Clinical manifestations

Presentation and course

Cerebral aneurysms may come to light through vascular imaging, through symptoms from parenchymal or cranial nerve compression, or due to rupture causing subarachnoid or parenchymal hemorrhage. When an aneurysm is detected, recognition of an infectious or neoplastic cause usually depends on inference from the clinical features or the setting; in some cases, resection of the aneurysm leads to pathological confirmation of its infectious or neoplastic nature.

Infectious aneurysms occur in the setting of systemic sepsis, confirmed by blood cultures, or in suspected infective endocarditis. In some cases, local intracranial infectious invasion of the blood vessel is evident. Clinical features of the aneurysm that are atypical for the usual saccular aneurysms often raise clues to the possible infectious etiology.

Infectious and neoplastic aneurysms are sometimes spherical in shape like the more common saccular aneurysm, but they are often fusiform, ectatic, or irregular in shape. They are often multifocal and involve more distal branches of intracranial arteries rather than the proximal branching points where saccular aneurysms are usually found. These characteristic imaging features can facilitate their identification (48). Infectious aneurysms more commonly occur in children or young adults than do typical saccular aneurysms. Finally, they occur in clinical settings that may give hint to their unusual nature, such as fever or signs of endocarditis for infectious aneurysms or molar pregnancy with brain metastases for choricarcinomatous neoplastic aneurysms.

Infectious aneurysms can present catastrophically with rupture, causing subarachnoid or intraparenchymal hemorrhage and presenting with sudden severe headache, focal neurologic signs, and depression of consciousness. Like other nonsaccular aneurysms, these aneurysms may also present with headache or focal signs related to compression of adjacent structures. There may be accompanying systemic or cerebral emboli from underlying endocarditis (12). Specific symptoms depend on aneurysm location. Infectious aneurysms can also be detected by directed screening or incidentally in imaging done for other reasons. Diagnostic criteria for infectious aneurysms have been proposed, classifying the diagnosis as clinically definite, probable, or possible, based on the presence of three, two, or one supportive features, respectively, including multiplicity, distal location, fusiform shape, change on serial imaging, younger age, history of lumbar puncture, fever at presentation, or intraparenchymal hemorrhage (22). Blood cultures should be performed to confirm bacteremia and endocarditis. Echocardiography reliably differentiates tumors from other cardiac abnormalities.

Neoplastic aneurysms due to direct involvement of the arterial wall with tumor cells are quite rare. A comprehensive systematic literature search found a total of 92 studies describing only 96 cases of neoplastic cerebral aneurysms (56). Neoplastic intracranial aneurysms usually present with subarachnoid or intraparenchymal hemorrhage, headache, nausea and vomiting, and focal neurologic signs. Transient ischemic attacks or infarction due to embolism may precede the hemorrhage. The aneurysm may rarely present as a mass lesion.

Cardiac myxoma is the most frequent source of metastasis to the vessel wall, accounting for 60% of cases of neoplastic aneurysms and typically producing multiple aneurysms (56). Myxomas are the most common primary tumor of the heart, and the most common location is the left atrium. Cardiac myxomas occur most commonly between ages 30 and 60 years and in females more than males. They present with neurologic, psychiatric, cardiac, or systemic symptoms. More than two thirds of myxomatous emboli migrate to the central nervous system, and both cerebral and systemic embolization is the presenting feature in one third to one half of cases. Ischemic cerebral infarct was the most common neurologic manifestation (48). The mobility, not the size, of the myxoma appears to relate to embolic potential (28). The aneurysms may appear up to decades after the cardiac myxoma was resected (55; 42; 09). Due to these delayed presentations, some advocate for monitoring for cerebral aneurysms even after resection of the myxoma has occurred (52). A case was reported from India wherein a patient who had a pedunculated left atrial myxoma removed 12 years prior, presenting with seizures, was found to have multiple fusiform aneurysms in the anterior and posterior circulation (26). The patient had no recurrent or residual cardiac lesion; however, he had a pathology-proven myxomatous lesion in the calf muscle.

The next most common cause of neoplastic aneurysm is metastatic choriocarcinoma, accounting for 26% of cases (56). Cerebral metastases occur in 10% to 20% of persons with choriocarcinoma and are often hemorrhagic, but neoplastic aneurysm formation is rare, limited to scattered single case reports in the literature. Most cases of choriocarcinoma occur in young women between the ages of 18 and 30 years and follow pregnancy with hydatidiform mole. Other abnormal pregnancies, and occasionally even normal pregnancies, are less frequently associated with this tumor. Neurologic symptoms occur from weeks to 2 years after delivery. In women of reproductive age, metastatic choriocarcinoma should be considered in the differential diagnosis of any intracranial hemorrhage. Whenever a history of hydatidiform mole, recent pregnancy, or unexplained vaginal bleeding is present, a neoplastic etiology for neurologic symptoms must be considered, including new aneurysm. An elevated serum or urine beta-human chorionic gonadotrophin level can confirm the diagnosis of choriocarcinoma. Of the 24 cases of choriocarcinoma-related oncotic aneurysms reviewed by Wang and colleagues, 22 cases had aneurysms in the middle cerebral artery (53). Eighteen of 24 cases were single aneurysms. Intracranial hemorrhage, either in the brain parenchyma or in the subarachnoid or subdural spaces, was the most frequent mode of presentation. Other presentations reported include carotid-cavernous fistula and infarct due to tumor embolus. Symptoms of other metastatic lesions may be present.

Other metastatic brain tumors causing neoplastic aneurysms have occasionally been described (56). These cases also present most often with intracranial hemorrhages. Whenever an atypical aneurysm, fusiform or distal in location, is discovered in a patient with known metastatic disease, a neoplastic aneurysm must be considered.

Prognosis and complications

As these aneurysms frequently present with intracerebral or subarachnoid hemorrhage, the prognosis can be grave. For infective aneurysms, the hemorrhage typically occurs in the setting of infectious endocarditis or other cause of septicemia, and the prognosis is also dependent on the systemic illness and cardiac status. There is divergence of opinion regarding the timing of cardiac surgery for treatment of an infected heart valve when infective aneurysms are present. Aneurysmal rupture can be a devastating complication of the surgical treatment of endocarditis, but hemodynamically significant cardiac lesions, if present, must be addressed surgically before aneurysmal clipping or endovascular treatment (31). For patients with intracranial hemorrhage from ruptured aneurysm, a 4-week delay of cardiac surgery may be advisable (43). If infective aneurysms are detected by screening prior to rupture, treatment with effective systemic antibiotics can lead to resolution of the aneurysms in 25% to 50% of cases, but there is risk of aneurysm growth and rupture while undertaking conservative treatment (36; 40; 41), and serial imaging is required to follow response to antibiotic treatment (01). Endovascular embolization of asymptomatic aneurysms may be undertaken prior to surgical treatments for infective endocarditis to lessen perioperative surgical risks (43).

Neurologic symptoms may lead to the diagnosis of a neoplastic aneurysm from atrial myxoma. Alternately, these aneurysms can arise months or years after the diagnosis of myxoma, even if the tumor is excised and no cardiac recurrence is documented (48). Still, 5% to 7% of persons suffer cardiac recurrence (46; 21). The aneurysms may enlarge, causing progressive neurologic deficits, rupture, and death, or they may stabilize and resolve without direct treatment of the aneurysm itself or after excision of the primary tumor (56). Myxoma-induced cerebral aneurysm and myxomatous metastases can mimic the clinical picture of central nervous system vasculitis or infective endocarditis (28). Not all aneurysms are symptomatic. Whether excision of an enlarging or asymptomatic myxomatous aneurysm alters the long-term prognosis is uncertain because most such persons have been followed for only 2 to 3 years without intervening death from the central nervous system lesion.

The prognosis of nonmetastatic choriocarcinoma has improved greatly with intensive chemotherapy. The survival rate exceeds 90%, but those with brain metastases (including aneurysms) carry a poor prognosis. Brain metastases, including aneurysms, complicate 3% to 28% of gestational choriocarcinoma cases and are considered the worst prognostic factor for the disease (53). However, they can be responsive to therapy, and isolated instances of long-term survival have been reported (16). Age, beta-human chorionic gonadotrophin levels, duration and intensity of chemotherapy, tumor size, and prior pregnancy are additional prognostic factors.

The very rare neoplastic aneurysms due to other tumor types also carry a grim prognosis, commensurate with the underlying malignancies (56; 34).

Clinical vignette

A 58-year-old man had history of bladder resection for cancer, hypertension, and diabetes. He presented with left hemiparesis, and imaging revealed right middle cerebral artery occlusion and right cerebral infarction. Etiological workup with transthoracic echocardiography revealed a vegetation on the aortic valve, with severe aortic valve insufficiency. Blood cultures were negative. Antibiotics were started. One week after presentation he underwent diagnostic cardiac catheterization. After catheterization, he developed new right-sided weakness and confusion, and brain CT showed a massive left frontal lobar hematoma with intraventricular extension. CT angiogram was performed, demonstrating a spherical 4 mm x 5 mm aneurysm lying in the midst of the intraparenchymal hematoma. Urgent craniotomy was performed, with evacuation of the hematoma and clipping of the aneurysm, which at surgery had the appearance of an infectious aneurysm. After this procedure, he slowly regained mental alertness and right-sided function but required a prolonged hospitalization for multiple medical complications and remained hemiparetic on the left side. He was eventually discharged to a long-term care facility.

Biological basis

Etiology and pathogenesis

Infectious aneurysms most often occur in the setting of bacterial sepsis, often bacterial endocarditis, with typical organisms including Staphylococcus and Streptococcus species. Viridans Streptococci is the most common organism, found in 25% to 40% of cases (36; 04). Less often, infectious aneurysms are truly mycotic, due to fungal species, including Aspergillosis and Candida species (31; 04). Frequently, the causative organism remains unidentified. Interestingly, a viral cause of infectious aneurysms has been recognized, with reports of aneurysms related to Varicella-zoster virus and a handful of case reports of arteriopathy and aneurysm formation in children and adults with HIV infection (49; 22).

Infectious aneurysms occur in infective endocarditis either as the result of embolization of septic material into the vasa vasorum of affected vessels or directly to the lumen, leading to arteritis and sometimes to peri-arterial abscess formation (31). At times, there can also be invasion of the arterial wall from external infections in meningitis, cavernous thrombophlebitis, osteomyelitis, or chronic sinus infections. The resultant weakening of the vessel wall, under the strain of pulsatile flow, can lead to rapidly progressive aneurysm formation and growth (31).

As mentioned previously, cardiac myxoma and choriocarcinoma are the tumors most frequently associated with neoplastic aneurysms. Patients with Carney complex, a hereditary lentiginosis syndrome caused by mutations in PRKAR1A, tend to develop myxomas, which can lead to neoplastic aneurysms (13). Rare reported cases of neoplastic aneurysms are related to other tumors, such as bronchogenic carcinoma, undifferentiated squamous cell carcinoma, small cell carcinoma, pleomorphic lung carcinoma, lung adenocarcinoma, malignant fibrous histiocytoma, lymphomatoid granulomatosis, testicular chorionepithelioma, intimal sarcoma, and primary brain tumors or vasculopathy after radiation treatment (33; 30; 44; 47).

There are several theories regarding the mechanism of aneurysm formation in neoplastic aneurysms. Postembolic vascular damage and endothelial scarring, or tumor cell infiltration of the vasa vasorum destroying the arterial wall, may sometimes lead to aneurysm formation without requiring growth of viable neoplastic cells in the arterial wall. However, many of the case reports include pathological evidence demonstrating the presence of proliferating tumor cells within the arterial wall, suggesting that tumor emboli can penetrate the intact or damaged arterial endothelium, with subintimal growth, destruction of the arterial wall, and fibroblastic proliferation (56). Smooth muscle cells are displaced by myxomatous or neoplastic tissue. Furuya and colleagues have demonstrated myxoma cells within the arterial lumen invading the subintima, making this the likely mechanism for myxomatous aneurysm formation (17). Choriocarcinoma and other trophoblastic tumors have an inherent tendency to invade the vasculature, just as they do the uterine wall, resulting in proliferation of the tumor cells into the vessel walls and rupture of the internal elastic lamina and aneurysm formation. The distribution of neoplastic aneurysms in the distal middle cerebral artery territory suggests embolism as the underlying mechanism. The presence of intraluminal tumor distant from the primary source also suggests intravascular embolism.

Epidemiology

Infectious cerebral aneurysms are estimated to represent 2% to 4.5% of all intracranial aneurysms and to occur in 3% to 15% of cases of infective endocarditis (31). However, only a fraction of the cerebral hemorrhages that occur in some 4% to 5% of cases of infective endocarditis are due to identifiable aneurysms, and embolic ischemic stroke as a complication of infectious endocarditis is several times more common than cerebral hemorrhage (31; 19). One series of neuroimaging findings in 426 HIV-infected children found that the incidence of fusiform aneurysms was 1.9% (37).

Neoplastic aneurysms are very rare. In an autopsy series, primary cardiac tumors occur in less than 0.01% to 0.33% of cases, 50% of which are myxomas, and 75% to 86% of these arise in the left atrium (06). Embolism occurs in about 30% to 50% of left atrial myxomas, of which half are cerebral. However, ischemic stroke is the usual result, with true neoplastic aneurysm formation a much less frequent outcome. A study by Vigano and colleagues examined 13 patients previously treated for left cardiac myxoma with MRI and MRA and found three aneurysms, for a surprisingly high prevalence of 23% (50); however, all three of these aneurysms had the appearance of typical saccular aneurysms of the proximal middle cerebral artery or carotid artery, suggesting an incidental or comorbid occurrence of saccular aneurysms in these patients.

In the United States, gestational choriocarcinoma occurrence is about 1 in 20,000 to 1 in 40,000 pregnancies (10); and choriocarcinoma occurs in 0.133 per 100,000 woman years for all races, 0.110 per 100,000 woman years in white women, and nearly double that among black women and others (45). In Europe, North America, Australia, some areas of Latin America, and the Middle East, rates of choriocarcinoma are reported as low as two to seven per 100,000 pregnancies, whereas in China, India, Indonesia, and Thailand rates are reportedly from 63 to 202 per 100,000 births (05). Approximately 80% of choriocarcinomas have distant metastases, with the brain being the second most common location after the lung. Brain metastases occur in 10% to 20% of cases, but formation of cerebral aneurysms from choriocarcinoma is rare.

Prevention

Prompt treatment of underlying systemic infections or neoplasms is the only preventative approach that can be cited.

Diagnostic workup

A patient with systemic illness and neurologic signs will usually be investigated with brain MRI scanning. For patients with infective endocarditis, MRI scanning with post-contrast and gradient-echo or susceptibility-weighted sequences will provide increased sensitivity for cerebral abscesses or microhemorrhages. In patients with subarachnoid or intracerebral hemorrhage, investigation for a causative aneurysm must be performed. Noninvasive vascular imaging with CT angiography or MR angiography has progressed to the stage of achieving excellent sensitivity for most cerebral aneurysms, and workup for aneurysm in the patient with neurologic signs should usually begin with one of these studies. However, the aneurysms occurring in the setting of bacterial endocarditis tend to be small and to involve the more distal cerebral vessels, so can more easily be missed in imaging focused on the circle of Willis. CTA and MRA can be employed with moderately high sensitivity and specificity for infectious aneurysms (54) but digital subtraction cerebral angiography may be required for detection of smaller and more distal aneurysms (51). In cases of unexplained intracranial hemorrhage with suspicion for cerebral aneurysm of infectious or neoplastic cause, if initial noninvasive CT or MR imaging is negative, catheter angiography should follow to fully assess for small or distal aneurysms.

Heightened concern for infectious aneurysms is present in a patient with infectious endocarditis requiring cardiac bypass for valve replacement surgery. Although cerebral angiography is the gold standard for detection of small intracranial aneurysms, the risks of catheter angiography are a deterrence. Although noninvasive imaging is not as sensitive as catheter angiography for direct detection of small aneurysms, often in the setting of endocarditis cranial embolism is signaled by microinfarctions or microhemorrhages (01). Modern MRI scanning with susceptibility imaging has an excellent sensitivity for brain microhemorrhages that might signal an aneurysm. Monteleone and colleagues found infectious aneurysms in only seven of 151 patients (4.6%) with infectious endocarditis who underwent cerebral angiography; fully negative MRI scanning conveyed a negative predictive value of 97.7% in these patients (32). They concluded that cerebral angiography is a necessary preoperative step only in those endocarditis patients with neurologic deficits or bleeding on brain MRI scanning.

In a metaanalysis performed by Ahn and colleagues, brain MRI findings were analyzed from 21 studies including a total of 2133 patients (02). When they excluded studies in which all patients had neurologic symptoms as the indication for MRI, they found that 6.2% of patients had direct evidence of infective aneurysms. The pooled frequency of therapeutic and surgical plan modification based on MRI findings were 12.8% and 14.2%, respectively, indicating a potential role of screening brain MRI with or without neurologic symptoms in patients with infective endocarditis.

Management

Infectious aneurysms. In patients with unruptured infectious aneurysms, appropriate antibiotic therapy is the first line of treatment. A proportion of unruptured aneurysms can reverse with antibiotic treatment and prolonged antibiotic therapy, accompanied by serial vascular imaging, may be initially attempted. However, a significant portion of the aneurysms also go on to enlarge, rupture, or be accompanied by new aneurysm formation, despite antibiotics (31; 39; 41). Follow-up imaging is necessary. A systematic review found that among the 30% of infectious aneurysms initially treated conservatively, 56% went on to eventual intervention or death (40). In a retrospective study from 2023, infectious aneurysms that were treated with medical management alone had a 48% risk of recurrence or hemorrhage and, in addition, salvage surgical management was required in 69% of cases who failed medical management (03). Although recognizing that this high failure rate of conservative management might reflect a publication bias towards interventional management or a bias towards intervening in healthier patients, Ragulojan and colleagues recognize that it might also at least raise the question of whether an aggressive approach to management should be standard (40). Risks of morbidity due to treatment must be balanced against long-term risks of aneurysm rupture, which are ill-defined for infectious aneurysms. By extrapolation from data available for conventional unruptured aneurysms, it may be supposed that increasing aneurysm size would correlate with increased risk of rupture, but infectious aneurysms can enlarge rapidly, and even small infectious aneurysms can rupture, motivating consideration early intervention in appropriately selected aneurysms (22).

In the setting of infectious endocarditis, antibiotic treatment is also generally recommended prior to valve replacement surgery unless cardiac failure or excessively high risk of embolization drive a decision for early surgery. Treatment of the systemic infection and of an unstable cardiovascular condition should generally precede procedural treatment of an unruptured infectious aneurysm. In stable cases, some authors have recommended using serial MRI to monitor for reversal of susceptibility-weighted “black dots” (indicative of possible infectious aneurysm) with antibiotic treatment in infectious endocarditis patients prior to undertaking elective open-heart surgery (25).

Ruptured infectious aneurysms, having produced intracranial hemorrhage, have a high risk of re-rupture and carry a grave prognosis. Aneurysm rupture in patients hospitalized with infective endocarditis results in a 50% mortality (31). High risks of rerupture with conservative management must be weighed against typically high risks accompanying contemplated interventions.

Infectious aneurysms can be treated either by open surgical approaches or by endovascular methods. Most infectious aneurysms are fusiform and surgical elimination often requires isolation of the aneurysm with sacrifice of the parent vessel, sometimes with vessel bypass. Open surgical treatment can allow for evacuation of a hematoma from a ruptured aneurysm, but sometimes the small aneurysm on a distal cortical vessel can be difficult to locate (40). In many cases, and more frequently in the last decade, an endovascular approach to aneurysm occlusion is undertaken. The aneurysm or the parent artery is occluded with glue, Onyx, or detachable coils, and rarely by detachable balloon (04). Coil embolization, Onyx, and liquid glue occlusion can be carried out with comparable rates of successful embolization (14). Flow-directing stents, an emerging approach for endovascular treatment of aneurysms, have rarely been reported in treatment of infectious aneurysms (36), but data are becoming more available over time. A case series showed successful embolization of infectious aneurysms using flow directing stents in all three patients after failed attempts at endovascular coiling (23). However, a literature review studying endovascular treatment of ruptured intracranial aneurysms showed that only 50% of infectious aneurysms were completely occluded with flow directing stents (20). Both of these studies were limited by small sample sizes, indicating the need for more data worldwide on this topic.

In a systematic literature review of endovascular treatment of infectious aneurysms, Petr and colleagues found a complete occlusion rate of 95%, with procedure-related morbidity of 13% and mortality of 6% (38). Aneurysm recurred in 8% (38). Similar results were found in a recent meta-analysis where 97% of patients studied had complete aneurysm occlusion with endovascular treatment (08).

The sequencing of aneurysm treatment with respect to cardiac valve replacement in cases of endocarditis can be problematic. In a systematic review of the literature Ragulojan and associates found that in cases in which the sequencing of aneurysm treatment and cardiac valve repair was reported, 85% of the time, cardiac surgery followed control of the aneurysm, usually by endovascular management (40).

Neoplastic aneurysms. Whenever a neoplastic aneurysm is diagnosed, a metastatic workup must be conducted. Serial angiography should be considered, especially if new neurologic symptoms arise or old ones progress, as delayed and recurrent aneurysm formation is well documented. Incidental neoplastic aneurysms can often be observed without immediate intervention. Aneurysms related to cardiac myxomas, in particular, are often multiple, tend to be relatively stable in follow-up, with a good prognosis, and treatment can be directed towards managing individual aneurysms that progress over serial studies (18).

Symptomatic myxomatous aneurysms should be excised whenever feasible. Excision or wrapping of the aneurysm is performed when hemorrhage has occurred or if the aneurysm enlarges. Endovascular parent vessel occlusion is increasingly a viable alternative. A case report has described targeted radiation therapy for multiple progressive fusiform aneurysms, with obliteration or stabilization of all aneurysms (24).

Most persons with aneurysms due to choriocarcinoma also have pulmonary metastases. One series on gestational trophoblastic neoplasia metastatic to brain reported cure rates as high as 60% to 80% with aggressive systemic chemotherapy in conjunction with intrathecal chemotherapy and whole-brain irradiation (11). Another series reported primary cure rates of 65% to 80% using aggressive multidrug cocktails, with salvage chemotherapy and radiation regimens yielding 90% cure rates (29). Intracranial surgery is reserved for those with mass lesions, ruptured aneurysms, or single aneurysms in noneloquent brain regions. Additionally, whole-brain radiation therapy to immediately control cerebral metastases has been reported with success (07).

Outcomes

With antibiotic therapy, infectious aneurysms decrease in size or resolve on serial angiograms in 30% to 50% of cases (31). However, overall morbidity and mortality is high, particularly in cases presenting with intracranial hemorrhage. In these cases, the prognosis will largely depend on the severity of the presenting hemorrhage. In a systematic literature review, an overall mortality of 24% has been found, with a significant trend toward decreasing mortality in more recent years (04). Open surgical treatment with isolation of the aneurysmal vessel can successfully prevent rupture and reduce mortality in many of the cases, although the friable nature of the inflamed vascular wall can add to the difficulty and morbidity of aneurysm clipping. Endovascular treatment approaches are increasingly applied, aiming for aneurysm coiling or aneurysm trapping through parent artery occlusion Despite concerns regarding placement of foreign material in an infected tissue, endovascular treatment is becoming the most frequent treatment strategy (04). A single center study encompassing both ruptured and unruptured infectious aneurysms showed good outcomes (mRS ≤ 2) measured at 6 months in 61% of patients treated with endovascular management (27).

Neoplastic aneurysms can stabilize or even completely resolve with appropriate treatment of the underlying tumor (56). In particular, aneurysms related to cardiac myxoma have a relatively positive prognosis, with 34 of 58 cases in the literature showing stabilization or disappearance on follow-up imaging. However, the prognosis is substantially worse (with very high mortality rates) in aneurysms due to choriocarcinoma or other neoplasms (56).

Special considerations

Pregnancy

Infectious aneurysm. Infectious aneurysm has been reported as a complication of infectious endocarditis in pregnancy and requires an individualized approach that is cognizant of the unique risks to mother and fetus.

Choriocarcinoma. Because there are only a handful of case reports in the literature regarding metastatic choriocarcinoma leading to intracranial aneurysms, the effect of any possible repeat pregnancy on aneurysm progression or recurrence is unknown.

Cardiac myxoma. No information is available.

Anesthesia

Anesthesia techniques similar to those used for other difficult aneurysm surgeries should be used. Electroencephalographic and evoked potential monitoring and barbiturates titrated to burst suppression must be considered. When prolonged interruption of blood flow is likely, hypothermic circulatory arrest may be necessary.