Cavernous hemangioma

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Cavernous hemangioma
Cavernous liver hemangioma - intermed mag.jpg
Micrograph of a cavernous liver hemangioma. H&E stain.
Specialty Oncology, hematology, cardiology, neurosurgery   OOjs UI icon edit-ltr-progressive.svg

Cavernous hemangioma, also called cavernous angioma, venous malformation, or cavernoma, [1] [2] is a type of venous malformation due to endothelial dysmorphogenesis from a lesion which is present at birth. A cavernoma in the brain is called a cerebral cavernous malformation or CCM. Despite its designation of a hemangioma, a cavernous hemangioma is not a tumor as it does not display endothelial hyperplasia. The abnormal tissue causes a slowing of blood flow through the cavities, or "caverns". The blood vessels do not form the necessary junctions with surrounding cells, and the structural support from the smooth muscle is hindered, causing leakage into the surrounding tissue. It is the leakage of blood, referred to as hemorrhage, that causes a variety of symptoms known to be associated with the condition.

Contents

Symptoms

People with this condition in the brain may or may not experience symptoms. Some complications of the condition are life-threatening or cause major disruptions to normal functioning. Dangerous seizures due to compression of the brain, bleeding inside the brain tissue, vision problems, difficulty with speaking or using words, memory loss, ataxia, or hydrocephalus can occur. Less serious symptoms may include headaches and weakness or numbness in the arms or legs, though these symptoms alone do not indicate a person has the condition. In the eye, it may cause disruption or damage to the extraocular muscles and optic nerve which may manifest as double vision, progressive proptosis, decreased visual acuity, or other vision changes. It can lead to partial or complete blindness. When the condition occurs in the liver it usually does not cause symptoms, but some may experience pain in the upper right abdomen, a feeling of fullness after eating only a small amount of food, decreased appetite, nausea, or vomiting. [3] [4]

Presentation

Cavernous hemangiomas can arise nearly anywhere in the body where there are blood vessels. They are sometimes described as resembling raspberries because of the appearance of bubble-like caverns. Unlike capillary hemangiomas, cavernous ones can be life-threatening and do not regress.

Causes

Most cases of cavernomas are thought to be congenital; however they can develop over the course of a lifetime. [5] While there is no definitive cause, research suggests that genetic mutations result in the condition. Congenital hemangiomas that appear on the skin are known as either vascular or red birthmarks.

Familial cerebral cavernous malformations are known to occur. The mutations may be inherited in an autosomal dominant fashion or occur sporadically. Overall, familial disease is thought to be responsible for one-third to one-half of cases. [6] In the US, approximately 50% of Hispanic patients with cerebral cavernous malformations have a familial form. In contrast, the familiar form of the condition accounts for only 10 to 20% of cases in Caucasians. [7] The reason for this difference is not presently known.

Several genes – K-Rev interaction trapped 1 (ССМ1), Malcavernin (CCM2) and Programmed cell death protein 10 (ССМ3) – have been identified as having mutations thought to be related to these lesions. [8] [9] [10] These genes are located at 7q21.2 (chromosome 7 long arm), 7p13 (chromosome 7 short arm) [11] and 3q25.2-q27 (chromosome 3 long arm) respectively. These lesions are further discussed in the Online Mendelian Inheritance in Man site – the reference numbers are OMIM 116860, OMIM 603284 and OMIM 603285 respectively.

Variations

Cerebral cavernomas

Cavernous hemangiomas located in the brain or spinal cord are referred to as cerebral cavernomas or more usually as cerebral cavernous malformations (CCMs), [12] [2] and can be found in the white matter, but often abut the cerebral cortex. When they contact the cortex, they can represent a potential seizure focus for the patient. Unlike other cavernous hemangiomas, there is no tissue within the malformation and its borders are not encapsulated. Therefore, they can change in size and number over time. [5]

Liver cavernous hemangioma

Cavernous hemangiomas are erroneously called the most common benign tumors of the liver. [13] Usually one malformation exists, but multiple lesions can occur in the left or right lobe of the liver in 40% of patients. [3] Their sizes can range from a few millimeters to 20 centimetres. Those over 5 cm are often referred to as giant hemangiomas. [3] These lesions are better classified as venous malformations.

Ultrasound of hemangioma in the liver. Hemangiomaliver.PNG
Ultrasound of hemangioma in the liver.

Eye cavernous hemangioma

In the eye, it is known as orbital cavernous hemangioma and is found in women more frequently than men, most commonly between the ages of 20–40. [14] This neoplasm is usually located within the muscle cone, which is lateral to the optic nerve. It is not usually treated unless the patient is symptomatic. Visual impairment happens when the optic nerve is compressed or the extraocular muscles are surrounded.

Mechanism

There are several known causes for cavernous hemangiomas, but some cases are still unknown. Radiation treatment used for other medical conditions has been suggested to cause cavernous malformation in some patients. [15] Hemangioma tumors are a result of rapid proliferation of endothelial cells and pericytic hyperplasia, or the enlargement of tissue as a result of abnormal cell division pericytes. The pathogenesis of hemangioma is still not understood. It has been suggested that growth factors and hormonal influences contribute to the abnormal cell proliferation. Cavernous liver hemangiomas are more commonly diagnosed in women who have been pregnant. [4] As a result of this, it is believed that estrogen levels may play a role in the incidence of liver cavernomas.

Genetic studies show that specific gene mutations or deletions are causes for the disease. The genes identified for cerebral cavernous hemangiomas (or malformations), are CCM1 (also KRIT1), CCM2 (also MGC4607, malcavernin) and CCM3 (also PDCD10). The loss of function of these genes is believed to be responsible for cerebral cavernous malformations. [16] Furthermore, it is also believed that a "second hit mutation" is necessary for the onset of the disease. This means that having a mutation in one of the two genes present on a chromosome is not enough to cause the cavernous malformation, but mutation of both alleles would cause the malformation. Additionally, research on hemangiomas in general has shown that loss of heterozygosity is common in tissue where hemangioma develops. [17] This would confirm that more than a single allele mutation is needed for the abnormal cell proliferation. KRIT1 has been shown to act as a transcription factor in the development of arterial blood vessels in mice. CCM2 has overlapping structure with CCM1 (KRIT1) and acts as a scaffolding protein when expressed. Both genes are involved with MAP3K3 and thus appear to be a part of the same pathway.

A simplified overview of mammalian MAPK pathways MAPK-pathway-mammalian.png
A simplified overview of mammalian MAPK pathways

CCM2 has been shown to cause embryonic death in mice. Lastly, the CCM3 gene has been shown to have similar expression to CCM1 and CCM2, suggesting a link in its functionality. Currently, no experiments have determined its exact function. [18] The lack of function of these genes in control of a proliferative signaling pathway would result in uncontrolled proliferation and the development of a tumor. In 2018, it was theorized that proliferation of endothelial cells with dysfunctional tight junctions, that are under increased endothelial stress from elevated venous pressure provides the pathophysiological basis for cavernous hemangioma development. [19]

Diagnosis

Small hemangioma on the scalp of a two-year-old female. Hemangioma.JPG
Small hemangioma on the scalp of a two-year-old female.

Gradient-Echo T2WI magnetic resonance imaging (MRI) is most sensitive method for diagnosing cavernous hemangiomas. [20] MRI is such a powerful tool for diagnosis, it has led to an increase in diagnosis of cavernous hemangiomas since the technology's advent in the 1980s. [15] The radiographic appearance is most commonly described as "popcorn" or "mulberry"-shaped. [21] Computed tomography (CT) scanning is not a sensitive or specific method for diagnosing cavernous hemangiomas. [22] Angiography is typically not necessary, unless it is required to rule out other diagnoses. Additionally, biopsies can be obtained from tumor tissue for examination under a microscope. It is essential to diagnose cavernous hemangioma because treatments for these lesions are less aggressive than that of cancerous tumors, such as angiosarcoma. However, since MRI appearance is practically pathognomonic, biopsy is rarely needed for verification. [22]

On ultrasound, cavernous haemangiomas in liver appeared as homogenous, hyperechoic lesions with posterior acoustic enhancement. On CT or MRI scans, it shows peripheral globular/nodular enhancement in the arterial phase, with portions of attenuation of enhancing areas. In the portal venous phase, it shows progressive centripetal enhancement. In delayed phase, it shows retention of contrast. It shows a high signal on T2 weighted images. [23]

Treatment

Asymptomatic lesions may not require treatment but may need to be monitored for any change in the size. A change in size of lesions in the nose, lips, or eyelids can be treated with steroid drugs to slow its progress. Steroids can be taken orally or injected directly into the tumor. Applying pressure to the tumor can also be used to minimize swelling at the site of the hemangioma. A procedure that uses small particles to close off the blood supply is known as sclerotherapy. This allows for tumor shrinkage and less pain. It is possible for the tumor to regrow its blood supply after the procedure has been done. [24] If the lesion caused by the cavernous hemangioma is destroying healthy tissue around it or if the patient is experiencing major symptoms, then surgery can be used to remove the cavernoma piecemeal. [22] A common complication of the surgery is hemorrhage and the loss of blood. There is also the possibility of the hemangioma reoccurring after its removal. [24] Additionally, the risk of a stroke or death is also possible. [25]

Treatments for cerebral cavernous hemangiomas include radiosurgery or microsurgery. [26] The treatment approach depends on the site, size and symptoms present, as well as the history of hemorrhage from the lesion. [26] Microsurgery is generally preferred if the cerebral cavernous hemangioma is superficial in the central nervous system, or the risk of damage to surrounding tissue from irradiation is too high. Additionally, a large hemorrhage with deterioration of the patient or intractable symptoms (such as seizures or coma) are further indications for microsurgical intervention. Gamma-knife radiation is the favored mechanism of radiosurgery. It provides a precise radiation dose to the cerebral cavernous hemangioma while relatively sparing the surrounding tissue. [26] These treatment approaches for cavernous hemangiomas in other regions of the body have limited research.

Prognosis

A few studies have worked on providing details related to the outlook of disease progression. Two studies show that each year 0.5% of people who have never had bleeding from their brain cavernoma, but had symptoms of seizures, were affected by bleeding. [25] In contrast, patients who have had bleeding from their brain cavernoma in the past had a higher risk of being affected by subsequent bleeding. The statistics for this are very broad, ranging from 4–23% a year. [25] Additional studies suggest that women and patients under the age of 40 are at higher risk of bleeding, but similar conducted studies did not reach the same conclusion. [25] However, when cavernous hemangiomas are completely excised, there is very little risk of growth or rebleeding. [27] In terms of life expectancy, not enough data has been collected on patients with this malformation in order to provide a representative statistical analysis. [15]

Epidemiology

The true incidence of cavernous hemangiomas is difficult to estimate because they are frequently misdiagnosed as other venous malformations. [28] Cavernous hemangiomas of the brain and spinal cord (cerebral cavernous hemangiomas (malformations) (CCM)), can appear at all ages but usually occur in the third to fourth decade of a person's life with no sexual preference. In fact, CCM is present in 0.5% of the population. However, approximately 40% of those with malformations have symptoms. Asymptomatic individuals are usually individuals that developed the malformation sporadically, while symptomatic individuals usually have inherited the genetic mutation. [5] The majority of diagnoses of CCM are in adults; however, 25% of cases of CCM are children. [5] Approximately 5% of adults have liver hemangiomas in the United States, but most are asymptomatic. [29] Liver hemangiomas usually occur between the ages of 30–50 and more commonly in women. [4] Cases of infantile liver cavernomas are extremely rare. Cavernous hemangioma of the eye is more prevalent in women than men and between the ages of 20–40. [14]

Research

In the treatment of a brain cavernous hemangioma, neurosurgery is usually the treatment chosen. [30] Research needs to be conducted on the efficacy of treatment with stereotactic radiation therapy, especially on the long-term. [31] However, radiotherapy is still being studied as a form of treatment if neurosurgery is too dangerous due to the location of the cavernoma. Genetic researchers are still working on determining the cause of the illness and the mechanism behind blood vessel formation. [25] Clinical trials are being conducted to better assess when it is appropriate to treat a patient with this malformation and with what treatment method. [15] Additionally, long-term studies are being conducted because there is no information related to the long-term outlook of patients with cavernoma. [32] An existing registry known as The International Cavernous Angioma Patient Registry [33] collects information from patients diagnosed with cavernoma in order to facilitate discovery of non-invasive treatments. [25]

Related Research Articles

Arteriovenous malformation Vascular anomaly

Arteriovenous malformation is an abnormal connection between arteries and veins, bypassing the capillary system. This vascular anomaly is widely known because of its occurrence in the central nervous system, but can appear in any location. Although many AVMs are asymptomatic, they can cause intense pain or bleeding or lead to other serious medical problems.

<span class="mw-page-title-main">Metastasis</span> Spread of a disease inside a body

Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, are metastases (mets). It is generally distinguished from cancer invasion, which is the direct extension and penetration by cancer cells into neighboring tissues.

Liver tumors are abnormal growth of liver cells on or in the liver. Several distinct types of tumors can develop in the liver because the liver is made up of various cell types. Liver tumors can be classified as benign (non-cancerous) or malignant (cancerous) growths. They may be discovered on medical imaging, and the diagnosis is often confirmed with liver biopsy. Signs and symptoms of liver masses vary from being asymptomatic to patients presenting with an abdominal mass, hepatomegaly, abdominal pain, jaundice, or some other liver dysfunction. Treatment varies and is highly specific to the type of liver tumor.

Central nervous system cavernous hemangioma Medical condition

Cerebral cavernous malformation (CCM) is a cavernous hemangioma that arises in the central nervous system (CNS). It can be considered to be a variant of hemangioma, and is characterized by grossly large dilated blood vessels and large vascular channels, less well circumscribed, and more involved with deep structures, with a single layer of endothelium and an absence of neuronal tissue within the lesions. These thinly walled vessels resemble sinusoidal cavities filled with stagnant blood. Blood vessels in patients with cerebral cavernous malformations (CCM) can range from a few millimeters to several centimeters in diameter. Most lesions occur in the brain, but any organ may be involved.

Hereditary hemorrhagic telangiectasia Medical condition (genetic disorder)

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler–Weber–Rendu disease and Osler–Weber–Rendu syndrome, is a rare autosomal dominant genetic disorder that leads to abnormal blood vessel formation in the skin, mucous membranes, and often in organs such as the lungs, liver, and brain.

Focal cortical dysplasia Medical condition

Focal cortical dysplasia (FCD) is a congenital abnormality of brain development where the neurons in an area of the brain failed to migrate in the proper formation in utero. Focal means that it is limited to a focal zone in any lobe. Focal cortical dysplasia is a common cause of intractable epilepsy in children and is a frequent cause of epilepsy in adults. There are three types of FCD with subtypes, including type 1a, 1b, 1c, 2a, 2b, 3a, 3b, 3c, and 3d, each with distinct histopathological features. All forms of focal cortical dysplasia lead to disorganization of the normal structure of the cerebral cortex :

<span class="mw-page-title-main">Cherry angioma</span> Small bright red dome-shaped bump on the skin

Cherry angioma, also called cherry hemangioma, is a small bright red dome-shaped bump on the skin. It ranges between 0.5 – 6 mm in diameter and usually several are present, typically on the chest and arms, and increasing in number with age. If scratched, they may bleed.

Sturge–Weber syndrome Medical condition

Sturge–Weber syndrome, sometimes referred to as encephalotrigeminal angiomatosis, is a rare congenital neurological and skin disorder. It is one of the phakomatoses and is often associated with port-wine stains of the face, glaucoma, seizures, intellectual disability, and ipsilateral leptomeningeal angioma. Sturge–Weber syndrome can be classified into three different types. Type 1 includes facial and leptomeningeal angiomas as well as the possibility of glaucoma or choroidal lesions. Normally, only one side of the brain is affected. This type is the most common. Type 2 involvement includes a facial angioma with a possibility of glaucoma developing. There is no evidence of brain involvement. Symptoms can show at any time beyond the initial diagnosis of the facial angioma. The symptoms can include glaucoma, cerebral blood flow abnormalities and headaches. More research is needed on this type of Sturge–Weber syndrome. Type 3 has leptomeningeal angioma involvement exclusively. The facial angioma is absent and glaucoma rarely occurs. This type is only diagnosed via brain scan.

Intraparenchymal hemorrhage Medical condition

Intraparenchymal hemorrhage (IPH) is one form of intracerebral bleeding in which there is bleeding within brain parenchyma. The other form is intraventricular hemorrhage (IVH).

Lymphangioma Malformations of the lymphatic system characterized by lesions that are thin-walled cysts

Lymphangiomas are malformations of the lymphatic system characterized by lesions that are thin-walled cysts; these cysts can be macroscopic, as in a cystic hygroma, or microscopic. The lymphatic system is the network of vessels responsible for returning to the venous system excess fluid from tissues as well as the lymph nodes that filter this fluid for signs of pathogens. These malformations can occur at any age and may involve any part of the body, but 90% occur in children less than 2 years of age and involve the head and neck. These malformations are either congenital or acquired. Congenital lymphangiomas are often associated with chromosomal abnormalities such as Turner syndrome, although they can also exist in isolation. Lymphangiomas are commonly diagnosed before birth using fetal ultrasonography. Acquired lymphangiomas may result from trauma, inflammation, or lymphatic obstruction.

Vascular tumor Medical condition

A vascular tumor is a tumor of vascular origin; a soft tissue growth that can be either benign or malignant, formed from blood vessels or lymph vessels. Examples of vascular tumors include hemangiomas, lymphangiomas, hemangioendotheliomas, Kaposi's sarcomas, angiosarcomas, and hemangioblastomas. An angioma refers to any type of benign vascular tumor.

KRIT1 Gene of the species Homo sapiens

Krev interaction trapped protein 1 is a protein that in humans is encoded by the CCM1 gene. This gene contains 16 coding exons and is located on chromosome 7q21.2. Loss of function mutations in CCM1 result in the onset of Cerebral cavernous malformation. Cerebral cavernous malformations (CCMs) are vascular malformations in the brain and spinal cord made of dilated capillary vessels.

CCM2

The CCM2 gene contains 10 coding exons and an alternatively spliced exon 1B. This gene is located on chromosome 7p13 and loss of function mutations on CCM2 lead to the onset of Cerebral Cavernous Malformations (CCM) illness. Cerebral cavernous malformations (CCMs) are vascular malformations in the brain and spinal cord made of dilated capillary vessels.

PDCD10

Programmed cell death protein 10 is a protein that in humans is encoded by the PDCD10 gene.

Cavernous venous malformations present as rounded, bright red or deep purple, spongy nodules, occurring chiefly on the head and neck and may involve both the skin and the mucous membranes.

Bonnet–Dechaume–Blanc syndrome Medical condition

Bonnet–Dechaume–Blanc syndrome, also known as Wyburn-Mason syndrome, is a rare congenital disorder characterized by arteriovenous malformations of the brain, retina or facial nevi. The syndrome has a number of possible symptoms and can, more rarely, affect the skin, bones, kidneys, muscles, and gastrointestinal tract. When the syndrome affects the brain, people can experience severe headaches, seizures, acute stroke, meningism, and progressive neurological deficits due to acute or chronic ischaemia caused by arteriovenous shunting.

<span class="mw-page-title-main">Blue rubber bleb nevus syndrome</span> Medical condition

Blue rubber bleb nevus syndrome is a rare disorder that consists mainly of abnormal blood vessels affecting the skin or internal organs – usually the gastrointestinal tract. The disease is characterized by the presence of fluid-filled blisters (blebs) as visible, circumscribed, chronic lesions (nevi).

A vascular anomaly is any of a range of lesions from a simple birthmark to a large tumor that may be disfiguring. They are caused by a disorder of the vascular system. A vascular anomaly is a localized defect in blood or lymph vessels. These defects are characterized by an increased number of vessels, and vessels that are both enlarged and sinuous. Some vascular anomalies are congenital, others appear within weeks to years after birth, and others are acquired by trauma or during pregnancy. Inherited vascular anomalies are also described and often present with a number of lesions that increase with age. Vascular anomalies can also be a part of a syndrome.

Diffuse neonatal hemangiomatosis (DNH) is a potentially fatal disorder where multiple benign (non-cancerous) blood vessel tumors (hemangiomas) are present in the skin and other organs. The mortality rate of diffuse neonatal hemangiomatosis is 50-90%. This disease is normally found in female Caucasian infants. The most common site of internal organ damage, or lesions, is the liver, which can redirect blood away from the heart and cause arteriovenous shunting. This can cause high cardiac output, leading to further complications such as congestive heart failure. This condition affecting the liver is also known as infantile hepatic hemangioma (IHH). Other sites of internal organ damage can include the intestines, nervous system, lungs, and sometimes the skeletal system. Early detection and treatment with steroids results in most newborn babies with this disease remaining healthy, with serious problems developing for some individuals during the hemangioma's growth phase.

<span class="mw-page-title-main">Vertebral hemangioma</span> Medical condition

Vertebral hemangiomas or haemangiomas (VHs) are a common vascular lesion found within the vertebral body of the thoracic and lumbar spine. These are predominantly benign lesions that are often found incidentally during radiology studies for other indications and can involve one or multiple vertebrae. Vertebral hemangiomas are a common etiology estimated to be found in 10-12% of humans at autopsy. They are benign in nature and frequently asymptomatic. Symptoms, if they do occur, are usually related to large hemangiomas, trauma, the hormonal and hemodynamic changes of pregnancy, or osseous expansion and extra-osseous extension into surround soft tissues or epidural region of the spinal canal.

References

  1. ↑ Awad IA, Polster SP (July 2019). "Cavernous angiomas: deconstructing a neurosurgical disease". Journal of Neurosurgery. 131 (1): 1–13. doi:10.3171/2019.3.JNS181724. PMC   6778695 . PMID   31261134.
  2. 1 2 Algra A, Rinkel GJ (February 2016). "Prognosis of cerebral cavernomas: on to treatment decisions". The Lancet. Neurology. 15 (2): 129–130. doi: 10.1016/S1474-4422(15)00340-3 . PMID   26654286.
  3. 1 2 3 Curry MP, Chopra S (2014). "Hepatic Hemangioma". UpToDate. Wolters Kluwer.
  4. 1 2 3 "Liver Hemangioma". MayoClinic. 2013.
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  7. ↑ Dashti SR, Hoffer A, Hu YC, Selman WR (July 2006). "Molecular genetics of familial cerebral cavernous malformations". Neurosurgical Focus. 21 (1): e2. doi: 10.3171/foc.2006.21.1.3 . PMID   16859255.
  8. ↑ Pagenstecher A, Stahl S, Sure U, Felbor U (March 2009). "A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells". Human Molecular Genetics. 18 (5): 911–8. doi:10.1093/hmg/ddn420. PMC   2640205 . PMID   19088124.
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  10. ↑ "Entrez Gene: PDCD10 programmed cell death 10".
  11. ↑ "OMIM Entry * 607929 - CCM2 GENE; CCM2". www.omim.org. Retrieved 2018-05-29.
  12. ↑ "What is a cavernoma?". Cavernoma Alliance UK.
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  14. 1 2 Burkat CN, Pargament J, Yen MT, Goel S, Nerad J. "Cavernous hemangioma". EyeWiki.
  15. 1 2 3 4 Salman RA. "Symptomatic brain cavernomas" (PDF). Cavernoma Alliance UK.
  16. ↑ Mouchtouris N, Chalouhi N, Chitale A, Starke RM, Tjoumakaris SI, Rosenwasser RH, Jabbour PM (2015). "Management of cerebral cavernous malformations: from diagnosis to treatment". TheScientificWorldJournal. 2015: 808314. doi: 10.1155/2015/808314 . PMC   4300037 . PMID   25629087.
  17. ↑ Marchuk DA (March 2001). "Pathogenesis of hemangioma". The Journal of Clinical Investigation. 107 (6): 665–6. doi:10.1172/jci12470. PMC   208951 . PMID   11254664.
  18. ↑ Mattassi R, Loose DA, Vaghi M (2009). Hemangiomas and Vascular Malformations (PDF). Springer-Verlag Italia. ISBN   978-88-470-0568-6. Archived from the original (PDF) on 2014-04-29.
  19. ↑ Maish WN (September 2019). "Developmental venous anomalies and brainstem cavernous malformations: a proposed physiological mechanism for haemorrhage". Neurosurgical Review. 42 (3): 663–670. doi:10.1007/s10143-018-1039-9. PMID   30291476. S2CID   52925057.
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  25. 1 2 3 4 5 6 "Cavernoma". U.K. National Health Service. 5 February 2019.
  26. 1 2 3 Poorthuis MH, Klijn CJ, Algra A, Rinkel GJ, Al-Shahi Salman R (December 2014). "Treatment of cerebral cavernous malformations: a systematic review and meta-regression analysis". Journal of Neurology, Neurosurgery, and Psychiatry. 85 (12): 1319–23. doi: 10.1136/jnnp-2013-307349 . PMID   24667206.
  27. ↑ Spetzler RF, Yashar K, Peter N (2015). Neurovascular surgery. ISBN   9781604067590. OCLC   967842929.
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  29. ↑ "Benign Liver Tumors". American Liver Foundation. 2011.
  30. ↑ Poorthuis MH, Klijn CJ, Algra A, Rinkel GJ, Al-Shahi Salman R (December 2014). "Treatment of cerebral cavernous malformations: a systematic review and meta-regression analysis". Journal of Neurology, Neurosurgery, and Psychiatry. 85 (12): 1319–23. doi: 10.1136/jnnp-2013-307349 . PMID   24667206.
  31. ↑ Poorthuis M, Samarasekera N, Kontoh K, Stuart I, Cope B, Kitchen N, Al-Shahi Salman R (April 2013). "Comparative studies of the diagnosis and treatment of cerebral cavernous malformations in adults: systematic review". Acta Neurochirurgica. 155 (4): 643–9. doi:10.1007/s00701-013-1621-4. PMID   23371401. S2CID   7859921.
  32. ↑ Polster SP, Cao Y, Carroll T, Flemming K, Girard R, Hanley D, et al. (April 2019). "Trial Readiness in Cavernous Angiomas With Symptomatic Hemorrhage (CASH)". Neurosurgery. 84 (4): 954–964. doi:10.1093/neuros/nyy108. PMC   6500884 . PMID   29660039.
  33. ↑ "Update Your Cavernous Angioma Patient Registry Profile". Angioma Alliance. 2 July 2020. Retrieved 2020-08-03.

Further reading


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