Hemangioblastoma

Hemangioblastoma

● highly vascular well-circumscribed benign solid or cystic neoplasm of CNS or retina

● the most common primary intra-axial tumor in the adult posterior fossa

● may occur sporadically or as part of von Hippel-Lindau disease

● on imaging, may be solid, or cystic with enhancing mural nodule

● ✔ Complete blood count (CBC): may be associated with erythrocytosis (polycythemia).

Hemangioblastomas (HGB) are histologically benign slow-growing tumors with neoplastic stromal cells and copious small vessels.

Hemangioblastoma Epidemiology.

Hemangioblastoma Classification.

Hemangioblastoma Etiology.

Hemangioblastomas are composed of endothelial cells, pericytes and stromal cells. In VHL syndrome the von Hippel-Lindau protein (pVHL) is dysfunctional, usually due to mutation and/or gene silencing. In normal circumstances, pVHL is involved in the inhibition of hypoxia-inducible factor 1 α (HIF-1α) by ubiquitin mediated proteosomal degradation. In these dysfunctional cells pVHL cannot degrade HIF-1α, causing it to accumulate. HIF-1α causes the production of vascular endothelial growth factor, platelet derived growth factor B, erythropoietin and transforming growth factor alpha, which act to stimulate growth of cells within the tumour.

Hemangioblastomas (HGB) are histologically benign slow-growing tumors with neoplastic stromal cells and copious small vessels. Intracranially, they occur almost exclusively in the p-fossa (hemangioblastomas are the most common primary intra-axial p-fossa tumor in adults). May occur in the cerebellar hemisphere, vermis, or brainstem. May also occur in the spinal cord (1.5–2.5% of spinal cord tumors). Also difficult to distinguish histologically from a renal cell carcinoma (which is common in VHL adds to the difficulty of this differential).

see Hemangioblastoma diagnosis.

Differentiation between hemangioblastoma and brain metastases remains a challenge in neuroradiology using conventional MRIAmide proton transfer imaging can provide unique molecular information. A study by Kamimura et al. from Kagoshima aimed to evaluate the usefulness of APT imaging in differentiating hemangioblastomas from brain metastases and compare APT imaging with diffusion-weighted imaging and dynamic susceptibility contrast perfusion-weighted imaging.

This retrospective study included 11 patients with hemangioblastoma and 20 patients with brain metastases. Region-of-interest analyses were employed to obtain the mean, minimum, and maximum values of APT signal intensity, apparent diffusion coefficient (ADC), and relative cerebral blood volume (rCBV), and these indices were compared between hemangioblastomas and brain metastases using the unpaired t-test and Mann-Whitney U test. Their diagnostic performances were evaluated using receiver operating characteristic (ROC) analysis and area under the ROC curve (AUC). AUCs were compared using DeLong’s method.

All MRI-derived indices were significantly higher in hemangioblastoma than in brain metastasis. ROC analysis revealed the best performance with APT-related indices (AUC = 1.000), although pairwise comparisons showed no significant difference between the mean ADC and mean rCBV.

APT imaging is a useful and robust imaging tool for differentiating hemangioblastoma from metastases 1)

see Hemangioblastoma treatment.

The outcome for hemangioblastoma is very good, if surgical extraction of the tumor can be achieved; excision is possible in most cases and permanent neurologic deficit is uncommon and can be avoided altogether if the tumor is diagnosed and treated early. Persons with VHL syndrome have a bleaker prognosis than those who have sporadic tumors since those with VHL syndrome usually have more than one lesion.

Hemangioblastomas can cause polycythemia due to the ectopic production of erythropoietin as a paraneoplastic syndrome.

Ten hemangioblastomas were investigated immunohistochemically. CD44, a mesenchymal stem cell marker, was detected in stromal cells of all cases, suggesting that stromal cells have mesenchymal stem cell-like properties. Neither CD31 nor α-SMA was expressed in stromal cells, suggesting that stromal cells have not acquired differentiated vascular cell properties. Both ephrin-B2 and EphB4, immature vascular cell markers, were detected in stromal cells of all cases. Jagged1, Notch1, and Hesr2/Hey2, which are known to be detected in both immature endothelial cells and mural cells, were expressed in stromal cells of all cases. Notch3, which is known to be detected in differentiating mural cells, was also expressed in all cases. These results suggest that stromal cells also have vascular progenitor cell properties. In conclusion, stromal cells of hemangioblastomas exhibit mesenchymal stem cell-derived vascular progenitor cell properties 2).


1)

Kamimura K, Nakajo M, Gohara M, Kawaji K, Bohara M, Fukukura Y, Uchida H, Tabata K, Iwanaga T, Akamine Y, Keupp J, Fukami T, Yoshiura T. Differentiation of hemangioblastoma from brain metastasis using MR amide proton transfer imaging. J Neuroimaging. 2022 Jun 22. doi: 10.1111/jon.13019. Epub ahead of print. PMID: 35731178.
2)

Takada S, Hojo M, Takebe N, Tanigaki K, Miyamoto S. Stromal cells of hemangioblastomas exhibit mesenchymal stem cell-derived vascular progenitor cell properties. Brain Tumor Pathol. 2018 Jun 23. doi: 10.1007/s10014-018-0323-2. [Epub ahead of print] PubMed PMID: 29936560.

Spontaneous Intracerebral Hemorrhage Risk Factors

Spontaneous Intracerebral Hemorrhage Risk Factors

Psychosocial, ethnic, and economic factors play a role in the prevalence of cerebral hemorrhage, with ICH being twice as common in low-income and middle-income countries compared with high-income countries. Other identified risk factors for ICH include age (i.e., each decade from 50 years of age is associated with a 2-fold increase in the incidence of ICH) and an elevated alcohol intake.

Etiologies of ICH to always consider include intracranial aneurysms (typically presenting as subarachnoid hemorrhage); arteriovenous malformations (ICH is the first presentation of AVMs in 60 % of cases); cerebral venous sinus thrombosis and venous infarction; brain tumors (<5 % of all ICH cases) including cerebral metastases (e.g., lung cancer, melanoma, renal cell carcinoma, thyroid carcinoma, and choriocarcinoma) and primary CNS tumors (e.g., glioblastoma multiforme and oligodendrogliomas); and drugs of abuse (e.g., cocaine, amphetamines). Because of the differing etiologies of ICH, a rapid and accurate diagnosis of the underlying etiology of ICH is essential to direct appropriate management strategies.

The most important modifiable risk factor in spontaneous ICH is chronic arterial hypertension:

see Hypertensive intracerebral hemorrhage.

Besides hypertension, cerebrovascular amyloid deposition (i.e., cerebral amyloid angiopathy) is associated with ICH in older patients.


Although cerebral amyloid angiopathy (CAA), which is Aβ deposition in the cerebral vessels, related cerebral hemorrhage rarely develops in young people, several patients with CAA-related cerebral hemorrhage under the age of 55 with histories of neurosurgeries with and without dura mater graft in early childhood have been reported. These patients might show that Aβ pathology is often recognized as Aβ-CAA rather than parenchymal Aβ deposition in the transmission of cerebral β-amyloidosis in humans, and Hamaguchi et al. proposed an emerging concept, “acquired CAA”. Considering that there have been several patients with acquired CAA with an incubation period from neurosurgery and the onset of CAA-related cerebral hemorrhage of longer than 40 years, the number of cases is likely to increase in the future, and detailed epidemiological investigation is required. It is necessary to continue to elucidate the pathomechanisms of acquired CAA and urgently establish a method for preventing the transmission of cerebral β-amyloidosis among individuals 1).

It is a common initial symptom of intracranial vascular malformations.

see Intracerebral hemorrhage from ruptured cerebral arteriovenous malformation.

see Aneurysmal intracerebral hemorrhage.

see Cerebral venous sinus thrombosis and venous infarction.

see Spontaneous intracranial hematoma caused by neoplasm.

Vasculitis.

Complication of AIDS.

Shunting for NPH

Coagulopathies (i.e., the use of antithrombotic or thrombolytic agents, congenital or acquired factor deficiencies) and systemic diseases, such as thrombocytopenia, are possible causes of ICH. The use of oral anticoagulants, especially vitamin K inhibitors (i.e., warfarin), has increased coagulopathy-associated ICH in recent years, accounting for more than 15 % of all cases.

Severe thrombocytopenia can result in petechial hemorrhages or spontaneous intracerebral hemorrhage (ICH).

see Anticoagulant Related Intracerebral Hemorrhage.


Intracerebral hemorrhage risk is increased with higher doses than the recommended 100 mg of alteplase (Activase®, recombinant tissue plasminogen activator (rt-PA)) 2) in older patients, in those with anterior MI or higher Killip class, and with bolus administration (vs. infusion) 3).

When heparin was used adjunctively, higher doses were associated with a higher risk of ICH 4) ICH is thought to occur in those patients with some preexisting underlying vascular abnormality 5). Immediate coronary angioplasty is safer than rt-PA when available 6).

Remote supratentorial hematoma soon after posterior fossa surgery for the removal of a space-occupying lesion is a rare but dramatic and dreaded complication, carrying significant morbidity and mortality 7) 8) 9) 10) 11) 12) 13) 14).

see Posterior reversible encephalopathy syndrome.

Ethanol

Cocaine

Inadvertent intrathecal injection of unapproved contrast agents.

The evidence linking vitamin D (VitD) levels and Spontaneous Intracerebral Hemorrhage Risk Factors remains inconclusive. Szejko et al. tested the hypothesis that lower genetically determined VitD levels are associated with a higher risk of ICH. They conducted a 2-sample Mendelian Randomization (MR) study using publicly available summary statistics from published genome-wide association study of VitD levels (417 580 study participants) and ICH (1545 ICH cases and 1481 matched controls). They used the inverse variance-weighted average method to generate causal estimates and the MR Pleiotropy Residual Sum and Outlier and MR-Egger approaches to assess for horizontal pleiotropy. To account for known differences in their underlying mechanism, we implemented stratified analysis based on the location of the hemorrhage within the brain (lobar or nonlobar). Our primary analysis indicated that each SD decrease in genetically instrumented VitD levels was associated with a 60% increased risk of ICH (odds ratio [OR], 1.60; [95% CI, 1.05-2.43]; P=0.029). They found no evidence of horizontal pleiotropy (MR-Egger intercept and MR Pleiotropy Residual Sum and Outlier global test with P>0.05). Stratified analyses indicated that the association was stronger for nonlobar ICH (OR, 1.87; [95% CI, 1.18-2.97]; P=0.007) compared with lobar ICH (OR, 1.43; [95% CI, 0.86-2.38]; P=0.17). Lower levels of genetically proxied VitD levels are associated with higher ICH risk. These results provide evidence for a causal role of VitD metabolism in ICH 15).

COVID-19 and Intracerebral Hemorrhage


1)

Hamaguchi T, Ono K, Yamada M. Transmission of Cerebral β-Amyloidosis Among Individuals. Neurochem Res. 2022 Mar 11. doi: 10.1007/s11064-022-03566-4. Epub ahead of print. PMID: 35277809.
2)

Public Health Service. Approval of Thrombolytic Agents. FDA Drug Bull. 1988; 18:6–7
3)

Mehta SR, Eikelboom JW, Yusuf S. Risk of intracranial hemorrhage with bolus versus infusion thrombolytic therapy: a meta-analysis. Lancet. 2000; 356:449–454
4)

Tenecteplase (TNKase) for thrombolysis. Med Letter. 2000; 42:106–108
5)

DaSilva VF, Bormanis J. Intracerebral Hemorrhage After Combined Anticoagulant-Thrombolytic Therapy for Myocardial Infarction: Two Case Reports and a Short Review. Neurosurgery. 1992; 30:943–945
6)

Grines CL, Browne KF, Marco J, et al. A Comparison of Immediate Angioplasty with Thrombolytic Therapy for Acute Myocardial Infarction. N Engl J Med. 1993; 328:673–679
7)

Bucciero A, Quaglietta P, Vizioli L. Supratentorial intracerebral hemorrhage after posterior fossa surgery: Case report. J Neurosurg Sci. 1991;35:221–4.
8)

Haines SJ, Maroon JC, Jannetta PJ. Supratentorial intracerebral hemorrhage following posterior fossa surgery. J Neurosurg. 1978;49:881–6.
9)

Harders A, Gilsbach J, Weigel K. Supratentorial space occupying lesions following infratentorial surgery early diagnosis and treatment. Acta Neurochir (Wien) 1985;74:57–60.
10)

Seiler RW, Zurbrugg HR. Supratentorial intracerebral hemorrhage after posterior fossa operation. Neurosurgery. 1986;18:472–4.
11)

Tondon A, Mahapatra AK. Superatentorial intracerebral hemorrhage following infratentorial surgery. J Clin Neurosci. 2004;11:762–5.
12)

Vrettou CS, Stavrinou LC, Halikias S, Kyriakopoulou M, Kollias S, Stranjalis G, et al. Factor XIII deficiency as a potential cause of supratentorial haemorrhage after posterior fossa surgery. Acta Neurochir (Wien) 2010;152:529–32.
13)

Pandey P, Madhugiri VS, Sattur MG, Devi BI. Remote supratentorial extradural hematoma following posterior fossa surgery. Childs Nerv Syst. 2008;24:851–4.
14)

Wolfsberger S, Gruber A, Czech T. Multiple supratentorial epidural haematomas after posterior fossa surgery. Neurosurg Rev. 2004;27:128–32.
15)

Szejko N, Acosta JN, Both CP, Leasure A, Matouk C, Sansing L, Gill TM, Hongyu Z, Sheth K, Falcone GJ. Genetically-Proxied Levels of Vitamin D and Risk of Intracerebral Hemorrhage. J Am Heart Assoc. 2022 Jun 22:e024141. doi: 10.1161/JAHA.121.024141. Epub ahead of print. PMID: 35730641.

Traumatic brain injury epidemiology in Europe

Traumatic brain injury epidemiology in Europe

In 2018 a systematic review provided a comprehensive, up-to-date summary of traumatic brain injury (TBI) epidemiology in Europe, describing incidence, mortality, age, and sex distribution, plus severity, mechanism of injury, and time trends. PubMed, CINAHL, EMBASE, and Web of Science were searched in January 2015 for observational, descriptive, English language studies reporting incidence, mortality, or case fatality of TBI in Europe. There were no limitations according to date, age, or TBI severity. Methodological quality was assessed using the Methodological Evaluation of Observational Research checklist. Data were presented narratively. Sixty-six studies were included in the review. Country-level data were provided in 22 studies, regional population or treatment center catchment area data were reported by 44 studies. Crude incidence rates varied widely. For all ages and TBI severities, crude incidence rates ranged from 47.3 per 100,000, to 694 per 100,000 population per year (country-level studies) and 83.3 per 100,000, to 849 per 100,000 population per year (regional-level studies). Crude mortality rates ranged from 9 to 28.10 per 100,000 population per year (country-level studies), and 3.3 to 24.4 per 100,000 population per year (regional-level studies.) The most common mechanisms of injury were traffic accidents and falls. Over time, the contribution of traffic accidents to total TBI events may be reducing. Case ascertainment and definitions of TBI are variable. Improved standardization would enable more accurate comparisons 1).


In 2016 aimed to estimate the hospital-based incidence, population-wide mortality, and the contribution of TBI to injury-related mortalities in European countries, and to provide European summary estimates for these indicators.

For this cross-sectional analysis, we obtained population data from Eurostat for hospital discharges and causes of death in European countries in 2012. Outcomes of interest were TBIs that required hospital admission or were fatal. We calculated age-adjusted hospital discharge rates and mortality rates and extrapolated data to 28 European Union countries and all 48 states in Europe. We present between-country comparisons, pooled age-adjusted rates, and comparisons with all-injury rates.

In 2012, 1 375 974 hospital discharges (data from 24 countries) and 33 415 deaths (25 countries) related to TBI were identified. The pooled age-adjusted hospital discharge rate was 287·2 per 100 000 (95% CI 232·9-341·5) and the pooled age-adjusted mortality rate was 11·7 per 100 000 (9·9-13·6). TBI caused 37% (95% CI 36-38) of all injury-related deaths in the analysed countries. Extrapolating our results, we estimate 56 946 (95% CI 47 286-66 099) TBI-related deaths and 1 445 526 (1 172 996-1 717 039) hospital discharges occurred in 2012 in the European Union (population 508·5 million) and about 82 000 deaths and about 2·1 million hospital discharges in the whole of Europe (population 737 million). We noted substantial between-country differences.

TBI is an important cause of death and hospital admissions in Europe. The substantial between-country differences observed warrant further study and suggest that the true burden of TBI in Europe has not yet been captured. Rigorous epidemiological studies are needed to fully quantify the effect of TBI on society. Despite a great degree of consistency in data reporting across countries already being achieved, further efforts in this respect could improve the validity of between-country comparisons 2).


In 2015 a total, 28 epidemiological studies on TBI from 16 European countries were identified in the literature. A great variation was found in case definitions and case ascertainment between studies. Falls and road traffic accidents (RTA) were the two most frequent causes of TBI, with falls being reported more frequently than RTA 3).

A search was conducted in the PubMed electronic database using the terms: epidemiology, incidence, brain injur*, head injur* and Europe. Only articles published in English and reporting on data collected in Europe between 1990 and 2014 were included. In total, 28 epidemiological studies on TBI from 16 European countries were identified in the literature. A great variation was found in case definitions and case ascertainment between studies. Falls and road traffic accidents (RTA) were the two most frequent causes of TBI, with falls being reported more frequently than RTA. In most of the studies a peak TBI incidence was seen in the oldest age groups. In the meta-analysis, an overall incidence rate of 262 per 100,000 for admitted TBI was derived.

Interpretation of published epidemiologic studies is confounded by differences in inclusion criteria and case ascertainment. Nevertheless, changes in epidemiological patterns are found: falls are now the most common cause of TBI, most notably in elderly patients. Improvement of the quality of standardised data collection for TBI is mandatory for reliable monitoring of epidemiological trends and to inform appropriate targeting of prevention campaigns 4).

In 2006 it was difficult to reach a consensus on all epidemiological findings across the 23 published European studies because of critical differences in methods employed across the reports 5).

In a retrospectivelongitudinal study of all TBI patients treated in ICU between 2013-2018, 77% (n=171) were male and the median age was 46 (Q1-Q3: 28-62). The most common mechanism of injury was fall from less than two meters (<2m) followed by road traffic accidents (RTA). The proportion of injuries due to RTA increased over the six-year period (p=0.006). 41.4% (n=92) of injuries had reported alcohol involvement. Patients with falls <2m had double the median age and double the rate of alcohol involvement compared to those suffering RTA (p<0.001, p<0.001). The neurosurgical intervention rate was 74% (n=165). The median duration of ICU admission and of intracranial pressure monitoring, advanced ventilation, and inotropic therapy increased over the six-year period (p=0.031, p=0.038, p=0.033, p<0.001). This study’s findings could inform precise and impactful public prevention measures. The increasing duration of ICU admission and of other interventions should be examined further for their effect on patient outcomes and resource consumption 6).

Traumatic brain injury epidemiology in Finland

A coordinated strategy to evaluate this public health problem in Romania would first of all rely on a related advanced monitoring system, to provide precise information about the epidemiology, clinical and paraclinical data, but concerning the social and economic connected consequences, too 7).

Traumatic brain injury epidemiology in Spain


1)

Brazinova A, Rehorcikova V, Taylor MS, Buckova V, Majdan M, Psota M, Peeters W, Feigin V, Theadom A, Holkovic L, Synnot A. Epidemiology of Traumatic Brain Injury in Europe: A Living Systematic Review. J Neurotrauma. 2018 Dec 19. doi: 10.1089/neu.2015.4126. Epub ahead of print. PMID: 26537996.
2)

Majdan M, Plancikova D, Brazinova A, Rusnak M, Nieboer D, Feigin V, Maas A. Epidemiology of traumatic brain injuries in Europe: a cross-sectional analysis. Lancet Public Health. 2016 Dec;1(2):e76-e83. doi: 10.1016/S2468-2667(16)30017-2. Epub 2016 Nov 29. PMID: 29253420.
3) , 4)

Peeters W, van den Brande R, Polinder S, Brazinova A, Steyerberg EW, Lingsma HF, Maas AI. Epidemiology of traumatic brain injury in Europe. Acta Neurochir (Wien). 2015 Oct;157(10):1683-96. doi: 10.1007/s00701-015-2512-7. Epub 2015 Aug 14. PubMed PMID: 26269030.
5)

Tagliaferri F, Compagnone C, Korsic M, Servadei F, Kraus J. A systematic review of brain injury epidemiology in Europe. Acta Neurochir (Wien). 2006 Mar;148(3):255-68; discussion 268. Review. PubMed PMID: 16311842.
6)

Forrest C, Healy V, Plant R. Temporal Trends in Traumatic Brain Injury. Ir Med J. 2022 May 25;115(5):597. PMID: 35696279.
7)

Popescu C, Anghelescu A, Daia C, Onose G. Actual data on epidemiological evolution and prevention endeavours regarding traumatic brain injury. J Med Life. 2015 Jul-Sep;8(3):272-7. Review. PubMed PMID: 26351526; PubMed Central PMCID: PMC4556905.
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