Cerebral cavernous malformation

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Cerebral cavernous malformation:

 

Also known as cavernous hemangioma, also called cavernous angioma, cavernoma, or cerebral cavernoma (CCM).

 

Cavernous hemangiomas located in the brain or spinal cord are referred to as cerebral cavernomas or more usually as cerebral cavernous malformations (CCMs).

CCMs are compact clusters of spongelike vascular spaces without intervening neural tissue.

CCMs can occur in the brain or spinal cord.

They are vascular lesions of the central nervous system composed of abnormally enlarged capillary cavities without intervening brain parenchyma.

 

Cavernous hemangiomas of the brain and spinal cord appear at all ages but usually occur in the third to fourth decades.

At surgery their appearance is as blebs or blood filled bubbles, resembling a cluster of grapes.

Symptoms due to CCM are typically related to accruing hemorrhage within and surrounding the lesion, and to the growth of the underlying malformation.

Common presentations include focal seizures in approximately 50% of cases, and focal neurological deficits in approximately 25%, both related to the site of the lesion.

CCM’s have a characteristic appearance on MRI.

CCMs are found in approximately 0.5% of the general population.

Sporadic CCM‘s are located in the cerebral hemispheres in approximately 66% of cases, the brainstem, approximately 20%, cerebellum, and 6%, and basil or deep ganglia in approximately 8%.

Lesions located in the brain, stem or language area have more symptoms associated because of the limited volume of bleeding. Required to cause pressure in these areas.

Approximately 20 to 50% of CCM‘s are asymptomatic, and found incidentally on imaging studies done for various reasons.

It is a rare, familial lesion and similar lesions can occur in the retina and skin.

CCM’s typically cannot be detected by angiography.

The risk of intracranial bleeding is approximately 0.1 to 1% annually for patients with incidentally located lesions and approximately 3 to 10% for those who present with bleeding.

The risk for hemorrhage in the cerebral area is greatest for those who experience a previous hemorrhage and is approximately 14 to 56% in the first one to five years after the  initial single hemorrhage.

Patients with CCM’s do not have an increased risk of bleeding during routine activities, including exercise.

Patients with CCM3 germline variants have higher risk of symptomatic bleeding and larger number of lesions than do patients with sporadic CCM‘s.

The rate of bleeding with familial lesions is approximately 4% per year, with approximately 60% of patients having symptomatic hemorrhage and approximately 32 to 60% having seizures.

Sporadic single lesions are most common and account for 85% of the cases, about 15% of which are familial.

CCM‘s can be induced by radiation.

CCMs have  no sexual preference. 

 

CCMs are  present in 0.5% of the population.

 

The condition affects one in 200-250 persons.

 

CCMs  can be found in the white matter, but often abut the cerebral cortex. 

 

Refers to a type of benign vascular tumor or hemangioma, where a collection of dilated blood vessels form a lesion. 

 

Cavernous malformations are composed of caverns or clusters of dilated capillaries with no intervening brain.

 

The endothelium of such blood vessels lack normal tight junctions, resulting in leakiness.

 

Grossly, the lesion is similar to mulberries or raspberries.

Familial CCM are associated with autosomal dominant germline variants  with incomplete penetrance with loss of function of CCM1, CCM2 or CCM3.

These variants result in failure of endothelial cell to cell binding and attachment to the extracellular matrix, affects signaling pathways and leads to endothelial cell overgrowth and poor adhesion to adjacent cells with the proliferation of blood filled bubbles which are abnormal dilated segments of capillaries.

T2-weighted MRI sequences demonstrated a reticulated central portion of the lesion with a popcorn appearance.

Typical features are of multiloculated structures seen, especially, on MRI, scans yesterday after the ministration of contrast, and on T2 weighted sequences.

A hemorrhagic CCM often has a hemosiderin ring/halo of increased intensity on MRI.

 

The T2 hyperintense signal reflects blood and thrombosis in the caverns. 

 

Hypotensive regions may reflect aging blood or calcium. 

 

The typical T2 hypo intense rim around the lesion reflects surrounding hemosiderin.

 

There is a slowing of blood flow through the cavities.

 

The blood vessels do not form the necessary junctions with surrounding cells.

 

The lack of structural support from the smooth muscle is hindered, causing blood to leak into the surrounding tissue. 

 

The  leakage of blood causes symptoms associated with the condition.

 

Patients may or may not experience symptoms. 

 

Complications of CCM: can be life-disruptions to normal functioning, seizures, hemorrhage inside the brain tissue, vision problems, difficulty with speaking, memory loss, ataxia, or hydrocephalus, headaches and weakness or numbness in the arms or legs.

 

Familial cerebral cavernous malformations is thought to be responsible for one-third to one-half of cases.

 

Mutations may be inherited in an autosomal dominant fashion.

 

Mutations may occur sporadically. 

 

PIK3CA mutations are represented to a greater extent than any other genes in CCM’s.

 

CCM genes affect endothelium stabilization and programmed cell death.

 

Approximately 50% of Hispanic patients with cerebral cavernous malformations in the US have a familial form. 

 

Familiar form of the condition accounts for only 10 to 20% of cases in Caucasians.

 

Several genes have been identified as having mutations thought to be related to these lesions, and these genes are located at chromosomes 7 and 3.

 

The loss of function of these genes is believed to be responsible for cerebral cavernous malformations.

 

It  is also believed that a second hit mutation is necessary for the onset of the disease. 

This two – hit mechanism occurs when one allele of CCM is lost as a result of a germline variant, followed by somatic loss of the remaining wild type allele.

CCMs that contact the cortex, can represent a potential seizure focus.

 

CNS CCMs borders are not encapsulated, and can change in size and number over time.

Radiation causes for cavernous hemangiomas, but some cases are still unknown. 

 

Loss  of heterozygosity is common in tissue where hemangioma develops, 

 

confirming  that more than a single allele mutation is needed for the abnormal cell proliferation. 

 

It is theorized that endothelial cell proliferation with dysfunctional tight junctions, that are under increased endothelial stress from elevated venous pressure provides the pathophysiological basis for cavernous hemangioma development.

 

Gradient-Echo magnetic resonance imaging by MRI is most sensitive method for diagnosing cavernous hemangiomas.

 

MRI associated with an increased diagnosis of cavernous hemangiomas.

 

MRI appearance is most commonly described as “popcorn” or “mulberry”-shaped.

 

Computed tomography (CT) scanning is not sensitive or specific enough for diagnosing cavernous hemangiomas.

 

Angiography is typically not required  for diagnoses. 

 

MRI appearance is essentially pathognomonic, and biopsy is rarely needed for diagnosis.

 

Applying pressure to the tumor can also be used to minimize swelling.

 

A procedure using small particles to close off the blood supply, sclerotherapy allows for tumor shrinkage and less pain. 

 

A common complication of the surgery is hemorrhage and the loss of blood. 

 

Hemangioma may reoccur after its removal.

 

The risk of a stroke or death is also possible with cerebral cavernous malformation.

Surgical resection is usually recommended as first-line therapy for most symptomatic CCM’s.

Surgical indications include symptomatic and progressive growth or hemorrhage and seizures that originate in the region of the CCM.

Studies show seizure control, and 80% of patients after resection and lesion recurrence is approximately 1%.

Approximately 4% of patients have long-term neurologic deficit risks from surgery.

cCM’s they have not bled or are asymptomatic or located in high risk areas a better observed.

Treatments for cerebral cavernous hemangiomas include radiosurgery or microsurgery.

Stereotactic radiation for patients with inaccessible lesions or who are poor candidate for surgery have partial or complete responses in approximately 80% of patients and clinical improvement in approximately 56%.

Cerebral cavernous hemangioma

 

treatment depends on the site, size and symptoms, as well as the history of hemorrhage from the lesion.

 

Microsurgery is preferred if the cerebral cavernous hemangioma is superficial in the CNS, or the risk of damage to surrounding tissue from irradiation is too high. 

 

Persistent symptoms of seizures or coma are indications for microsurgical intervention. 

 

Gamma-knife radiation provides precise radiation dose to the cerebral cavernous hemangioma while relatively sparing the surrounding tissue.

 

Two studies showed  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.

 

Patients who have had bleeding from their brain cavernoma in the past have a higher risk of subsequent bleeding: 

 

4-23% a year.

 

If  cavernous hemangiomas are completely excised, there is very little risk of growth or rebleeding.

 

Approximately 40% of malformations have associated symptoms. 

 

Asymptomatic individuals are usually individuals that developed the CCM malformation sporadically.

Sporadic CCM’s differ from familial lesions with greater genetic heterogeneity and more commonly present as a single lesion.

Symptomatic individuals with CCM usually have inherited the genetic mutation.

Genetic testing for CCM identifies pathogenic variants in more than 75% of patients with multiple lesions.

The majority of diagnoses of CCM are in adult patients.

 

25% of cases of CCM occur in children.

 

Neurosurgery is usually the treatment for brain cavernous hemangioma.

Treatment options include observation, surgical, excision, and stereotactic, a radiation: with growing symptomatic lesions are considered for intervention.

 

Efficacy of treatment with stereotactic radiation therapy is being studied.

 

There is no information related to the long-term outlook of patients with cavernoma.