VHL-Related Neuroendocrine Neoplasms And Beyond: An Israeli Specialized Center Real-Life Report.

OBJECTIVE: Von Hippel-Lindau (VHL) syndrome is a rare and complex disease. In 1996, we described a 3 generation VHL 2A kindred with 11 mutation carriers. We aim to share our experience regarding the long-term follow-up of this family and the management of all our other VHL patients focusing on frequently encountered neuroendocrine neoplasms: pheochromocytoma/paraganglioma and pancreatic neuroendocrine neoplasms (PNEN). METHODS: All VHL patients in follow-up at our tertiary center from 1980 to 2019 were identified. Clinical, laboratory, imaging, and therapeutic characteristics were retrospectively analyzed. RESULTS: We identified 32 VHL patients in 16 different families, 7/16 were classified as VHL 2 subtype. In the previously described family, the 4 initially asymptomatic carriers developed a neuroendocrine tumor; 7 new children were born, 3 of them being mutation carriers; 2 patients died, 1 due to metastatic PNEN-related liver failure. Pheochromocytoma was frequent (22/32), bilateral (13/22;59%), often diagnosed in early childhood when active screening was timely performed, associated with paraganglioma in 5/22, rarely malignant (1/22), and recurred after surgery in some cases after more than 20 years. PNEN occurred in 8/32 patients (25%), and was metastatic in 3 patients. Surgery and palliative therapy allowed relatively satisfactory outcomes. Severe disabling morbidities due to central-nervous system and ophthalmologic hemangiomas, and other rare tumors as chondrosarcoma in 2 patients and polycythemia in 1 patient were observed. CONCLUSION: A multidisciplinary approach and long-term follow-up is mandatory in VHL patients to manage the multiple debilitating morbidities and delay mortality in these complex patients.

[SPONTANEOUS PARENCHYMAL INTRACRANIAL HEMORRHAGE - A DIAGNOSTIC CHALLENGE].

INTRODUCTION: Non-traumatic intracranial hemorrhage (ICH) is a devastating event associated with a high rate of morbidity and mortality. Patient age, hemorrhage location, number of foci, and underlying diseases are important clues to the etiology. Non-contrast head CT, given its availability and high sensitivity in detecting blood products, is frequently the first tool to readily detect ICH; however, different types of hemorrhages may share a common appearance on CT and the optimal therapeutic approach varies depending on etiology. An additional diagnostic work-up is frequently indicated to make the final diagnosis and to assist in urgent patient management. CT- and MR angiography, and digital angiography can diagnose vascular anomalies, CT venography can reveal cerebral vein thrombosis, diffusion-weighted MRI (DWI) may show hemorrhagic transformation of an infarct, and susceptibility-weighted MRI (SWI) may detect hypertensive and amyloid angiopathy-related microbleeds. MR also has a major role in revealing underlying etiologies such as cavernoma, primary brain tumor or metastases. These imaging tools assist in determining the cause of ICH, and also in assessing the risk of deterioration. Prognostic factors such as size, location, mass effect, and detection of the "spot sign" all play an important role in foreseeing possible deterioration, thus allowing prompt intervention. This study will present cases of intraparenchymal hemorrhage from different etiologies in patients who presented to the Hadassah-Hebrew University Medical Center, with the goal of illustrating the role of imaging in patient management and decision-making.

Homozygous null variant in CRADD, encoding an adaptor protein that mediates apoptosis, is associated with lissencephaly.

Lissencephaly is a severe malformation of cortical development, most often attributed to abnormalities in neuronal migration. It is associated with a severe prognosis including developmental delay, intellectual disability, and seizures. Lissencephaly can be reliably diagnosed during late gestation by neurosonography or fetal magnetic resonance imaging (MRI). We report two sibling male fetuses who were diagnosed with delayed cortical sulcation highly suggestive of lissencephaly during late pregnancy. After receiving genetic counseling, the parents elected to terminate the pregnancies based on the neuroradiological findings and the associated severe prognosis. Whole exome sequencing (WES) of an affected fetus, and subsequent Sanger sequencing of the second fetus, revealed a homozygous frameshift variant in CRADD, which encodes an adaptor protein that interacts with PIDD and caspase-2 to initiate apoptosis. Biallelic variants in this gene have been recently reported to cause "thin" lissencephaly and intellectual disability. Interestingly, the allegedly healthy father was also found to be homozygous for the variant, prompting evaluation by brain MRI which revealed hypogyration. This study underscores the phenotypic variability of pathogenic variants in CRADD and the challenges of prenatal genetic counseling.

Hindbrain malformation and myoclonic seizures associated with a deleterious mutation in the INPP4A gene.

Hindbrain malformations with predominant cerebellar involvement have many causes including chromosomal disorders, specific genetic syndromes, and prenatal disruptions. The combination of a hindbrain malformation and myoclonic epilepsy is rare. Using exome sequencing in a consanguineous family, we identified a homozygous genomic deletion of 1770 bp within the INPP4A gene in a patient with myoclonic epilepsy, microcephaly, and atrophy of the inferior vermis and cerebellum. INPP4A participates in the excitatory glutamate signaling pathway and is essential for the degradation of phosphatidylinositol (3,4)-bisphosphate. Glutamatergic signaling is important for hindbrain development and is implicated in the pathogenesis of epilepsy, as well as excitotoxic cell death. Indeed, excessive glutamatergic stimulation was previously reported in INPP4A knockout mice. Our data adds a new etiology to the spectrum of hindbrain malformations in human, and when presented with myoclonic epilepsy may lead to the clinical suspicion of INPP4A defect. The present report further underscores the importance of phosphoinositides for the development of the inferior cerebellum and vermis.

Safety and Efficacy of Intravenous Alteplase before Endovascular Thrombectomy: A Pooled Analysis with Focus on the Elderly.

Current guidelines advocate intravenous thrombolysis (IVT) prior to endovascular thrombectomy (EVT) for all patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO). We evaluated outcomes with and without IVT pretreatment. Our institutional protocols allow AIS patients presenting early (<4 h from onset or last seen normal) who have an Alberta Stroke Program Early CT Score (ASPECTS) ≥6 to undergo EVT without IVT pretreatment if the endovascular team is in the hospital (direct EVT). Rates of recanalization and hemorrhagic transformation (HT) and neurological outcomes were retrospectively compared in consecutive patients undergoing IVT+EVT vs. direct EVT with subanalyses in those ≥80 years and ≥85 years. In the overall cohort (IVT+EVT = 147, direct EVT = 162), and in subsets of patients ≥80 years (IVT+EVT = 51, direct EVT = 50) and ≥85 years (IVT+EVT = 19, direct EVT = 32), the IVT+EVT cohort and the direct EVT group had similar baseline characteristics, underwent EVT after a comparable interval from symptom onset, and reached similar rates of target vessel recanalization. No differences were observed in the HT frequency, or in disability at discharge or after 90 days. Patients receiving direct EVT underwent more stenting of the carotid artery due to stenosis during the EVT procedure (22% vs. 6%, p = 0.001). Direct EVT and IVT+EVT had comparable neurological outcomes in the overall cohort and in the subgroups of patients ≥80 and ≥85 years, suggesting that direct EVT should be considered in patients with an elevated risk for HT.

LDH and PDH Activities in the Ischemic Brain and the Effect of Reperfusion-An Ex Vivo MR Study in Rat Brain Slices Using Hyperpolarized [1-13C]Pyruvate.

Ischemic stroke is a leading cause for neurologic disability worldwide, for which reperfusion is the only available treatment. Neuroimaging in stroke guides treatment, and therefore determines the clinical outcome. However, there are currently no imaging biomarkers for the status of the ischemic brain tissue. Such biomarkers could potentially be useful for guiding treatment in patients presenting with ischemic stroke. Hyperpolarized 13C MR of [1-13C]pyruvate is a clinically translatable method used to characterize tissue metabolism non-invasively in a relevant timescale. The aim of this study was to utilize hyperpolarized [1-13C]pyruvate to investigate the metabolic consequences of an ischemic insult immediately during reperfusion and upon recovery of the brain tissue. The rates of lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH) were quantified by monitoring the rates of [1-13C]lactate and [13C]bicarbonate production from hyperpolarized [1-13C]pyruvate. 31P NMR of the perfused brain slices showed that this system is suitable for studying ischemia and recovery following reperfusion. This was indicated by the levels of the high-energy phosphates (tissue viability) and the chemical shift of the inorganic phosphate signal (tissue pH). Acidification, which was observed during the ischemic insult, has returned to baseline level following reperfusion. The LDH/PDH activity ratio increased following ischemia, from 47.0 ± 12.7 in the control group (n = 6) to 217.4 ± 121.3 in the ischemia-reperfusion group (n = 6). Following the recovery period (ca. 1.5 h), this value had returned to its pre-ischemia (baseline) level, suggesting the LDH/PDH enzyme activity ratio may be used as a potential indicator for the status of the ischemic and recovering brain.

Bisphosphonate-related osteonecrosis of the jaw: clinical correlations with computerized tomography presentation.

The aim of this study was to correlate clinical and computerized tomography (CT) features of bisphosphonate-related osteonecrosis of the jaws (BRONJ). All ONJ patients for whom there was complete CT scan imaging were eligible. Selected clinical parameters retrieved from their medical records were analyzed for correlation with CT parameters. The clinical presentation of BRONJ was supported by findings in CT imaging in 78.3%. The lesion's size on CT correlated with the presence of purulent secretion (p = 0.03). When sequestrum was present, the median lesion's size on CT was relatively big (28 mm, range 21-43 mm). The mandibular canal cortex was never breached. CT has reasonable detection competence for diagnosing BRONJ. Purulent secretion indicates the likelihood that a more extensive involvement will be displayed on CT. A large lesion on CT should raise the index of suspicion for sequestrum. The CT appearance of a continuous cortex of the mandibular canal may serve as a differential parameter between BRONJ and metastasis to the jaw.

Unique persistent neurological sequelae of heat stroke.

Heat stroke is a rare clinical phenomenon, characterized by systemic heat and cytokine-induced organ damage. Permanent neurological deficits rarely develop following heat strokes, and cerebellar dysfunction predominates among these rare cases. We report a case of severe heat stroke with recovery from severe multiorgan failure but with persistent neurological manifestations. These included a combination of resolving right-sided signs as well as persistent frontal subcortical dysfunction, with minimal, if any, cerebellar involvement. This combination and the absence of cerebellar involvement is an unusual neurological sequelae of heat stroke.

Extensive bone erosion caused by pseudotumoral aneurysm growth.

Carotid ophthalmic aneurysms constitute 0.9-6.5% of the aneurysms of the ICA with up to 20% of the cases presenting with visual symptoms. We report a case of an adult woman, presented with chronic headaches and protracted visual alterations progressing to left eye amaurosis. Neuroradiological exams, revealed a giant partially thrombosed carotid ophthalmic aneurysm extending anteriorly, causing pseudotumoral spheno-orbital bone erosion. The patient underwent surgical clipping, evacuation of the thrombotic mass and decompression of the optic pathways with rapid recovery of the vision. This unusual case, contributes to the available body of evidence on aneurysms growth.

Emergency endovascular revascularization of tandem occlusions: Internal carotid artery dissection and intracranial large artery embolism.

Internal carotid artery dissection (ICAD) with concomitant occlusive intracranial large artery emboli is an infrequent cause of acute stroke, with poor response to intravenous thrombolysis. Reports on the management of this entity are limited. We present our recent experience in the endovascular management of occlusive ICAD and major intracranial occlusion. Consecutive anterior circulation acute stroke patients meeting Medical Center criteria for endovascular management of ICAD from June 2011 to June 2015 were included. Clinical, imaging, and procedure data were collected retrospectively under Institutional Review Board approval. The endovascular procedure for carotid artery revascularization and intracranial stent thrombectomy is described. Six patients met inclusion criteria (National Institutes of Health Stroke Scale score 12-24, time from symptom onset 2-8hours). Revascularization of the extracranial carotid dissection and stent thrombectomy were achieved in 5/6 patients, resulting in complete recanalization (Thrombolysis in Myocardial Infarction flow grade 3 in a mean 2.7hours), and modified Rankin Scale score 0-2 at 90 day follow-up. In one patient, attempts to microcatheterize the true arterial lumen failed and thrombectomy was therefore not feasible. No arterial dissection, arterial rupture or accidental stent detachment occurred, and there was no intracerebral hemorrhage or hemorrhagic transformation. Our preliminary data on this selected subgroup of patients suggest the presented approach is safe, feasible in a significant proportion of patients, and efficacious in achieving arterial recanalization and improving patient outcome. Crossing the dissected segment remains the most important limiting factor in achieving successful ICA recanalization. Further evaluation in larger series is warranted.

Emergent stenting to treat patients with carotid artery dissection: clinically and radiologically directed therapeutic decision making.

BACKGROUND AND PURPOSE: Carotid artery dissection (CAD) is a common cause of stroke in young patients. Clots formed at the low-flow zone in the false arterial lumen may give rise to distal emboli, and the mural hematoma may eventually occlude the artery. Anticoagulation is currently the accepted treatment, but it is unknown which patients will improve spontaneously, which will respond to anticoagulation, and which will have an exacerbation of ischemic symptoms despite therapy. Endovascular treatment of CAD may be an attractive alternative to anticoagulation, and methods of identifying patients who stand to benefit from such therapy need to be established. METHODS: We present here 3 cases of spontaneous symptomatic CAD in which endovascular stenting procedures were performed on the basis of a paradigm aimed at identifying potentially salvageable but at-risk brain tissue by combining clinical with MRI (diffusion and perfusion) and angiographic data. RESULTS: Diffusion-perfusion MRI mismatches and/or evidence of cerebral ischemia on angiographic parenchymography were identified in all patients. They did not respond to anticoagulation, were therefore treated with endovascular stents, and had excellent outcomes. CONCLUSIONS: Endovascular stent placement may be an immediate, effective, and safe method of restoring vessel lumen integrity. It may be considered for selected patients who are clinically symptomatic despite anticoagulant treatment and in whom neuroimaging methods suggest that the neurological signs originate from a viable, hypoperfused, ischemic penumbra.

Fibrous dysplasia in combination with aneurysmal bone cyst of the occipital bone and the clivus: case report and review of the literature.

OBJECTIVE AND IMPORTANCE: Fibrous dysplasia of the cranium is a relatively uncommon disorder that affects primarily the anterior cranial region; its occurrence in the cranial base in combination with aneurysmal bone cyst (ABC) constitutes an extremely rare condition, only two cases of which have been reported previously in the literature. It is important to recognize and treat these cases properly because of the special location in the cranial base and the possibility of neural structure impingement. CLINICAL PRESENTATION: We report the case of a 19-year-old man with a slowly enlarging mass of the occiput, with computed tomographic and magnetic resonance imaging revealing involvement of petrous and basisphenoid bone and growing ABC. INTERVENTION: Open biopsy confirmed the diagnosis of fibrous dysplasia. Partial excision of the lesion and removal of the ABC were performed in a second stage after embolization. CONCLUSION: ABC associated with fibrous dysplasia of the cranial base may enlarge rapidly after puberty and require excision. This is facilitated by preoperative embolization.

Vitamins in the prevention or delay of cognitive disability of aging.

During the 20th century, the average lifespan in the industrialized societies has enormously increased and it is still rising. With the increase in the number of old people, a parallel increase in the number of the disabled elderly is postulated. Thus, the whole society might suffer from an imbalance between the productive segment of the society and a huge segment of helpless people. Moderation of the physiological processes, which enhance disability in aging, turns out to be a major concern in health research and clinical practice. Preservation of brain integrity, which is partly influenced by nutrition, presumably is the main target in the attempt to delay the development of disability of aging. Optimal micronutrient status would moderate the deterioration in brain integrity. The human brain is probably the most vulnerable tissue affected by a long-term unbalanced nutrition and is particularly vulnerable to reactive oxygen species and to oxidative stress, because of its high oxygen requirement, its iron storage capacity and its elevated polyunsaturated fatty acid content, and because of its low synthesis capacity of endogenous antioxidants. The capability of central nervous system (CNS) cells to regenerate is most limited, because their repair is inhibited by anti-apoptotic molecules. Efficient autophagy is the major mechanism that moderates accumulation of aggregating compounds. Autophagy is probably a crucial and a major process in the preservation of brain integrity. Micronutrients (vitamins, trace-elements and also antioxidants) most likely affect brain integrity by normalizing efficient autophagy. Brain sensitivity to metabolic disorders is demonstrated by the effect of homocysteine on metabolic pathways, on brain integrity and on the cognitive capacity. Brain imaging might be used as a surrogate for detecting long-lasting low status of micronutrients. Comprehensive evaluation of brain scans concomitantly with blood micronutrient examinations may provide reliable criteria for the estimation of the optimal micronutrient intakes or blood concentrations. Recommended dietary intakes for micronutrients are based on a list of biomarkers, but have not been suggested a safe range for their intake or blood concentration. According to many studies, a U-shaped curve prevails for the effect of serum calcidiol concentration on the relative risk of morbidity and mortality. An increased relative risk of morbidity and mortality with lower serum calcidiol has been shown in almost all the studies. A safe range of 20-40 ng/mL was identified for serum calcidiol. A significant detrimental effect of serum calcidiol on the hazard ratio for the combined data of all-cause mortality and acute coronary syndrome morbidity was shown at a concentration higher than 36 ng/ml. Most of the tolerable upper intake levels for the micronutrients, published by authorized institutions, were set without considering the long-term effects of overdosing. Excessive intake of almost all the micromutrients, particularly for a long period of time, produces adverse effects. In most of the elderly people prevail an insufficient intake of one or more micronutruients. Therefore, until an efficient laboratory system for evaluating blood levels is established, a moderate 'multivitamin' supplementation at an amount of about half the American RDA for most of the micronutrients is suggested.

Acute pseudotumoral hemicerebellitis: diagnosis and neurosurgical considerations of a rare entity.

Acute pseudotumoral hemicerebellitis is an exceptionally rare unilateral presentation of acute cerebellitis mimicking a tumor. It typically has a benign course without specific therapy; thus, recognizing this entity is important to avoid needless surgical intervention. MRI provides the key for diagnosis and usually reveals a diffusely swollen cerebellar hemisphere with no well-defined mass. Some patients will require neurosurgical assistance by means of ventriculostomy or posterior fossa decompression. We present a 17-year-old girl with pseudotumoral hemicerebellitis, review the available literature, and discuss the diagnosis and therapeutic dilemma from the neurosurgical perspective.

Preoperative embolization of hypervascular spinal tumors: current practice and center experience.

Preoperative transarterial embolization of hypervascular spinal tumors has been extensively used, and is considered to be a highly effective adjuvant technique in reducing intraoperative blood loss during surgery. Moreover, it has been reported to increase the feasibility and safety of the surgical procedure, leading to better surgical outcomes. We review the English literature in an attempt to identify indications, appropriate timing of embolization in relation to surgery, technical aspects of the procedure, complications, and the contribution of embolization to the surgical management of spinal tumors. In addition, we report our experience with embolization of hypervascular metastases.

Emergent stent-assisted angioplasty of extracranial internal carotid artery and intracranial stent-based thrombectomy in acute tandem occlusive disease: technical considerations.

OBJECTIVE: Tandem occlusions of the internal carotid artery (ICA) and a major intracranial artery respond poorly to intravenous thrombolytic therapy, and are usually managed by endovascular means. This study describes experience with stent-assisted endovascular ICA revascularization and stent-based thrombectomy. METHODS: In patients with tandem ICA-middle cerebral artery (MCA)/distal ICA occlusion, the carotid occlusion was recanalized by primary angioplasty and stent implantation, and the distal occlusion by stent-based thrombectomy. Two variant techniques are described. RESULTS: Seven consecutive patients, mean age 64.1 years (range 49-75) and mean admission National Institutes of Health Stroke Scale score of 23, were included. Occlusion sites were tandem proximal ICA and MCA trunk (six patients) and tandem proximal left ICA and ICA terminus (one patient). Complete recanalization with complete perfusion (Thrombolysis in Myocardial Infarction [TIMI] 3, Thrombolysis in Cerebral Infarction [TICI] 3) was achieved in six patients and partial recanalization with partial perfusion (TIMI 2, TICI 2A) in one. Mean time to therapy was 4.9 h (range 3-6.5); mean time to recanalization was 55 min (range 38-65 min). CT performed 1 day after recanalization showed cortical sparing (>90% of the cortex at risk) in seven patients. Five patients (72%) presented with good clinical outcome (modified Rankin Scale (mRS) score 0-2) at 1 month; one patient (patient No 7) reached an mRS score of 3 and one patient died. CONCLUSIONS: In selected cases of acute ICA occlusion and concomitant major vessel embolic stroke, angioplasty and stenting of the proximal occlusion and stent-based thrombectomy of the intracranial occlusion may be feasible, effective and safe, and provide early neurological improvement. Further experience and prospective studies are warranted.

Neurocysticercosis in travelers: a nation-wide study in Israel.

BACKGROUND: Cysticercosis, a human infestation by Taenia solium is endemic in many resource-limited countries. In developed countries it is mostly encountered among immigrant populations. Only few cases are reported in travelers. This report summarizes a nation-wide study of neurocysticercosis (NCC) diagnosed among Israeli travelers to endemic countries, with an estimation of disease incidence among the traveler population. METHODS: We performed a retrospective, nation-wide survey of travel-related NCC in Israel between the years 1994 and 2009. RESULTS: Nine cases of NCC were diagnosed in Israeli travelers during the study years. Most patients had traveled to South and/or Southeast Asia. The most common symptom at diagnosis was a seizure. The average interval between return from the suspected travel and symptom onset was 3.2 ± 1.8 years. Two patients suffered from multiple lesions, whereas the rest had a single lesion. Antihelminthic treatment was given to most patients with resolution of symptoms. Median duration of antiepileptic treatment was 16 ± 41 months after albendazole was given. Antiepileptic treatment was discontinued without any complications. The estimated attack rate of clinical disease was 1 : 275,000 per travel episode to an endemic region. CONCLUSIONS: NCC in travelers is a rare phenomenon commonly presenting as seizure disorder manifesting months to years post-travel. Antihelminthic therapy followed by 12 to 24 months of antiepileptic therapy resulted in complete resolution of symptoms in our patients.

Sinus vein thrombosis as presenting finding in the congenital central hypoventilation syndrome: an insight on the pathophysiology of the association.

Congenital central hypoventilation syndrome (CCHS) is an increasingly recognized diagnosis causing central hypoventilation and may be definitively diagnosed by genetic testing. Previous authors reported the association between CCHS and central sinus venous thrombosis (CSVT) and hypothesized that CCHS could be secondary to CSVT. We report a case of CCHS with the typical PHOX2B mutation who also suffered from CSVT. We assume that effects, secondary to CCHS, upon the central venous system may explain the etiological connection between CSVT and CCHS including dysautoregulation, venous stasis or polycythemia. We believe that CCHS should be included in the differential diagnosis of patients with CSVT accompanied by respiratory abnormalities.

Atlas guided identification of brain structures by combining 3D segmentation and SVM classification.

This study presents a novel automatic approach for the identification of anatomical brain structures in magnetic resonance images (MRI). The method combines a fast multiscale multi-channel three dimensional (3D) segmentation algorithm providing a rich feature vocabulary together with a support vector machine (SVM) based classifier. The segmentation produces a full hierarchy of segments, expressed by an irregular pyramid with only linear time complexity. The pyramid provides a rich, adaptive representation of the image, enabling detection of various anatomical structures at different scales. A key aspect of the approach is the thorough set of multiscale measures employed throughout the segmentation process which are also provided at its end for clinical analysis. These features include in particular the prior probability knowledge of anatomic structures due to the use of an MRI probabilistic atlas. An SVM classifier is trained based on this set of features to identify the brain structures. We validated the approach using a gold standard real brain MRI data set. Comparison of the results with existing algorithms displays the promise of our approach.