONCLUSIONS: Neurosurgical management may represent a rescue option for otherwise unmanageable acute carotid stent thrombosis.

Choline and N-acetyl aspartate levels in the dorsolateral prefrontal cortex at the beginning of the recovery phase as markers of increased risk for depressive episode recurrence under different duration of maintenance therapy and after it: a retrospective cohort study.

AIM: To evaluate the relationship between the dynamics of proton magnetic resonance spectroscopy (1H-MRS) brain metabolite levels at the beginning of the recovery phase of the index depressive episode and the time to the recurrence of depression. METHODS: This retrospective cohort study analyzed the changes in N-acetyl aspartate (NAA), choline (Cho), and glutamate-glutamine in 48 patients with recurrent depression treated with maintenance antidepressant monotherapy at a stable dose. 1H-MRS was performed at the start of the recovery phase and 6 months later. 1H-MRS parameters, index episode descriptors, and depressive disorder course were analyzed by Cox proportional hazards model. RESULTS: NAA and Cho decrease six months after the beginning of the recovery period were time-independent risk factors for depressive episode recurrence. Hazard ratio associated with NAA decrease was 2.02 (95% confidence interval 1.06-3.84) and that associated with Cho decrease was 2.06 (95% confidence interval 1.02-4.17). These changes were not related to symptoms severity, as Montgomery-Asberg Depression Scale score remained generally unchanged (mean -0.01; standard deviation 1.6) over the first 6 months of recovery. CONCLUSION: Patients receiving maintenance antidepressant therapy after recovery who experience a decrease in NAA or Cho levels early in the recovery phase have a double risk of depressive episode recurrence. Sustained NAA and Cho levels at the beginning of the recovery phase may indicate increased brain resilience conferred by antidepressant therapy, while NAA and Cho decrease may indicate only the trait-related temporal effect of therapy in another stratum of patients.

Neurosyphilis: The shape of a rising threat.

This report describes a case of neurosyphilis presenting with memory disturbances, attention deficit, and acute psychotic decompensation in an immunocompetent man. Despite the known connection of neurosyphilis with psychiatric symptoms, this cause often remains unrecognized. This report emphasizes the importance of maintaining a suspicion for the disease in patients with vague symptoms and describes the diagnostic difficulties.

Hypopituitarism after gamma knife radiosurgery for pituitary adenoma.

PURPOSE: The aim of the study was to investigate the incidence of and risk factors for hypopituitarism after gamma knife radiosurgery (GKRS) for pituitary adenoma. MATERIALS AND METHODS: We conducted a retrospective analysis of the pituitary function of 90 patients who underwent GKRS for pituitary adenoma at the University Hospital Centre Zagreb between 2003 and 2014. Twenty seven of them met the inclusion criteria and the others were excluded from the study due to pituitary insufficiency which was present before GKRS. Eighteen patients had non-functioning and 9 patients had secretory adenomas. Median patients' age was 56 years (24-82). GKRS was performed using the Leksell gamma knife Model C. The median prescription radiation dose was 20 Gy (15-25) and the median tumor volume size was 3.4 cm3 (0.06-16.81). New onset hypopituitarism was defined as a new deficit of one of the three hormonal axes (corticotroph, thyreotroph, or gonadotroph) ≥3 months following GKRS. SPSS was used for statistical analysis, with the significance level at P<0.05. RESULTS: During the median follow-up period of 72 months (range 6-144), 30% of patients developed new hypopituitarism after GKRS. This corresponds to incidence of one new case of hypopituitarism per 15 patient-years. Age, gender, tumor function, tumor volume, suprasellar extension, prescription dose of radiation, as well as dose-volume to the pituitary gland, stalk and hypothalamus were not predictive factors for the development of hypopituitarism. CONCLUSIONS: In our cohort of patients with pituitary tumors who underwent GKRS, 30% developed new hypopituitarism during the follow-up period.

A Rapid Biochemical and Radiological Response to the Concomitant Therapy with Temozolomide and Radiotherapy in an Aggressive ACTH Pituitary Adenoma.

Background and Importance. In the last eight years temozolomide (TMZ) has been used as the last-line treatment modality for aggressive pituitary tumors to be applied after the failure of surgery, medical therapy, and radiotherapy. The objective was to achieve a rapid control of tumor growth and hormone normalization with concurrent chemoradiotherapy in a patient with very aggressive ACTH pituitary adenoma. Clinical Presentation. We describe a patient with an aggressive ACTH-producing adenoma treated with concurrent temozolomide and radiotherapy. The patient suffered from an aggressive ACTH adenoma resistant to surgical and medical treatment. After two months of concurrent temozolomide and radiotherapy, cortisol normalization and significant tumor shrinkage were observed. After 22 months of follow-up, there is still no evidence of tumor recurrence. Conclusion. Concurrent treatment with temozolomide and irradiation appears to be highly effective in the achievement of the tumor volume control as well as in the control of ACTH secretion in aggressive ACTH adenoma.