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.

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.

Prevalence of Fabry disease and GLA variants in young patients with acute stroke: The challenge to widen the screening. The Fabry-Stroke Italian Registry.

BACKGROUND: Fabry disease (FD) is a treatable X-linked lysosomal storage disorder caused by GLA gene variants leading to alpha-galactosidase A deficiency. FD is a rare cause of stroke, and it is still controversial whether in stroke patients FD should be searched from the beginning or at the end of the diagnostic workup (in cryptogenic strokes). METHODS: Fabry-Stroke Italian Registry is a prospective, multicentric screening involving 33 stroke units. FD was sought by measuring α-galactosidase A activity (males) and by genetic tests (males with reduced enzyme activity and females) in patients aged 18-60 years hospitalized for TIA, ischemic stroke, or intracerebral hemorrhage. We diagnosed FD in patients with 1) already known pathogenic GLA variants; 2) novel GLA variants if additional clinical, laboratory, or family-derived criteria were present. RESULTS: Out of 1906 patients, we found a GLA variant in 15 (0.79%; 95%CI 0.44-1.29) with a certain FD diagnosis in 3 (0.16%; 95%CI 0.03-0.46) patients, none of whom had hemorrhage. We identified 1 novel pathogenic GLA variant. Ischemic stroke etiologies in carriers of GLA variants were: cardioaortic embolism (33%), small artery occlusion (27%), other causes (20%), and undetermined (20%). Mild severity, recurrence, previous TIA, acroparesthesias, hearing loss, and small artery occlusion were predictors of GLA variant. CONCLUSION: In this large multicenter cohort the frequency of FD and GLA variants was consistent with previous reports. Limiting the screening for GLA variants to patients with cryptogenic stroke may miss up to 80% of diagnoses. Some easily recognizable clinical features could help select patients for FD screening.

IV Thrombolysis With or Without Endovascular Treatment for Suspected Ischemic Stroke in Patients With Intracranial Tumors.

BACKGROUND AND OBJECTIVES: IV thrombolysis (IVT) for suspected ischemic stroke in patients with intracranial neoplasms is off-label. However, data on risks of intracranial hemorrhage (ICH) are scarce. METHODS: In a multicenter registry-based analysis within the European Thrombolysis in Ischemic Stroke Patients (TRISP) collaboration, we assessed frequencies of symptomatic and fatal ICH after IVT for suspected ischemic stroke in patients with intracranial tumors by descriptive statistics and analyzed associations with clinical and imaging characteristics by binary logistic regression. Definition of symptomatic ICH was based on the clinical criteria of the European Cooperative Acute Stroke-II trial including hemorrhage at any site in cranial imaging and concurrent clinical deterioration. RESULTS: Screening data of 21,289 patients from 14 centers, we identified 105 patients receiving IVT; among them were 29 patients (28%) with additional endovascular treatment, with suspected, that is, imaging-based, or histologically confirmed diagnosis of intracranial tumors. Among 104 patients with CT or MRI after IVT available, symptomatic and fatal ICH were observed in 9 and 4 patients (9% and 4%, respectively). Among 82 patients with suspected or confirmed meningioma, symptomatic and fatal ICH occurred in 6 and 3 patients (7% and 4%), respectively. In 18 patients with intra-axial suspected or confirmed primary or secondary brain tumors, there was 1 symptomatic nonfatal ICH (6%). Of 4 patients with tumors of the pituitary region, 2 patients (50%) had symptomatic ICH including 1 fatal ICH (25%). Tumor size was not associated with the occurrence of symptomatic ICH (odds ratio 2.8, 95% CI 0.3-24.8, p = 0.34). DISCUSSION: In our dataset from routine clinical care, we provide insights on the safety of IVT for suspected ischemic stroke in patients with intracranial tumors, a population that is commonly withheld thrombolysis in clinical practice and prospective trials. Except for a potential high risk of symptomatic ICH after IVT in patients with tumors of the pituitary region, frequencies of symptomatic ICH in patients with intracranial tumors in our cohort seem to be in the upper range of rates observed in previous studies within the TRISP cooperation. These results may guide individual treatment decisions in patients with acute stroke and intracranial tumors with potential benefit of IVT.

From Fibromuscular Dysplasia to Arterial Dissection and Back.

Fibromuscular dysplasia (FMD) is an idiopathic and systemic non-inflammatory and non-atherosclerotic arterial disease. Fifteen to 25% of patients with FMD present with arterial dissection in at least one arterial bed. Conversely, a substantial number of patients with renal, carotid, and visceral dissection have underlying FMD. Also, while few patients with FMD develop coronary artery dissection, lesions suggestive of multifocal FMD have been reported in 30-80% of patients with spontaneous coronary artery dissection (SCAD), and the relation between these two entities remains controversial. The frequent association of FMD with arterial dissection, both in coronary and extra-coronary arteries raises a number of practical and theoretical questions: (i) Are FMD and arterial dissections two different facets of the same disease or distinct though related entities? (ii) Is SCAD just a manifestation of coronary FMD or a different disease? (iii) What is the risk and which are predictive factors of developing arterial dissection in a patient with FMD? (iv) What proportion of patients who experienced an arterial dissection have underlying FMD, and does this finding influence the risk of subsequent arterial complications? In this review we will address these different questions using fragmentary, mostly cross-sectional evidence derived from large registries and studies from Europe and the United States, as well as arguments derived from demographics, clinical presentation, imaging, and when available histology and genetics. From there we will derive practical consequences for nosology, screening and follow-up.

Mechanisms and Neuroimaging Patterns of Hypereosinophilia-Related Ischemic Stroke: A Narrative Review through Three Cases.

BACKGROUND: Hypereosinophilic syndromes (HES) are a group of relatively rare disorders in which neurological manifestations, including ischemic stroke, are common. The hypothesized pathophysiological mechanisms are hypercoagulability, cardioembolism (mainly mediated by myocardial involvement) and damage to the endothelium. A variable ischemic pattern has been described, including an association of territorial and border zone ischemic stroke. METHODS: Three patients who presented to our department with acute stroke were selected aiming to show these three different mechanisms inferred from the stroke pattern on brain Magnetic Resonance Imaging (MRI) and to simultaneously illustrate the three main causes of HES. RESULTS AND DISCUSSION: The first patient is a 55-year-old man with an abrupt onset of aphasia due to an acute ischemic stroke involving the left parietal lobule and the angular gyrus; recent lab test had shown hypereosinophilia. An extensive workup excluded primary and secondary causes of hypereosinophilia so a diagnosis of idiopathic hypereosinophilia was done and he was treated with high doses of steroids. The second patient had severe hypereosinophilia and developed multiple small, scattered ischemic lesions, mainly in border zone zones. The history of severe asthma and recurrent sinusitis supported the diagnosis of EGPA (Eosinophilic Granulomatosis with Polyangiitis); considering the severe clinical conditions and the presumptive role of hypereosinophilia in determining her symptoms, steroid treatment was promptly started, with good clinical response. The third patient also presented with multiple metachronous ischemic lesions, both in cortical and border zone distribution and marked eosinophilia; the diagnostic work-up found an ovarian cancer. She was treated with steroids and then underwent surgery and adjuvant chemotherapy. CONCLUSIONS: HES should be considered in stroke etiological evaluation, although it is a rare disorder, and border zones pattern without large artery steno-occlusion on neuroimaging may help to raise the suspicion in the neurovascular diagnostic pathway. A thorough research of the sources of hypereosinophilia should be performed to select the appropriate therapy.

Neurovascular Manifestations of Iron-Deficient Anemia: Narrative Review and Practical Reflections through a Teaching Case.

Anemia is one of the most frequent diseases worldwide, affecting one-third of the general population. Anemia in general and in particular, iron-deficient anemia (IDA), has been associated to a higher risk of thrombotic manifestations, including ischemic stroke and cerebral venous thrombosis (CVT), as well as systemic extra-cerebral arterial and venous thrombosis. Despite these data, anemia is seldom considered as an etiological factor of stroke. An individual case encompassing all known neurovascular and systemic arterial and venous thrombotic manifestations related to IDA is presented with the focus on clinical reasoning issues in the diagnostic pathways, starting from the neuroradiological signs. The main questions have been identified and addressed in a narrative review of the most relevant data in the literature from a pragmatic and clinical viewpoint. The presented case concerns a 46-year-old man admitted to the Stroke Unit because of acute ischemic stroke with multiple thrombi in large intracranial and extracranial vessels, multifocal ischemic lesions in several arterial territories and the concurrent finding of asymptomatic CVT, pulmonary embolism with lung infarction and aortic thrombosis. An extended diagnostic work-up excluded the main etiologies (arterial dissection, cardiac embolism, genetic and acquired prothrombotic disorders, such as cancer and antiphospholipid syndrome), except for a severe IDA, such as to require blood transfusions followed by anticoagulant therapy for the several thrombotic manifestations. Neuroimaging and systemic vascular findings have been analyzed, and the main issues proposed by the case in the diagnostic pathway have been identified and discussed in a pragmatic clinical road map reviewing the data provided by the literature. Conclusions: IDA is a common but treatable condition that, independently or synergically, may increase the risk of thrombotic events. The diagnostic and therapeutic approach has not yet been defined, and each case should be individually addressed in a pragmatic clinical road map.

Pediatric Moyamoya Disease and Syndrome in Italy: A Multicenter Cohort.

Background: Moyamoya is a rare progressive cerebral arteriopathy, occurring as an isolated phenomenon (moyamoya disease, MMD) or associated with other conditions (moyamoya syndrome, MMS), responsible for 6-10% of all childhood strokes and transient ischemic attacks (TIAs). Methods: We conducted a retrospective multicenter study on pediatric-onset MMD/MMS in Italy in order to characterize disease presentation, course, management, neuroradiology, and outcome in a European country. Results: A total of 65 patients (34/65 women) with MMD (27/65) or MMS (38/65) were included. About 18% (12/65) of patients were asymptomatic and diagnosed incidentally during investigations performed for an underlying condition (incMMS), whereas 82% (53/65) of patients with MMD or MMS were diagnosed due to the presence of neurological symptoms (symptMMD/MMS). Of these latter, before diagnosis, 66% (43/65) of patients suffered from cerebrovascular events with or without other manifestations (ischemic stroke 42%, 27/65; TIA 32%, 21/65; and no hemorrhagic strokes), 18% (12/65) of them reported headache (in 4/12 headache was not associated with any other manifestation), and 26% (17/65) of them experienced multiple phenotypes (≥2 among: stroke/TIA/seizures/headache/others). Neuroradiology disclosed ≥1 ischemic lesion in 67% (39/58) of patients and posterior circulation involvement in 51% (30/58) of them. About 73% (47/64) of patients underwent surgery, and 69% (45/65) of them received aspirin, but after diagnosis, further stroke events occurred in 20% (12/61) of them, including operated patients (11%, 5/47). Between symptom onset and last follow-up, the overall patient/year incidence of stroke was 10.26% (IC 95% 7.58-13.88%). At last follow-up (median 4 years after diagnosis, range 0.5-15), 43% (26/61) of patients had motor deficits, 31% (19/61) of them had intellectual disability, 13% (8/61) of them had epilepsy, 11% (7/61) of them had behavioral problems, and 25% (13/52) of them had mRS > 2. The proportion of final mRS > 2 was significantly higher in patients with symptMMD/MMS than in patients with incMMS (p = 0.021). Onset age <4 years and stroke before diagnosis were significantly associated with increased risk of intellectual disability (p = 0.0010 and p = 0.0071, respectively) and mRS > 2 at follow-up (p = 0.0106 and p = 0.0009, respectively). Conclusions: Moyamoya is a severe condition that may affect young children and frequently cause cerebrovascular events throughout the disease course, but may also manifest with multiple and non-cerebrovascular clinical phenotypes including headache (isolated or associated with other manifestations), seizures, and movement disorder. Younger onset age and stroke before diagnosis may associate with increased risk of worse outcome (final mRS > 2).

Epilepsy in patients undergoing cardiac surgery with ExtraCorporeal Circulation: case series and description of a peculiar clinical phenotype.

BACKGROUND: Extracorporeal circulation (ECC) is now being increasingly used in critical care settings. Epileptic seizures are a recognized but under reported complication in patients receiving this care. Acute symptomatic post-operative seizures have been described, as well as remote seizure, mostly in the form of convulsive seizures. Epilepsy has also been reported, although with lower frequency and mainly with convulsive seizures, while different seizure semiology is rarely described. CASE PRESENTATION: We report a case series of four patients developing epilepsy with homogeneous features following heart surgery with ECC. We present neurophysiological and neuroradiological data and we describe the peculiar characteristics of epilepsies in terms of seizure semiology, frequency, and drug response. The main features are: an insulo-temporal or parieto-occipital semiology, often multifocal and without loss of consciousness or motor manifestations, a high frequency of seizures but with low impact on daily life, and a good response to anti-epileptic therapy. CONCLUSIONS: We hypothesize a pathogenetic mechanism and we discuss the clinical implications of identifying these forms of epilepsy which tend to be often under-recognized.

Clinical Features of Patients With Cervical Artery Dissection and Fibromuscular Dysplasia.

BACKGROUND AND PURPOSE: Observational studies have suggested a link between fibromuscular dysplasia and spontaneous cervical artery dissection (sCeAD). However, whether patients with coexistence of the two conditions have distinctive clinical characteristics has not been extensively investigated. METHODS: In a cohort of consecutive patients with first-ever sCeAD, enrolled in the setting of the multicenter IPSYS CeAD study (Italian Project on Stroke in Young Adults Cervical Artery Dissection) between January 2000 and June 2019, we compared demographic and clinical characteristics, risk factor profile, vascular pathology, and midterm outcome of patients with coexistent cerebrovascular fibromuscular dysplasia (cFMD; cFMD+) with those of patients without cFMD (cFMD-). RESULTS: A total of 1283 sCeAD patients (mean age, 47.8±11.4 years; women, 545 [42.5%]) qualified for the analysis, of whom 103 (8.0%) were diagnosed with cFMD+. In multivariable analysis, history of migraine (odds ratio, 1.78 [95% CI, 1.13-2.79]), the presence of intracranial aneurysms (odds ratio, 8.71 [95% CI, 4.06-18.68]), and the occurrence of minor traumas before the event (odds ratio, 0.48 [95% CI, 0.26-0.89]) were associated with cFMD. After a median follow-up of 34.0 months (25th to 75th percentile, 60.0), 39 (3.3%) patients had recurrent sCeAD events. cFMD+ and history of migraine predicted independently the risk of recurrent sCeAD (hazard ratio, 3.40 [95% CI, 1.58-7.31] and 2.07 [95% CI, 1.06-4.03], respectively) in multivariable Cox proportional hazards analysis. CONCLUSIONS: Risk factor profile of sCeAD patients with cFMD differs from that of patients without cFMD. cFMD and migraine are independent predictors of midterm risk of sCeAD recurrence.

Association between Migraine and Cryptogenic Ischemic Stroke in Young Adults.

OBJECTIVE: To assess the association between migraine and cryptogenic ischemic stroke (CIS) in young adults, with subgroup analyses stratified by sex and presence of patent foramen ovale (PFO). METHODS: We prospectively enrolled 347 consecutive patients aged 18 to 49 years with a recent CIS and 347 age- and sex-matched (±5 years) stroke-free controls. Any migraine and migraine with (MA) and migraine without aura (MO) were identified by a screener, which we validated against a headache neurologist. We used conditional logistic regression adjusting for age, education, hypertension, diabetes, waist-to-hip ratio, physical inactivity, current smoking, heavy drinking, and oral estrogen use to assess independent association between migraine and CIS. The effect of PFO on the association between migraine and CIS was analyzed with logistic regression in a subgroup investigated with transcranial Doppler bubble screen. RESULTS: The screener performance was excellent (Cohen kappa > 0.75) in patients and controls. Compared with nonmigraineurs, any migraine (odds ratio [OR] = 2.48, 95% confidence interval [CI] = 1.63-3.76) and MA (OR = 3.50, 95% CI = 2.19-5.61) were associated with CIS, whereas MO was not. The association emerged in both women (OR = 2.97 for any migraine, 95% CI = 1.61-5.47; OR = 4.32 for MA, 95% CI = 2.16-8.65) and men (OR = 2.47 for any migraine, 95% CI = 1.32-4.61; OR = 3.61 for MA, 95% CI = 1.75-7.45). Specifically for MA, the association with CIS remained significant irrespective of PFO. MA prevalence increased with increasing magnitude of the right-to-left shunt in patients with PFO. INTERPRETATION: MA has a strong association with CIS in young patients, independent of vascular risk factors and presence of PFO. ANN NEUROL 2021;89:242-253.

Prior Stroke in PFO Patients Is Associated With Both PFO-Related and -Unrelated Factors.

Background and Purpose: To identify factors associated with prior stroke at presentation in patients with cryptogenic stroke (CS) and patent foramen ovale (PFO). Methods: We studied cross-sectional data from the International PFO Consortium Study (NCT00859885). Patients with first-ever stroke and those with prior stroke at baseline were analyzed for an association with PFO-related (right-to-left shunt at rest, atrial septal aneurysm, deep venous thrombosis, pulmonary embolism, and Valsalva maneuver) and PFO-unrelated factors (age, gender, BMI, hypertension, diabetes mellitus, hypercholesterolemia, smoking, migraine, coronary artery disease, aortic plaque). A multivariable analysis was used to adjust effect estimation for confounding, e.g., owing to the age-dependent definition of study groups in this cross-sectional study design. Results: We identified 635 patients with first-ever and 53 patients with prior stroke. Age, BMI, hypertension, diabetes mellitus, hypercholesterolemia, coronary artery disease, and right-to-left shunt (RLS) at rest were significantly associated with prior stroke. Using a pre-specified multivariable logistic regression model, age (Odds Ratio 1.06), BMI (OR 1.06), hypercholesterolemia (OR 1.90) and RLS at rest (OR 1.88) were strongly associated with prior stroke.Based on these factors, we developed a nomogram to illustrate the strength of the relation of individual factors to prior stroke. Conclusion: In patients with CS and PFO, the likelihood of prior stroke is associated with both, PFO-related and PFO-unrelated factors.

Genetic Screening of Anderson-Fabry Disease in Probands Referred From Multispecialty Clinics.

BACKGROUND: Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disease, caused by defects of the alpha-galactosidase A (GLA) gene. AFD can affect the heart, brain, kidney, eye, skin, peripheral nerves, and gastrointestinal tract. Cardiology (hypertrophic cardiomyopathy), neurology (cryptogenic stroke), and nephrology (end-stage renal failure) screening studies suggest the prevalence of GLA variants is 0.62%, with diagnosis confirmation in 0.12%. OBJECTIVES: This study sought to expand screening from these settings to include ophthalmology, dermatology, gastroenterology, internal medicine, pediatrics, and medical genetics to increase diagnostic yield and comprehensively evaluate organ involvement in AFD patients. METHODS: In a 10-year prospective multidisciplinary, multicenter study, we expanded clinical, genetic, and biochemical screening to consecutive patients enrolled from all aforementioned clinical settings. We tested the GLA gene and α-galactosidase A activity in plasma and leukocytes. Inclusion criteria comprised phenotypical traits and absence of male-to-male transmission. Screening was extended to relatives of probands harboring GLA mutations. RESULTS: Of 2,034 probands fulfilling inclusion criteria, 37 (1.8%) were carriers of GLA mutations. Cascade family screening identified 60 affected relatives; clinical data were available for 4 affected obligate carriers. Activity of α-galactosidase A in plasma and leukocytes was diagnostic in male subjects, but not in female subjects. Of the 101 family members harboring mutations, 86 were affected, 10 were young healthy carriers, and 5 refused clinical evaluation. In the 86 patients, involved organs or organ systems included the heart (69%), peripheral nerves (46%), kidney (45%), eye (37%), brain (34%), skin (32%), gastrointestinal tract (31%), and auditory system (19%). Globotriaosylceramide accumulated in organ-specific and non-organ-specific cells in atypical and classic variants, respectively. CONCLUSIONS: Screening probands with clinically suspected AFD significantly increased diagnostic yield. The heart was the organ most commonly involved, independent of the clinical setting in which the patient was first evaluated.