Neurovascular Issues in Antiphospholipid Syndrome: Arterial Vasculopathy from Small to Large Vessels in a Neuroradiological Perspective.

Antiphospholipid syndrome (APS) is an autoimmune prothrombotic condition characterized by venous thromboembolism, arterial thrombosis, and pregnancy morbidity. Among neurological manifestations, arterial thrombosis is only one of the possible associated clinical and neuroradiological features. The aim of this review is to address from a neurovascular point of view the multifaceted range of the arterial side of APS. A modern neurovascular approach was proposed, dividing the CNS involvement on the basis of the size of affected arteries, from large to small arteries, and corresponding clinical and neuroradiological issues. Both large-vessel and small-vessel involvement in APS were detailed, highlighting the limitations of the available literature in the attempt to derive some pathomechanisms. APS is a complex disease, and its neurological involvement appears multifaceted and not yet fully characterized, within and outside the diagnostic criteria. The involvement of intracranial large and small vessels appears poorly characterized, and the overlapping with the previously proposed inflammatory manifestations is consistent.

Statin use and long-term risk of recurrent intracerebral haemorrhage: the MUCH-Italy.

BACKGROUND: Whether statin use after spontaneous intracerebral haemorrhage (ICH) increases the risk of recurrent ICH is uncertain. METHODS: In the setting of the Multicentric Study on Cerebral Haemorrhage in Italy we followed up a cohort of 30-day ICH survivors, consecutively admitted from January 2002 to July 2014, to assess whether the use of statins after the acute event is associated with recurrent cerebral bleeding. RESULTS: 1623 patients (mean age, 73.9±10.3 years; males, 55.9%) qualified for the analysis. After a median follow-up of 40.5 months (25th to 75th percentile, 67.7) statin use was not associated with increased risk of recurrent ICH either in the whole study group (adjusted HR, 0.99; 95% CI 0.64 to 1.53) or in the subgroups defined by haematoma location (deep ICH, adjusted HR, 0.74; 95% CI 0.35 to 1.57; lobar ICH, adjusted HR, 1.09; 95% CI 0.62 to 1.90), intensity of statins (low-moderate intensity statins, adjusted HR, 0.93; 95% CI 0.58 to 1.49; high-intensity statins, adjusted HR, 1.48; 95% CI 0.66 to 3.31) and use of statins before the index event (adjusted HR, 0.66; 95% CI 0.38 to 1.17). CONCLUSIONS: Statin use appears to be unrelated to the risk of ICH recurrence.

RNF213 Polymorphisms in Intracranial Artery Dissection.

The ring finger protein 213 gene (RNF213) is involved in several vascular diseases, both intracranial and systemic ones. Some variants are common in the Asian population and are reported as a risk factor for moyamoya disease, intracranial stenosis and intracranial aneurysms. Among intracranial vascular diseases, both moyamoya disease and intracranial artery dissection are more prevalent in the Asian population. We performed a systematic review of the literature, aiming to assess the rate of RNF213 variants in patients with spontaneous intracranial dissections. Four papers were identified, providing data on 53 patients with intracranial artery dissection. The rate of RNF213 variants is 10/53 (18.9%) and it increases to 10/29 (34.5%), excluding patients with vertebral artery dissection. All patients had the RNF213 p.Arg4810Lys variant. RNF213 variants seems to be involved in intracranial dissections in Asian cohorts. The small number of patients, the inclusion of only patients of Asian descent and the small but non-negligible coexistence with moyamoya disease familiarity might be limiting factors, requiring further studies to confirm these preliminary findings and the embryological interpretation.

Cerebellar mutism syndrome caused by bilateral cerebellar hemorrhage in adults: a case report and review of the literature.

Cerebellar mutism syndrome (CMS) is a frequent complication of surgical intervention on posterior fossa in children. It has been only occasionally reported in adults and its features have not been fully characterized. In children and in young adults, medulloblastoma is the main reason for neurosurgery. A single case of postsurgical CMS is presented in an adult patient with a cerebellar hemorrhage and a systematic review of the published individual cases of CMS in adults was done. Literature review of individual cases found 30 patients, 18/30 (60%) males, from 20 to 71 years at diagnosis. All but one case was post-surgical, but in one of the post-surgical cases iatrogenic basilar artery occlusion was proposed as cause for CMS. The causes were: primary tumors of the posterior fossa in 16/22 (72.7%) metastasis in 3/30 (10%), ischemia in 3/30 (10%) cerebellar hemorrhage in 3/30 (10%), and benign lesions in 2/30 (6.7%) patients. 8/30 patients (26.7%) were reported as having persistent or incomplete resolution of CMS within 12 months. CMS is a rare occurrence in adults and spontaneous cerebellar hemorrhage has been reported in 3/30 (10%) adult patients. The generally accepted hypothesis is that CMS results from bilateral damage to the dentate nucleus or the dentate-rubro-thalamic tract, leading to cerebro-cerebellar diaschisis. Several causes might contribute in adults. The prognosis of CMS is slightly worse in adults than in children, but two thirds of cases show a complete resolution within 6 months.

Persistent intracranial steno-occlusion from calcified embolism: a treatment challenge.

INTRODUCTION: Calcified arterial cerebral embolism is a rare occurrence among large and medium vessel occlusions causing ischemic stroke and its diagnosis and treatment is a challenge. The sources of calcified embolism might be a calcific atheroma from the aortic arch and carotid artery, but also heart valve disease has been reported in the literature. Calcified embolism is frequently simultaneous on multiple vascular territories. The prognosis of patients is usually poor, including patients treated by using endovascular thrombectomy (EVT) and this diagnosis could be easily missed in the acute phase. In addition, the optimal secondary prevention has not been yet fully stated. METHODS: We are presenting two cases of acute stroke due to calcified embolism in the middle cerebral artery (MCA) coming from a complicated carotid atheroma, non-stenosing in the first case (a 49 years old man) and stenosing in the second case (a 71 years old man) without clinical indications to intravenous thrombolysis and/or EVT, extensively investigated in the acute phase and followed-up for over 12 months with a favorable clinical course and the persisting steno-occlusion in the involved MCA. In both cases, antiplatelet treatment and targeting of vascular risk factors were done without recurrences in the follow-up period. DISCUSSION: Cerebral calcified embolism has been reported in 5.9% of cases of acute ischemic stroke in a single center series and only in 1.2% of a large retrospective cohort of EVT-treated patients. In both series the prognosis was poor and only one third of EVT-treated patients had functional independence at 3-months follow-up. The natural history of these subtype of ischemic stroke is relatively poorly understood and both etiological diagnosis and treatment have not yet defined. It is possible that some cases might be underdiagnosed and underreported. CONCLUSIONS: Calcified cerebral embolism is a rare cause of stroke, but it is largely underreported and both acute phase and secondary preventive treatment have to be defined.

Stroke-Induced Secondary Neurodegeneration of the Corticospinal Tract-Time Course and Mechanisms Underlying Signal Changes in Conventional and Advanced Magnetic Resonance Imaging.

Secondary neurodegeneration refers to the final result of several simultaneous and sequential mechanisms leading to the loss of substance and function in brain regions connected to the site of a primary injury. Stroke is one of the most frequent primary injuries. Among the subtypes of post-stroke secondary neurodegeneration, axonal degeneration of the corticospinal tract, also known as Wallerian degeneration, is the most known, and it directly impacts motor functions, which is crucial for the motor outcome. The timing of its appearance in imaging studies is usually considered late (over 4 weeks), but some diffusion-based magnetic resonance imaging (MRI) techniques, as diffusion tensor imaging (DTI), might show alterations as early as within 7 days from the stroke. The different sequential pathological stages of secondary neurodegeneration provide an interpretation of the signal changes seen by MRI in accordance with the underlying mechanisms of axonal necrosis and repair. Depending on the employed MRI technique and on the timing of imaging, different rates and thresholds of Wallerian degeneration have been provided in the literature. In fact, three main pathological stages of Wallerian degeneration are recognizable-acute, subacute and chronic-and MRI might show different changes: respectively, hyperintensity on T2-weighted sequences with corresponding diffusion restriction (14-20 days after the injury), followed by transient hypointensity of the tract on T2-weighted sequences, and by hyperintensity and atrophy of the tract on T2-weighted sequences. This is the main reason why this review is focused on MRI signal changes underlying Wallerian degeneration. The identification of secondary neurodegeneration, and in particular Wallerian degeneration, has been proposed as a prognostic indicator for motor outcome after stroke. In this review, the main mechanisms and neuroimaging features of Wallerian degeneration in adults are addressed, focusing on the time and mechanisms of tissue damage underlying the signal changes in MRI.

Early seizures and risk of epilepsy and death after intracerebral haemorrhage: The MUCH Italy.

INTRODUCTION: It is unclear which patients with non-traumatic (spontaneous) intracerebral haemorrhage (ICH) are at risk of developing acute symptomatic seizures (provoked seizures occurring within the first week after stroke onset; early seizures, ES) and whether ES predispose to the occurrence of remote symptomatic seizures (unprovoked seizures occurring more than 1 week after stroke; post-stroke epilepsy, PSE) and long-term mortality. PATIENTS AND METHODS: In the setting of the Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy) we examined the risk of ES and whether they predict the occurrence of PSE and all-cause mortality in a cohort of patients with first-ever spontaneous ICH and no previous history of epilepsy, consecutively hospitalized in 12 Italian neurological centers from 2002 to 2014. RESULTS: Among 2570 patients (mean age, 73.4 ± 12.5 years; males, 55.4%) 228 (8.9%) had acute ES (183 (7.1%) short seizures and 45 (1.8%) status epilepticus (SE)). Lobar location of the hematoma (OR, 1.49; 95% CI, 1.06-2.08) was independently associated with the occurrence of ES. Of the 2,037 patients who were followed-up (median follow-up time, 68.0 months (25th-75th percentile, 77.0)), 155 (7.6%) developed PSE. ES (aHR, 2.34; 95% CI, 1.42-3.85), especially when presenting as short seizures (aHR, 2.35; 95% CI, 1.38-4.00) were associated to PSE occurrence. Unlike short seizures, SE was an independent predictor of all-cause mortality (aHR, 1.50; 95% CI, 1.005-2.26). DISCUSSION AND CONCLUSION: The long-term risk of PSE and death after an ICH vary according to ES subtype. This might have implications for the design of future clinical trials targeting post-ICH epileptic seizures.

Tumor-like Lesions in Primary Angiitis of the Central Nervous System: The Role of Magnetic Resonance Imaging in Differential Diagnosis.

Primary Angiitis of the Central Nervous System (PACNS) is a rare disease and its diagnosis is a challenge for several reasons, including the lack of specificity of the main findings highlighted in the current diagnostic criteria. Among the neuroimaging pattern of PACNS, a tumefactive form (t-PACNS) is a rare subtype and its differential diagnosis mainly relies on neuroimaging. Tumor-like mass lesions in the brain are a heterogeneous category including tumors (in particular, primary brain tumors such as glial tumors and lymphoma), inflammatory (e.g., t-PACNS, tumefactive demyelinating lesions, and neurosarcoidosis), and infectious diseases (e.g., neurotoxoplasmosis). In this review, the main features of t-PACNS are addressed and the main differential diagnoses from a neuroimaging perspective (mainly Magnetic Resonance Imaging-MRI-techniques) are described, including conventional and advanced MRI.

The Prepetrous Segment of the Internal Carotid Artery as a Neglected Site of Symptomatic Atherosclerosis: A Single-Center Series.

(1) Background: Non-stenotic complicated plaques are a neglected cause of stroke, in particular in young patients. Atherosclerosis has some preferential sites in extracranial arteries and the prepetrous segment of the internal carotid artery has been rarely described as site of atheroma in general and of complicated atheroma in stroke patients. The aim of this study is to describe the rate of the prepetrous internal carotid artery's (ICA) involvement in a single-center case series of young stroke patients. (2) Methods: All patients < 50 years old with acute ischemic stroke admitted to a single-center Stroke Unit during two time periods (the first one from 1 January 2018 to 31 December 2019, and the second one from 1 January 2021 to 30 June 2022), were prospectively investigated as part of a screening protocol of the Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO) study [ClinicalTrials.gov ID NCT01934725], including extracranial vascular examination by using computed tomography (CT) or magnetic resonance imaging (MRI). (3) Results: Two out of ninety-three consecutive patients (2.15%) had a complicated atheroma in the prepetrous ICA as the cause of stroke and both CT angiography and high-resolution vessel wall MRI were applied to document the main features of positive remodeling, cap rupture, ulceration, intraplaque hemorrhage, and a transient thrombus superimposed on the atheroma. The two patients had a different evolution of healing in the first case and a persisting ulceration at 12 months in the second case. (4) Conclusions: The prepetrous ICA is a rarely described location of complicated atheroma in stroke patients at all ages and it represents roughly 2% of causes of acute stroke in this single-center case series in young people.

Long-Term Risk of Arterial Thrombosis After Intracerebral Hemorrhage: MUCH-Italy.

BACKGROUND: The identification of patients surviving an acute intracerebral hemorrhage who are at a long-term risk of arterial thrombosis is a poorly defined, crucial issue for clinicians. METHODS: In the setting of the MUCH-Italy (Multicenter Study on Cerebral Haemorrhage in Italy) prospective observational cohort, we enrolled and followed up consecutive 30-day intracerebral hemorrhage survivors to assess the long-term incidence of arterial thrombotic events, to assess the impact of clinical and radiological variables on the risk of these events, and to develop a tool for estimating such a risk at the individual level. Primary end point was a composite of ischemic stroke, myocardial infarction, or other arterial thrombotic events. A point-scoring system was generated by the ß-coefficients of the variables independently associated with the long-term risk of arterial thrombosis, and the predictive MUCH score was calculated as the sum of the weighted scores. RESULTS: Overall, 1729 patients (median follow-up time, 43 months [25th to 75th percentile, 69.0]) qualified for inclusion. Arterial thrombotic events occurred in 169 (9.7%) patients. Male sex, diabetes, hypercholesterolemia, atrial fibrillation, and personal history of coronary artery disease were associated with increased long-term risk of arterial thrombosis, whereas the use of statins and antithrombotic medications after the acute intracerebral hemorrhage was associated with a reduced risk. The area under the receiver operating characteristic curve of the MUCH score predictive validity was 0.716 (95% CI, 0.56-0.81) for the 0- to 1-year score, 0.672 (95% CI, 0.58-0.73) for the 0- to 5-year score, and 0.744 (95% CI, 0.65-0.81) for the 0- to 10-year score. C statistic for the prediction of events that occur from 0 to 10 years was 0.69 (95% CI, 0.64-0.74). CONCLUSIONS: Intracerebral hemorrhage survivors are at high long-term risk of arterial thrombosis. The MUCH score may serve as a simple tool for risk estimation.

Posterior reversible encephalopathy syndrome and acute ischemic stroke: an underreported association.

INTRODUCTION: Posterior reversible encephalopathy syndrome (PRES) is a rare and complex disorder with variable clinical presentation and a typical magnetic resonance imaging (MRI) pattern of vasogenic edema with typical and atypical locations. It is often triggered by other diseases and drugs and the most prototypical association is with persistently elevated arterial pressure values. Among the potential cerebrovascular complications, intracranial bleeding has been described, but ischemic stroke is uncommonly reported. METHODS: We are presenting a case of a male patient with prolonged and sustained arterial hypertension acutely presenting with lacunar ischemic stroke involving the right corona radiata and composite MRI findings with the association of chronic small vessel disease (SVD) markers, acute symptomatic lacunar stroke, and atypical, central variant, posterior fossa dominant PRES. In the MRI follow-up, the white matter hyperintensities in T2-fluid attenuated inversion recovery (FLAIR sequences) due to PRES. DISCUSSION: The pathophysiology of PRES is not yet fully known, but the association with markedly increased values of arterial pressure is typical. In this context, ischemic stroke has not been considered in the clinical and neuroradiological manifestations of PRES and it has been only occasionally reported in the literature. In this case, the main hypothesis is that sustained hypertension may have triggered both manifestations, PRES, and ischemic stroke and the last one allowed to diagnose the first one. CONCLUSIONS: Atypical variants of PRES are not so rare and it may also occur in typical triggering situations. The association with ischemic stroke is even rarer and it may add some clues to the pathomechanisms of PRES.

The Venular Side of Cerebral Amyloid Angiopathy: Proof of Concept of a Neglected Issue.

Small vessel diseases (SVD) is an umbrella term including several entities affecting small arteries, arterioles, capillaries, and venules in the brain. One of the most relevant and prevalent SVDs is cerebral amyloid angiopathy (CAA), whose pathological hallmark is the deposition of amyloid fragments in the walls of small cortical and leptomeningeal vessels. CAA frequently coexists with Alzheimer's Disease (AD), and both are associated with cerebrovascular events, cognitive impairment, and dementia. CAA and AD share pathophysiological, histopathological and neuroimaging issues. The venular involvement in both diseases has been neglected, although both animal models and human histopathological studies found a deposition of amyloid beta in cortical venules. This review aimed to summarize the available information about venular involvement in CAA, starting from the biological level with the putative pathomechanisms of cerebral damage, passing through the definition of the peculiar angioarchitecture of the human cortex with the functional organization and consequences of cortical arteriolar and venular occlusion, and ending to the hypothesized links between cortical venular involvement and the main neuroimaging markers of the disease.

Secondary neurodegeneration of ipsilateral substantia nigra in acute ischemic stroke.

INTRODUCTION: Secondary neurodegeneration after stroke is a complex phenomenon affecting remote and synaptically linked cerebral areas. The involvement of the substantia nigra in this process has been rarely described in infarcts involving the striatum. METHODS: We are presenting a case of ischemic stroke involving the right striatum due to atrial fibrillation and associated in a few days with the neuroimaging finding of hyperintensity of the ipsilateral substantia nigra and striatonigral tract on T2-fluid attenuated inversion recovery and diffusion-weighted imaging sequences of brain magnetic resonance imaging. This finding was not related to clinical manifestations and substantially disappeared within 3 months from stroke onset. DISCUSSION: The pathophysiology of secondary degeneration of the substantia nigra is poorly understood and it relies on animal models and autoptic studies. The main putative mechanism is not ischemic but excitotoxic with a different role of the internal and external globus pallidus and a different effect on the pars compacta and pars reticularis of the substantia nigra. In animal models, inflammatory mechanisms seem play a role only in the late phase. The main studies on humans were presented in detail. CONCLUSIONS: A better understanding of the secondary degeneration of the substantia nigra has the potentiality to offer a chance for neuroprotection in acute stroke, but further studies are needed.

Perfusion Status in Lacunar Stroke: A Pathophysiological Issue.

The pathophysiology of lacunar infarction is an evolving and debated field, where relevant information comes from histopathology, old anatomical studies and animal models. Only in the last years, have neuroimaging techniques allowed a sufficient resolution to directly or indirectly assess the dynamic evolution of small vessel occlusion and to formulate hypotheses about the tissue status and the mechanisms of damage. The core-penumbra concept was extensively explored in large vessel occlusions (LVOs) both from the experimental and clinical point of view. Then, the perfusion thresholds on one side and the neuroimaging techniques studying the perfusion of brain tissue were focused and optimized for LVOs. The presence of a perfusion deficit in the territory of a single small perforating artery was negated for years until the recent proposal of the existence of a perfusion defect in a subgroup of lacunar infarcts by using magnetic resonance imaging (MRI). This last finding opens pathophysiological hypotheses and triggers a neurovascular multidisciplinary reasoning about how to image this perfusion deficit in the acute phase in particular. The aim of this review is to summarize the pathophysiological issues and the application of the core-penumbra hypothesis to lacunar stroke.

CT Perfusion in Lacunar Stroke: A Systematic Review.

BACKGROUND: The main theory underlying the use of perfusion imaging in acute ischemic stroke is the presence of a hypoperfused volume of the brain downstream of an occluded artery. Indeed, the main purpose of perfusion imaging is to select patients for endovascular treatment. Computed Tomography Perfusion (CTP) is the more used technique because of its wide availability but lacunar infarcts are theoretically outside the purpose of CTP, and limited data are available about CTP performance in acute stroke patients with lacunar stroke. METHODS: We performed a systematic review searching in PubMed and EMBASE for CTP and lacunar stroke with a final selection of 14 papers, which were examined for data extraction and, in particular, CTP technical issues and sensitivity, specificity, PPV, and NPV values. RESULTS: A global cohort of 583 patients with lacunar stroke was identified, with a mean age ranging from 59.8 to 72 years and a female percentage ranging from 32 to 53.1%.CTP was performed with different technologies (16 to 320 rows), different post-processing software, and different maps. Sensitivity ranges from 0 to 62.5%, and specificity from 20 to 100%. CONCLUSIONS: CTP does not allow to reasonable exclude lacunar infarct if no perfusion deficit is found, but the pathophysiology of lacunar infarct is more complex than previously thought.

Right-to-left shunts and hormonal therapy influence cerebral vasomotor reactivity in patients with migraine with aura.

Patent Foramen Ovale and impaired cerebral hemodynamics were proposed among the pathophysiological mechanisms explaining the increased risk for stroke in patients with Migraine with Aura (MA). Our study aimed at comparing the vasomotor reactivity (VMR) of the anterior and the posterior cerebral circulation in patients with Migraine with Aura, in patients with acute vascular ischemic accidents, and in controls. We hypothesized that VMR in MA patients is preserved in the anterior circulation and reduced in the posterior circulation. We prospectively assessed with Transcranial Doppler the vasomotor reactivity to breath holding of the Middle and Posterior Cerebral Arteries (MCA, PCA) in MA patients, in acute vascular patients and healthy controls. We also evaluated the possible effect of clinical characteristics of MA (attack frequency, aura length or type, disease history), vascular factors and the presence of right-to-left shunt on VMR. Diverging from our hypothesis, MA patients displayed a higher breath-holding index (BHI) than controls in the MCA (1.84±0.47%/s vs 1.53±0.47%/s, p = .001) as well as in the PCA (1.87±0.65%/s vs 1.47±0.44%/s, p < .001). In MA patients, MCA BHI was higher in those with large right-to-left shunts (2.09±0.42 vs 1.79±0.47, p = .046) and lower in those taking estrogens (1.30±0.30%/s vs 1.9±0.45%/s, p = .009). We did not observe an effect of MA characteristics on BHI. The increased BHI in MA patients with large right-to-left shunts could be explained by the vasoactive effect in the cerebral circulation of substances bypassing the deactivating pulmonary filters or by a constitutional trait of the vascular system associating persistent right-to-left shunts and hyper-reactive hemodynamics. Our results discourage the hypothesis that altered hemodynamics contribute to increasing the stroke risk in all MA patients. However, estrogens can lower VMR, curtailing the hemodynamic resources of MA patients.