Neurosurgery for Cerebral Aneurysm

Overview

The word aneurysm comes from the Latin word aneurysma, which means dilatation. Aneurysm is an abnormal local dilatation in the wall of a blood vessel, usually an artery, due to a defect, disease, or injury.
Aneurysms can be true or false. A false aneurysm is a cavity lined by blood clot. The 3 major types of true intracranial aneurysms are saccular, fusiform, and dissecting. See image below.

Common locations of cerebral saccular aneurysms. The relative incidences are shown

This article reviews the types, pathology, clinical picture, and management of intracranial aneurysms. For patient education resources, see the Headache Center, as well as Aneurysm, Brain. 

Causes and Classification of Intracranial Aneurysms

The common causes of intracranial aneurysm include hemodynamically induced or degenerative vascular injury, atherosclerosis (typically leading to fusiform aneurysms), underlying vasculopathy (eg, fibromuscular dysplasia), and high-flow states, as in arteriovenous malformation (AVM) and fistula.
Uncommon causes include trauma, infection, drugs, and neoplasms (primary or metastatic).
Intracranial aneurysms are classified as follows:

• Saccular aneurysms
  

  • Developmental or degenerative
  • Traumatic
  • Mycotic
  • Oncotic
  • Flow-related
  • Vasculopathy-related
  • Drug-related
• Fusiform aneurysms
• Dissecting aneurysms

Saccular Aneurysms

Developmental/Degenerative Aneurysms

Pathology

Saccular aneurysms are rounded berrylike outpouchings that arise from arterial bifurcation points, most commonly in the circle of Willis (see image below). These are true aneurysms, ie, they are dilatations of a vascular lumen caused by weakness of all vessel wall layers.

A normal artery wall consists of 3 layers: the intima, which is the innermost endothelial layer; the media, which consists of smooth muscle; and the adventitia, the outermost layer, which consists of connective tissue. The aneurysmal sac itself is usually composed of only intima and adventitia. The intima is typically normal, although subintimal cellular proliferation is common. The internal elastic membrane is reduced or absent, and the media ends at the junction of the aneurysm neck with the parent vessel. Lymphocytes and phagocytes may infiltrate the adventitia. The lumen of the aneurysmal sac often contains thrombotic debris. Atherosclerotic changes in the parent vessel are also common.
Etiology
Most saccular or intracranial berry aneurysms were once thought to be congenital in origin, arising from focal defects in the media and gradually developing over a period of years as arterial pressure first weakens and subsequently balloons out the vessel wall.
Recent studies have found scant evidence for congenital, developmental, or inherited weakness of the arterial wall. Although genetic conditions are associated with increased risk of aneurysm development (see Associated conditions), most intracranial aneurysms probably result from hemodynamically induced degenerative vascular injury. The occurrence, growth, thrombosis, and even rupture of intracranial saccular aneurysms can be explained by abnormal hemodynamic shear stresses on the walls of large cerebral arteries, particularly at bifurcation points.
Less common causes of saccular aneurysms include trauma, infection, tumor, drug abuse (cocaine), and high-flow states associated with AVMs or fistulae.
Incidence
The true incidence of intracranial aneurysms is unknown but is estimated at 1-6% of the population.Published data vary according to the definition of what constitutes an aneurysm and whether the series is based on autopsy data or angiographic studies. In one series of patients undergoing coronary angiography, incidental intracranial aneurysms were found in 5.6% of cases, and another series found aneurysms in 1% of patients undergoing 4-vessel cerebral angiography for indications other than subarachnoid hemorrhage (SAH). Familial intracranial aneurysms have been reported. Whether this represents a true increased incidence is unclear.

Associated conditions

Congenital abnormalities of the intracranial vasculature, such as fenestrations of the vertebrobasilar junction or persistent trigeminal arteries, are associated with an increased incidence of saccular aneurysms. Fenestrations associated with saccular aneurysms have been found both at the fenestration site and on other, nonfenestrated vessels in the same patient. However, recent evidence indicates that the incidence of aneurysm at a fenestration site is not different from the typical association of other vessel bifurcations with saccular intracranial aneurysm.
Vasculopathies such as fibromuscular dysplasia (FMD), connective tissue disorders, and spontaneous arterial dissection are associated with an increased incidence of intracranial aneurysm.
Conditions that have been associated with increased incidence of cerebral aneurysms are as follows:

• Polycystic kidney disease
• Coarctation of the aorta
• Anomalous vessels
• FMD
• Connective tissue disorders (eg, Marfan, Ehlers-Danlos)
• High-flow states (eg, vascular malformations, fistulae)
• Spontaneous dissections

Autosomal dominant polycystic kidney disease (ADPKD) is by far the most common genetic abnormality associated with intracranial aneurysms, with an estimated 5-40% of ADPKD patients harboring such lesions. These lesions are often multiple. All patients with ADPKD should undergo screening using magnetic resonance angiography (MRA). The proper age to begin screening patients with ADPKD, as well as the frequency of rescreening (if the initial MRA findings are negative), are unresolved issues.
Screening for intracranial aneurysms is also recommended for people who have 2 immediate relatives with intracranial aneurysms.

Multiplicity

Intracranial aneurysms are multiple in 10-30% of all cases (see image below).About 75% of patients with multiple intracranial aneurysms have 2 aneurysms, 15% have 3, and 10% have more than 3. A strong female predilection is observed with multiple aneurysms. Although the overall female-to-male ratio is 5:1, the ratio rises to 11:1 in patients with more than 3 aneurysms.
 The circle of Willis has been dissected, and 3 berry aneurysms are observed. Multiple aneurysms are observed in about 20-30% of cases of berry aneurysm. Such aneurysms are congenital in the sense that the defect in the arterial wall may be present from birth, but the actual aneurysm develops over years, so rupture is most likely to occur in middle-aged adults. 

Multiple aneurysms are also associated with vasculopathies such as FMD and other connective tissue disorders.
Multiple aneurysms can be bilaterally symmetric (ie, mirror aneurysms) or located asymmetrically on different vessels. More than one aneurysm can be present on the same artery.
Aneurysms typically become symptomatic in people aged 40-60 years, with the peak incidence of SAH occurring in people aged 55-60 years.Intracranial aneurysms are uncommon in children and account for less than 2% of all cases. Aneurysms in the pediatric age group are often more posttraumatic or mycotic than degenerative and have a slight male predilection. Aneurysms found in children are also larger than those found in adults, averaging 17 mm in diameter.
Aneurysms commonly arise at the bifurcations of major arteries. Most saccular aneurysms arise on the circle of Willis (see images below) or the middle cerebral artery (MCA) bifurcation.
Common locations of cerebral saccular aneurysms. The relative incidences are shown

• Anterior circulation aneurysms: Approximately 86.5% of all intracranial aneurysms arise on the anterior (carotid) circulation. Common locations include the anterior communicating artery (30%), the internal carotid artery (ICA) at the posterior communicating artery origin (25%), and the MCA bifurcation (20%). The ICA bifurcation (7.5%) and the pericallosal/callosomarginal artery bifurcation account for the remainder (4%).
• Posterior circulation aneurysms: About 10% of all intracranial aneurysms arise on the posterior (vertebrobasilar) circulation. Seven percent arise from the basilar artery bifurcation, and the remaining 3% arise at the origin of the posterior inferior cerebellar artery (PICA) where it comes off of the vertebral artery.
• Miscellaneous locations: These lesions account for 3.5% of all lesions and involve sites such as the superior cerebellar artery and the anterior inferior cerebellar artery where they branch off the basilar artery. Saccular aneurysms are uncommon in locations other than the sites mentioned above. Aneurysms that develop at distal sites in the intracranial circulation are often caused by trauma or infection (see Traumatic aneurysms). Nontraumatic distal aneurysms, particularly along the anterior cerebral artery (ACA), have a high frequency of multiplicity and spontaneous hemorrhage.

Clinical presentation
Most aneurysms do not cause symptoms until they rupture; when they rupture, they are associated with significant morbidity and mortality.

• Subarachnoid hemorrhage
  

  • The most common presentation of intracranial aneurysm is subarachnoid hemorrhage (SAH; see images below). In North America, 80-90% of nontraumatic SAHs are caused by the rupture of an intracranial aneurysm. Another 5% are associated with bleeding from an AVM or tumor, and the remaining 5-15% are idiopathic. Remembering that trauma is overwhelmingly the most common cause of SAH is important, and a good history is often helpful in this regard. Increases in the number of patients taking antiplatelet or anticoagulant agents means that even a . minortrauma could result in SAH
  • The white arrow on the black card marks the site of a ruptured berry aneurysm in the circle of Willis. This is a major cause of subarachnoid hemorrhage. The subarachnoid hemorrhage from a ruptured aneurysm is more of anirritant-producing vasospasm than a mass lesion
  •   . Shown here is a CT scan of an aneurysmal subarachnoid hemorrhage. The CT scan in a 55-year-old woman shows subarachnoid blood within the interpeduncular and ambient cisterns and the right sylvian fissure caused by a ruptured aneurysm at the junction of the right carotid artery and theposterior communicating artery

   . A CT scan in an 82-year-old woman shows extensive subarachnoid blood within the cortical sulci, intraventricular hemorrhage, and an intracerebral hematoma adjacent to a large ruptured aneurysm of the anterior communicating artery.
  
  

  • On presentation, patients typically report experiencing the worst headache of their lives. The association of meningeal signs should increase suspicion of SAH. For a full description of the SAH, refer to the article Subarachnoid Hemorrhage.
  • Subhyaloid hemorrhages, often bilateral, located between the retina and vitreous membrane, may be observed in up to 25% of patients.
  • The most widely used clinical method for grading the clinical severity of SAH is the Hunt and Hess scale, which measures the clinical severity of the hemorrhage on admission and has been shown to correlate well with outcome, as follows:
    • Grade 0 - Unruptured aneurysm
    • Grade 1 - Asymptomatic or minimal headache and slight nuchal rigidity
    • Grade 2 - Moderate-to-severe headache, nuchal rigidity, no neurologic deficit other than cranial nerve palsy
    • Grade 3 - Drowsiness, confusion, or mild focal deficit
    • Grade 4 - Stupor, moderate-to-severe hemiparesis, possible early decerebrate rigidity, and vegetative disturbances
    • Grade 5 - Deep coma, decerebrate rigidity, and moribund appearance
  • The Fisher grade, which describes the amount of blood seen on a noncontrast head CT, is also useful in correlating the likelihood of developing vasospasm (discussed below), the most common cause of death and disability from SAH. Vasospasm is overwhelmingly most common in Fisher grade 3 and rarely found in patients with no blood on CT scan.
    • Fisher 1 - No blood detected
    • Fisher 2 - Diffuse or vertical layers less than 1 mm thick
    • Fisher 3 - Localized clot or vertical layer greater than or equal to 1 mm
    • Fisher 4 - Intracerebral or intraventricular clot with diffuse or no SAH
  • Other symptoms: Signs and symptoms of aneurysm other than those associated with SAH are relatively uncommon. Some intracranial aneurysms produce cranial neuropathies. A common example is the third nerve palsy that is secondary to posterior communicating artery aneurysm. Other, less common, symptoms include visual loss caused by an ophthalmic artery aneurysm that compresses the optic nerve, seizures, headaches, and transient ischemic attacks or cerebral infarction secondary to emboli (usually associated with large or giant partially thrombosed MCA aneurysms). The so-called giant aneurysms (diameter >2.5 cm) are more often symptomatic because of their mass effect. 

  
  Clinical outcome
  Vasospasm is the leading cause of disability and death from aneurysm rupture (see images below). Of patients with SAH, 10% die before reaching medical attention and another 50% die within one month. Fifty percent of survivors have neurological deficits. Ruptured aneurysms are most likely to rebleed within the first day (2-4%), and this risk remains very high for the first 2 weeks (about 25%) if left untreated. Early referral to a hospital that has physicians experienced in treating intracranial aneurysms, early treatment (open surgery and clipping or endovascular coiling), and aggressive treatment of vasospasm are 3 factors that have been correlated with improved outcomes.
  
  Outcomes associated with unruptured aneurysms are based primarily on whether they are treated and the results of that treatment.
  
  Natural history
  
  The risk of rupture among aneurysms that have not bled is unknown and, for many years, was believed to be 1-2% per year. Prior to the advent of endovascular coiling, most aneurysms were surgically treated via craniotomy (clipped) to prevent a future disastrous hemorrhage. A study (International Study of Unruptured Intracranial Aneurysms [ISUIA]) published in 1998 (retrospective component) and 2003 (prospective component) that involved 2621 and 1692 subjects, respectively, with intracranial aneurysms without intervention to determine the true natural history risk, has changed our current understanding of the natural history risk of aneurysms.
  Surprisingly, the study found that, for certain aneurysms, particularly those smaller than 7 mm and those located in the anterior circulation in patients who had not had a hemorrhage from another aneurysm, the risk of subsequent rupture was extremely small (0.05% per year in the retrospective and a 5-year cumulative risk of rupture of 0% in the prospective arm). Aneurysms at other locations (such as the basilar tip and the posterior communicating artery), aneurysms larger than 10 mm, and aneurysms that are found in patients who had bled from a prior aneurysm were found to have higher risks (about 0.5% per year). Despite these results, other recent reports continue to estimate the rupture risk for unruptured aneurysms at 1% per year.Critics of the ISUIA study emphasized that the selection was biased because surgeons who entered patients into the study felt that these aneurysms were less likely to bleed. Thus, the results of this study have significantly affected the way aneurysms are managed, with more and more aneurysms undergoing conservative management as opposed to invasive therapy, particularly if the aneurysms are small and asymptomatic.Untreated ruptured aneurysms have a very high risk of rebleeding after the initial hemorrhage. The risk is estimated at 20-50% in the first 2 weeks, and such rebleeding carries a mortality rate of nearly 85%. Aneurysms that have not ruptured but have manifested with other symptoms such as a new onset third nerve palsy (considered a true emergency that requires urgent treatment of the aneurysm), brain stem compression due to a giant aneurysm, or visual loss (caused by an ophthalmic artery aneurysm), for example, should be treated because the natural history risk of rupture is believed to be significantly higher (6% per year) than that of incidentally discovered lesions.Cigarette smoking, female sex, and younger age have recently been shown to correlate with aneurysm growth and rupture.
  The apex of vessel bifurcations is the site of maximum hemodynamic stress in a vascular network. Vascular and internal flow hemodynamics have a crucial effect on the origin, growth, and configuration of intracranial aneurysms. In the aneurysm, wall shear stress caused by the rapid changes of blood flow direction (the result of systole and diastole) continually damages the intima at an aneurysm cavity neck. These augmented hemodynamic stresses probably cause the initiation and subsequent progression of most saccular aneurysms. Thrombosis and rupture are also explained by intra-aneurysmal hemodynamic stresses.Studies demonstrate that the geometric relationship between an aneurysm and its parent artery is the principal factor that determines intra-aneurysmal flow patterns. In lateral aneurysms, such as those that arise directly from the ICA, blood typically moves into the aneurysm at the distal aspect of its ostium and exits at its proximal aspect, producing a slow-flow vortex in the aneurysm center. Opacification of the lumen then proceeds in a cranial-to-caudal fashion. Contrast stagnation within these aneurysms is often pronounced.
  In contrast to lateral aneurysms, intra-aneurysmal circulation is rapid, and vortex formation with contrast stasis is rare when aneurysms arise at the origin of branching vessels or a terminal bifurcation. These patterns of intra-aneurysmal flow are important not only for the formation and progression of an aneurysm itself but also because they may influence the selection and placement of endovascular treatment devices.
  In giant saccular aneurysms (>2.5 cm), slow growth can occur by recurrent hemorrhages into the lesion. The highly vascularized membranous wall of giant intracranial aneurysms is the most likely source of these intra-aneurysmal hemorrhages. Giant sacs commonly contain multilayered laminated clots of varying ages and consistency. The outer wall is fibrous and thick. These multilaminated giant aneurysms seldom rupture into the subarachnoid space and typically produce symptoms related to their mass effect.
  

  Traumatic Aneurysms

  Traumatic aneurysms account for less than 1% of all aneurysms. The following 2 general types of traumatic aneurysms are identified: aneurysms secondary to penetrating trauma and aneurysms secondary to nonpenetrating trauma.
  
  Penetrating trauma
  
  Intracerebral aneurysms secondary to penetrating injuries are commonly due to high-velocity missile wounds of the head. A recent study demonstrated a 50% overall prevalence of major vascular lesions in civilian patients with penetrating missile injuries examined in the acute stage. Nearly half of these patients had traumatic aneurysms. The diagnosis of posttraumatic aneurysm may be delayed or overlooked on CT scan because the lesion is often obscured by the presence of an accompanying hemorrhagic intraparenchymal contusion.
  Penetrating injuries to extracranial vessels can cause lacerations, arteriovenous fistulae, dissection, or traumatic pseudoaneurysm. The carotid artery is the most frequently involved vessel. Pathologically, a false aneurysm lacks any components of a vessel wall. These false aneurysms, or pseudoaneurysms, are really cavities, typically within adjacent blood clots, that communicate with a vessel lumen. Radiographically, a false aneurysm projects beyond the vessel margin into the adjacent soft tissues. The periadventitial hematoma can be delineated on CT scan or magnetic resonance (MR) studies.
  Occasionally, the external carotid artery is a site of traumatic injury. The superficial temporal artery (STA) is the most commonly affected vessel. STA traumatic pseudoaneurysm occurs as a complication of scalp trauma and may result from penetrating injury or blunt trauma.
  Meningeal vessels are uncommon sites of traumatic pseudoaneurysm development; most occur on branches of the middle meningeal artery. When a meningeal pseudoaneurysm hemorrhages, it is usually into the epidural space. Direct penetrating injury to the vertebral artery (VA) is uncommon. Occasionally, cervical spine fracture-dislocations damage the VA. These typically produce dissection or occlusion; pseudoaneurysms are rare.
  
  Nonpenetrating trauma
  
  Intracranial aneurysm secondary to nonpenetrating trauma is rare and usually occurs at the skull base (where it involves the petrous, cavernous, or supraclinoid ICA) or along the peripheral intracranial vessels. ICA aneurysms at the skull base can be caused by blunt trauma or skull fracture. Hyperextension and head rotation may stretch the ICA over the lateral mass of C1 or shear the artery at its intracranial entrance.
  Peripheral intracranial aneurysms can be caused by closed head injury. The distal anterior cerebral artery and peripheral cortical branches are commonly involved sites distal to the circle of Willis. Frontolateral impacts produce shearing forces between the inferior free margin of the falx cerebri and the distal ACA. This can cause a common type of nonpenetrating traumatic intracranial aneurysm, a traumatic aneurysm of the pericallosal artery. Suspect the presence of a traumatic distal ACA aneurysm if a juxtafacial hematoma is observed on CT scan.
  Suspect traumatic cortical artery aneurysm if a delayed hematoma near the brain periphery develops adjacent to the site of a skull fracture.
  
  Treatment
  
  Although cases have been reported to resolve spontaneously, direct treatment is usually recommended. Such aneurysms can usually be approached either surgically (clipping) or endovascularly (coiling), depending on the location. For aneurysms located proximally near the skull base, balloon-test occlusion and parent vessel sacrifice may be an option. For distal aneurysms, coiling or clipping with vascular bypass (if important branch vessels are incorporated into the aneurysm neck) may both be considered.
  

  Mycotic Aneurysms

  The term mycotic aneurysm refers to any aneurysm that results from an infectious process that involves the arterial wall. These aneurysms may be caused by a septic cerebral embolus that causes inflammatory destruction of the arterial wall, beginning with the endothelial surface. A more likely explanation is that infected embolic material reaches the adventitia through the vasa vasorum. Inflammation then disrupts the adventitia and muscularis, resulting in aneurysmal dilatation.
  Mycotic aneurysms were once estimated to account for 2-3% of all intracranial aneurysms but were described as decreasing in the antibiotic era. However, with the increased incidence of drug abuse and immunocompromised states from various causes, mycotic aneurysms may have increased in frequency.The thoracic aorta has been described as the most common site of mycotic aneurysm. Intracranial mycotic aneurysms are less common. They occur with greater frequency in children and are often found on vessels distal to the circle of Willis. Rarely, deep neck space infections are complicated by pseudoaneurysm of the cervical ICA.
  
  Treatment
  
  Mycotic aneurysms generally have a fusiform morphology and are usually very friable. Therefore, treatment is difficult or risky. Most cases are treated emergently with antibiotics, which are continued for 4-6 weeks. Serial angiography (at 1.5, 3, 6, and 12 mo) helps document the effectiveness of medical therapy. Even if aneurysms seem to be shrinking, they may subsequently grow, and new ones may form.
  Serial MRA may be a viable alternative in some cases. Aneurysms may continue to shrink following completion of antibiotic therapy. Delayed clipping or coiling may be more feasible; indications include patients with SAH, increasing size of aneurysm while on antibiotics (this is controversial; some argue that this is not mandatory), and failure of the aneurysm to shrink after 4-6 weeks of antibiotics. Patients with subacute bacterial endocarditis who require valve replacement should have bioprosthetic (ie, tissue) valves instead of mechanical valves to eliminate the need for risky anticoagulation.
  

  Oncotic Aneurysms

  Extracranial oncotic pseudoaneurysms with exsanguinating epistaxis are a common terminal event with malignant head and neck tumors. Intracranial oncotic aneurysms are less common. They are often bizarre-shaped and on distal branches of the intracranial vessels, remote from the more typical saccular aneurysms located on the circle of Willis. Such aneurysms may be associated with either primary or metastatic tumors. Neoplastic aneurysms result from direct vascular invasion by a tumor or implantation of metastatic emboli that infiltrate and disrupt the vessel wall. Myxomatous aneurysms are one type of oncotic intracranial aneurysm that are associated with atrial myxomas in a small percentage of cases.
  Endovascular treatment using balloon-test occlusion (to determine whether the patient can tolerate vessel sacrifice), followed by intentional vessel occlusion (if the patient passes the test), is one common way to treat such aneurysms. Stent-assisted coiling, in which a porous stent is placed across the aneurysm and is followed by filling the aneurysm with coiling, is another option. Emergent treatment with a covered stent (graft stent) has been used to avert life-threatening intracranial bleeding.
  
  See the images below.
  
  CT angiography reconstruction showing a large irregularly shaped presumed mycotic middle cerebral artery aneurysm.
    Coronal CT angiography showing a large irregularly shaped presumed mycoticmiddle cerebral artery aneurysm (see previous image).
    Digital subtraction angiogram, right internal carotid injection, showing a large irregularly shaped presumed mycotic middle cerebral artery aneurysm.
   Digital subtraction angiogram, right internal carotid injection, 3-dimensional reconstruction, showing a large irregularly shaped presumed mycotic middle cerebral artery aneurysm (see previous image).
  
  Primary tumors
  
  Intracranial aneurysms associated with primary brain tumors are less common than those caused by metastases. The incidence of saccular aneurysms in patients with primary cerebral neoplasms does not appear to be significantly higher than the incidence of aneurysms in the general population, although some authors report a slightly higher incidence with meningiomas.
  
  Metastatic tumors
  
  Some metastatic tumors that have been implicated in the development of intracranial aneurysm include left atrial myxoma and choriocarcinoma. Because metastatic tumors are common at the gray-white junction, aneurysms due to metastatic implants often involve peripheral cerebral vessels.
  

  Flow-Related Aneurysms

  The coexistence of AVMs and aneurysms is well known. The frequency of aneurysms with AVM has been reported as 2.7-30%. Flow-related aneurysms occur along proximal and distal feeding vessels. Proximal lesions arise in the circle of Willis or on vessels that feed the AVM and are probably related to increased hemodynamic stress. No increased frequency of hemorrhage is reported in patients with proximal feeding-artery aneurysms.
  Distal flow-related aneurysms are located in distal branches to the AVM. Intranidal aneurysms have been reported in 8-12% of AVMs. These lesions are thin-walled vascular structures without the elastic or muscular layers that characterize arteries. Whether intranidal aneurysms arise from venous ectasias (dilatation) or from the flow-weakened walls of arterial vessels is unclear. Nevertheless, these thin-walled structures are exposed to arterial pressure and are considered a likely site for AVM hemorrhage.
  Treatment of aneurysms associated with AVMs is similar to that of aneurysms not associated with AVMs, with the following differences:
  

  • Small flow-related aneurysms have been shown to disappear or shrink after successful treatment of the AVM, and this possibility must be considered, particularly if no hemorrhage has occurred.
  • AVMs that bleed often have intra-nidal aneurysms; when these are found, they should be targeted for urgent therapy secondary to their presumed ability to rebleed with increased frequency.
  • In AVMs that manifest as SAH and circle of Willis aneurysms, presume that the aneurysm (not the AVM) is the source of the SAH and treat urgently to prevent rebleeding.

  Vasculopathy-Related, Vasculitis-Related, and Drug-Related Aneurysms

  Some vasculopathies, such as FMD (see Multiplicity), have an increased incidence of cephalocervical aneurysms. Some vasculitides, such as systemic lupus erythematosus (SLE) and even Takayasu arteritis, have been associated with aneurysms. Substance abuse, especially with cocaine, can cause certain forms of vasculitis that contribute to aneurysm formation or can cause hemorrhage from preexisting vascular abnormalities such as AVMs or saccular aneurysms because of their ability to cause sudden rapid surges of increased systemic blood pressure to high values.
  

  Vasculopathies

  • SLE: Commonly reported CNS vascular lesions with SLE include infarcts and transient ischemic attacks. Intracranial hemorrhages are present in approximately 10% of patients with CNS symptoms. Although uncommon, arteritic and nonvasculitic aneurysms occur in SLE. These can be saccular, fusiform, or a bizarre-looking mixture of both.
  • Takayasu arteritis: The characteristic vascular lesions include occlusion, stenosis, and luminal irregularities, but ectasia and aneurysm formation have been described in Takayasu arteritis.
  • FMD: Some investigators report a 20-50% incidence of aneurysms in patients with cervical FMD. Other abnormalities associated with FMD include spontaneous dissection, dissecting aneurysm (see Dissecting Aneurysms), and arteriovenous fistulae.
  • Drug abuse: Various intracranial vascular lesions have been reported with substance abuse.
    

    • Cocaine abuse is associated with various CNS complications, including SAH, cerebral ischemia or infarction, intraparenchymal hemorrhage, seizures, vasculitis, vasospasm, and death. Approximately 50% of patients who have a drug abuse problem along with CNS symptoms have SAH; of these, about half have an underlying abnormality such as aneurysm or vascular malformation. Hemorrhage may also be related to the acute hypertensive response that occurs with cocaine use.
    • Heroin, ephedrine, and methamphetamine use can cause cerebral vasculitis. Necrotizing angiitis, histologically similar to periarteritis nodosa, has been identified in patients who abuse methamphetamines. Focal arterial ectasias, aneurysms, and sacculations have been reported in this form of drug-induced cerebral arteritis. 
    
    

    Fusiform Aneurysms

    Pathology

    Fusiform aneurysms are also known as atherosclerotic aneurysms. These lesions are exaggerated arterial ectasias that occur because of a severe and unusual form of atherosclerosis. Damage to the media results in arterial stretching and elongation that may extend over a considerable length. These ectatic vessels may have more focal areas of fusiform or even saccular enlargement. Intraluminal clots are common, and perforating branches often arise from the entire length of the involved parent vessel.
    

    Clinical presentation

    Fusiform aneurysms usually occur in older patients. The vertebrobasilar system is commonly affected. Fusiform aneurysms may thrombose, producing brainstem infarction as small ostia of perforating vessels that emanate from the aneurysm become occluded. They can also compress the adjacent brain or cause cranial nerve palsies.
    

    Imaging

    Fusiform atherosclerotic aneurysms usually arise from elongated tortuous arteries. Patent aneurysms enhance strongly after contrast administration; thrombosed aneurysms are hyperintense on noncontrast CT scans. Tubular calcification with intraluminal and mural thrombi in the ectatic parent vessels and aneurysm wall is common. Occasionally, fusiform aneurysms cause erosion of the skull base.
    On angiography, fusiform aneurysms often have bizarre shapes, with serpentine or giant configurations. Intraluminal flow is often slow and turbulent. These aneurysms typically do not have an identifiable neck. MRI is helpful in delineating the relationship between vessels and adjacent structures such as the brainstem and cranial nerves.

    Dissecting Aneurysms

    Pathology

    In arterial dissections, blood accumulates within the vessel wall through a tear in the intima and internal elastic lamina. The consequences of this intramural hemorrhage vary. If blood dissects subintimally, it causes luminal narrowing or even occlusion. If the intramural hematoma extends into the subadventitial plane, a saclike outpouching may be formed (see image below). Do not confuse these focal aneurysmal dilatations with the pseudoaneurysms that result from arterial rupture and subsequent encapsulation of the perivascular hematoma. Thus, uncomplicated dissections do not project beyond the lumen of the parent vessel, and dissections with saclike outpouchings are termed dissecting aneurysms. The term false saccular aneurysm, or pseudoaneurysm, should be used for encapsulated, cavitated, paravascular hematomas that communicate with the arterial lumen.
    

    Etiology

    Dissecting aneurysms may arise spontaneously. More commonly, trauma or an underlying vasculopathy such as FMD is implicated.
    

    Location

    Most dissecting aneurysms that involve the craniocerebral vessels affect the extracranial segments; intracranial dissections are rare and usually occur only with severe head trauma. Although the common carotid artery (CCA) can be involved by cephalad extension of an aortic arch dissection, the CCA and carotid bulb are usually spared. The ICA is commonly affected. Most dissections involve the midcervical ICA segment and terminate at the extracranial opening of the petrous carotid canal.
    The VA is also a common site of arterial dissection. The common location is between the VA exit from C2 and the skull base. Involvement of the first segment, which extends from the VA origin to its entry into the foramen transversarium (usually at the C6 level), is relatively rare.
    

    Imaging

    Dissecting aneurysms are elongated, ovoid, or saccular contrast collections that extend beyond the vessel lumen. MR studies delineate an intravascular or perivascular hematoma associated with dissections, particularly during the subacute stage. MRA is a helpful screening procedure, but catheter angiography is the procedure of choice for imaging vessel details such as dissection site.

    Imaging of Intracranial Aneurysms

    Imaging Overview

    The 3 major modalities used to reveal and study the size, location, and morphology of an intracranial aneurysm include thin-section CT scanning after an intravenous injection using special computer software (CT angiography [CTA]; see first image below), MRA (see second image below), and catheter angiography (see the final 3 images below). The preferred initial method for evaluation of unruptured intracranial aneurysms is either MRA or CTA, whereas angiography is the preferred modality in patients who have had a subarachnoid hemorrhage (SAH), although CTA alone has been used.

  
  
  

 

Hemangioblastoma

Background

In 1928, Cushing and Bailey introduced the term hemangioblastoma.  It refers to a benign vascular neoplasm that arises almost exclusively in the central nervous system. According to the World Health Organization classification of tumors of the nervous system, hemangioblastomas are classified as meningeal tumors of uncertain origin.

Supratentorial hemangioblastoma proved by histologic analysis. Carotid arteriogram demonstrates a vascular, dense, tumor filled from the anterior cerebral vessels and not involving the sagittal sinus. 

Supratentorial hemangioblastoma proved by histologic analysis. Carotid arteriogram demonstrates a vascular, dense, tumor filled from the anterior cerebral vessels and not involving the sagittal sinus.

History of the Procedure

Since its original description, hemangioblastomas have been found in multiple regions of the central nervous system. Predominant involvement of the cerebellum and the spinal cord was noted, but true incidence of this tumor was not discovered until the recent increased availability of noninvasive diagnostic imaging modalities, particularly magnetic resonance imaging. This, in addition to significant improvement in surgical approaches and microsurgical technique, have made hemangioblastoma, although dangerous, a potentially treatable and curable disease. 

Epidemiology

Frequency

Incidence and location

Hemangioblastomas are rare, and according to various series, they account for 1-2.5% of all intracranial neoplasms.Most hemangioblastomas are located in the posterior cranial fossa; in that region, hemangioblastomas comprise 8-12% of neoplasms. Hemangioblastoma is the most common primary adult intraaxial posterior fossa tumor. Cerebellar hemangioblastomas are frequently referred to as Lindau tumors because Swedish pathologist Arvid Vilhelm Lindau first described them in 1926.
The second most common location of hemangioblastomas is the spinal cord, where the frequency ranges from 2-3% of primary spinal cord neoplasms to 7-11% of spinal cord tumors. This tumor's occurrence in other locations, such as the supratentorial compartment, the optic nerve,the peripheral nerves,or the soft tissues of extremities is extremely rare.

Sex and age distribution

Hemangioblastomas are more common in men than in women. In most clinical series, the male-to-female ratio is approximately 2:1. Although hemangioblastomas may develop at any age, they rarely affect children; the usual age at diagnosis is between the third and fifth decades.

von Hippel-Lindau disease

Most hemangioblastomas arise sporadically. However, in approximately one quarter of all cases, they are associated with von Hippel-Lindau (VHL) disease, an autosomal dominant hereditary syndrome that includes retinal angiomatosis, central nervous system hemangioblastomas, and various visceral tumors most commonly involving the kidneys and adrenal glands.This syndrome is classified as a phakomatosis, although it does not include any cutaneous manifestations. The syndrome has variable penetrance, but its dominant mode of transmission compels performing at least a screening of family members of patients diagnosed with VHL disease. In some patients with VHL disease, hemangioblastomas may produce erythropoietinlike substances, resulting in polycythemia at the time of diagnosis.

Etiology

Etiology of the hemangioblastoma is obscure, but its presence in various clinical syndromes may suggest an underlying genetic abnormality. The genetic hallmark of hemangioblastomas is the loss of function of the von Hippel-Lindau (VHL) tumor suppressor protein.

Pathophysiology

Upon gross examination, hemangioblastomas are usually cherry red in color. They may include a cyst that contains a clear fluid, but solid tumors are as common as cystic ones. The tumor usually grows inside the parenchyma of the cerebellum, brain stem, or spinal cord; it is attached to the pia mater and gets its rich vascular supply from the pial vessels. However, extramedullary and extradural hemangioblastomas also have been described.

Presentation

The clinical presentation of hemangioblastomas usually depends on the anatomical location and growth patterns. Cerebellar lesions may present with signs of cerebellar dysfunction, such as ataxia and discoordination, or with symptoms of increased intracranial pressure due to associated hydrocephalus.
In general, intracranial hemangioblastomas present with a long history of minor neurological symptoms that, in most cases, are followed by a sudden exacerbation, which may necessitate immediate neurosurgical intervention.Patients with spinal cord lesions most frequently present with pain, followed by signs of segmental and long-track dysfunction due to progressive compression of the spinal cord.
Patients with VHL disease may present with ocular or systemic symptoms due to involvement of other organs and systems.The polycythemia that may develop in some patients with hemangioblastomas usually is clinically asymptomatic.Spontaneous hemorrhage is possible in both intraspinal and intracranial hemangioblastomas, but this risk is low and tumors smaller than 1.5 cm carry virtually no risk of spontaneous hemorrhage.

Indications

In many cases, symptoms caused by the growth of the neoplasm itself may be an indication for surgical intervention. In others, symptomatic obstruction of the cerebrospinal fluid (CSF) pathways may necessitate the operation. Asymptomatic lesions that sometimes are encountered in patients with multiple hemangioblastomas may be safely observed with frequent MRI scans to rule out tumor enlargement.

Relevant Anatomy

Presence of a hemangioblastoma rarely, if ever, alters normal anatomy. In choosing the appropriate surgical approach to the tumor, one must take into consideration the position of the mass, presence (or absence) of a large cystic component, associated hydrocephalus and surrounding edema, and the eloquence of neighboring neural and vascular structures. In most cases, cerebellar lesions may be removed through a suboccipital craniectomy, whereas spinal lesions are best addressed from a posterior direction through a laminectomy approach.

Contraindications

As always, surgical resection should be offered to the patient unless the risk of operation outweighs its potential benefits. Acute anticoagulation, the presence of active systemic infection, and severe medical problems that would make general anesthesia too risky generally are considered contraindications for an elective neurosurgical operation. However, the decision should be made on an individual basis.

Hemangioblastoma Workup

 

Laboratory Studies

• Perform blood tests to help reveal associated lesions that may be a part of the VHL disease complex. Unfortunately, finding polycythemia does not help in diagnosing the tumor.

Imaging Studies

• The diagnostic workup of suspected hemangioblastomas must include, in addition to history, physical, and thorough neurological examination, complete neural axis imaging and abdominal CT scan or ultrasound. The goal of these additional tests is to reveal associated lesions that may be a part of VHL disease complex.
• Radiographically, hemangioblastomas are best diagnosed with MRI. MRI of hemangioblastomas usually shows an enhancing mass clearly delineated from the surrounding brain or spinal cord tissue. The tumor tissue may be hypointense or isointense on precontrast T1-weighted images and hyperintense on T2-weighted images.
• Plain radiographs usually do not aid in diagnosis. Myelography and cisternography, which were considered the tests of choice in the past, now are almost never used in the diagnostic workup of hemangioblastomas.
• Plain computed tomography (CT) scan may reveal hypodensity of the tumoral cyst and associated hydrocephalus. CT scans with intravenous contrast show uniform enhancement of the tumor nodule that, in association with the adjacent cyst, may be extremely characteristic of posterior fossa hemangioblastomas.
• Cerebral and spinal angiography reveals a highly vascular tumor blush, and this diagnostic modality may be extremely useful for assessing the vascular supply to the tumor. This information may help the surgeon during tumor resection.
• In patients with hemangioblastomas, complete neural axis imaging usually is recommended in order to rule out multiple lesions, especially in those cases in which VHL syndrome is either diagnosed or clinically suspected.

Other Tests

• Perform a detailed ophthalmologic evaluation to help reveal associated lesions that may be a part of the VHL disease complex.

Histologic Findings

Histologically, hemangioblastomas are vascular neoplasms. In addition to relatively normal-appearing endothelial cells that line capillary spaces, hemangioblastomas have 2 distinct cellular components that may occur in the same tumor in different proportions. The first type is small, perivascular, endothelial cells that have dark compact nuclei and sparse cytoplasm. Cells of the second type contain multiple vacuoles and granular eosinophilic cytoplasm rich in lipids. These stromal cells may show some nuclear pleomorphism, but mitotic figures rarely are seen. The exact histogenetic origin of stromal cells is unknown, but the latest studies indicate that they may represent a heterogeneous population of abnormally differentiating mesenchymal cells of angiogenic lineage, with some morphological features of endothelium, pericytes, and smooth-muscle cells.^[
Two histological subtypes (cellular and reticular) have been described in primary hemangioblastomas of the central nervous system and have been found to correlate with the probability of tumor recurrence. The reticular subtype is more commonly encountered; the cellular subtype is associated with higher probability of recurrence.
No histologic grading system exists for hemangioblastomas.

Staging

No established histologic grading system exists for hemangioblastomas.

Hemangioblastoma Treatment & Management

Medical Therapy

Because hemangioblastomas are benign tumors and generally are not invasive in nature, they may be cured by surgical excision. Therefore, surgical resection is considered a standard of treatment and should be offered to the patient unless the risk of operation outweighs its potential benefits.
Other therapeutic modalities include endovascular embolization of the solid component of the tumor,which may decrease the vascularity of the tumor and lower blood loss during its resection, and stereotactic radiosurgery of the tumor using either a linear accelerator or a Gamma Knife.Antiangiogenic treatment of hemangioblastoma has also been recently described.

Surgical Therapy

Surgical treatment of hemangioblastomas is total resection, with the main goal being the preservation of surrounding neural tissue.The tumors usually are well demarcated from the surrounding brain or spinal cord, but this border of separation does not contain any particular membrane or capsule.
The surgical approach must be wide enough to avoid compression of the healthy tissues during retraction. Thorough evaluation of preoperative imaging studies is the key to the safest possible exposure of the tumor. In addition to MRI and CT scans, review the angiography findings to identify the principal blood supply to the tumor mass.

Preoperative Details

Prior to surgery, patients should undergo adequate medical evaluation and complete neural axis imaging. Patients and their families must be informed about the risks and possible complications of surgery, particularly the potential for neurological deterioration.

Intraoperative Details

The tumor is usually easy to visualize because of its reddish-colored solid component and the yellow fluid inside the cyst.If the cyst is present, it may be emptied by cutting the covering pial membrane or by aspirating the cystic contents using a syringe with a short small-caliber needle. Decompression of the cyst allows for improved delineation of the interface between the tumor and the brain or spinal cord.
The surface of the tumor may be coagulated with wide bipolar forceps; however, avoid penetration of the tumor itself because of its extreme vascularity and difficulties with hemostasis. Try to dissect the tumor circumferentially by careful coagulation and cutting the small feeding vessels and adhesions between the tumor and the surrounding brain or spinal cord and by putting cottonoid strips into the developing plane to avoid direct pressure on the brain or spinal cord tissue.Once the feeding vessels are identified, they are coagulated and cut. Try to coagulate the arterial feeders prior to the draining veins, but this is not as crucial as it is in arteriovenous malformations.
After the tumor is totally removed, the raw surface of the brain or spinal cord remains relatively bloodless, and the oozing blood stops after a few minutes of gently packing the resection cavity with wet cotton balls, avoiding the need for additional coagulation.
If an associated hydrocephalus exists, it must be addressed separately, usually by means of external ventricular drainage (EVD) prior to tumor resection. After the tumor is removed, the need for permanent shunt placement may be determined by the patient's response to EVD clamping. In most cases, an intramedullary syrinx does not require a separate drainage procedure because it usually resolves after tumor removal.

Postoperative Details

In regards to general surgical management, having blood products available for transfusion is very important because the vascular character of hemangioblastomas may result in serious intraoperative blood loss. Additionally, anesthesia for patients with VHL disease may be quite challenging due to the presence of associated renal and endocrine dysfunction.

Follow-up

Follow-up care for patients with hemangioblastomas should include regular neurological and imaging checks to confirm the absence of tumor recurrence and/or development of distant lesions.

Complications

With an adequate preoperative workup, most complications of surgery for hemangioblastoma may be avoided. Meticulous maintenance of hemostasis, attention to minor details, and great respect for neural and vascular elements may significantly decrease the risk of postoperative complications. The main emphasis, as usual, should be placed on preventing complications rather than on treatment.

Outcome and Prognosis

Long-term results of hemangioblastoma management generally are favorable. Advancement of neuroimaging methods, improvements in microsurgical technique, and the addition of preoperative embolization have significantly lowered morbidity and mortality associated with hemangioblastoma surgery.
Subarachnoid dissemination of hemangioblastomas is extremely rare, and local recurrences after complete tumor resection seem to be more frequent in patients with von Hippel-Lindau (VHL) disease, in patients diagnosed at a young age, and in patients with multiple hemangioblastomas. The results of one study found that resection of brainstem hemangioblastomas is generally a safe and effective treatment for patients with VHL disease. However, due to VHL disease–associated progression, long-term decline in functional status may occur. The recurrence rate varies in different surgical series but generally remains less than 25%. Recently, histological subtype was found to correlate with a probability of hemangioblastoma recurrence, with a 25% recurrence rate in cellular subtype and an 8% recurrence rate in reticular subtype.

Conclusion

Hemangioblastomas are benign tumors of uncertain origin that are located predominantly in the posterior cranial fossa and the spinal cord. Although most hemangioblastomas are sporadic, they are associated with autosomally dominant VHL disease in approximately 25% of cases. The tumors may be solid or cystic, and patients usually present with either focal neurological symptoms or increased intracranial pressure due to obstruction of CSF pathways. Most hemangioblastomas can be cured with surgical resection, and long-term recurrence rates seem to depend on the presence of VHL disease and multicentric lesions.

Future and Controversies

Future treatment of hemangioblastoma will greatly depend on gaining an understanding of its genetic background. Obviously, if identifying a genetic defect responsible for tumor formation and growth becomes possible, this defect could be reversed and tumor growth could be prevented. Also, finding specific genetic and molecular targets in hemangioblastomas may enable treatment using nonsurgical means, with higher success rates and lower risks of complications.

 Photomicrograph shows the classic microscopic appearance of a cerebellar hemangioblastoma with numerous capillaries and polygonal stroma cells shows vacuoles of cytoplasm and hyperchromatic nucleus (hematoxylin-eosin stain, high-power magnification).

 

 

Pseudocholinesterase Deficiency

Background

Pseudocholinesterase deficiency is an inherited enzyme abnormality that results in abnormally slow metabolic degradation of exogenous choline ester drugs such as succinylcholine. A variety of pathologic conditions, physiologic alterations, and medications also can lower plasma pseudocholinesterase activity.

This condition is recognized most often when respiratory paralysis unexpectedly persists for a prolonged period of time following administration of standard doses of succinylcholine.The mainstay of treatment in these cases is ventilatory support until diffusion of succinylcholine from the myoneural junction permits return of neuromuscular function of skeletal muscle. The diagnosis is confirmed by a laboratory assay demonstrating decreased plasma cholinesterase enzyme activity. See the image below.

Noninvasive ventilation. A bilevel positive airway pressure (BIPAP) prototype is shown here. Expiratory positive airway pressure is the expiratory pressure setting that determines the amount of positive end-expiratory pressure that is applied. The inspiratory positive airway pressure setting is the pressure support. The device can be used in spontaneous mode or timed mode (with a mandatory backup respiratory frequency).

 

Genetic analysis may demonstrate a number of allelic mutations in the pseudocholinesterase gene, including point mutations resulting in abnormal enzyme structure and function and frameshift or stop codon mutations resulting in absent enzyme synthesis. Partial deficiencies in inherited pseudocholinesterase enzyme activity may be clinically insignificant unless accompanied by a concomitant acquired cause of pseudocholinesterase deficiency. Clinically significant effects generally are not observed until the plasma cholinesterase activity is reduced to less than 75% of normal.

Pathophysiology

Pseudocholinesterase is a glycoprotein enzyme, produced by the liver, circulating in the plasma. It specifically hydrolyzes exogenous choline esters; however, it has no known physiologic function.

Pseudocholinesterase deficiency results in delayed metabolism of only a few compounds of clinical significance, including the following: succinylcholine, mivacurium, procaine, and cocaine.Of these, its most clinically important substrate is the depolarizing neuromuscular blocking agent, succinylcholine, which the pseudocholinesterase enzyme hydrolyzes to succinylmonocholine and then to succinic acid.

In individuals with normal plasma levels of normally functioning pseudocholinesterase enzyme, hydrolysis and inactivation of approximately 90-95% of an intravenous dose of succinylcholine occurs before it reaches the neuromuscular junction. The remaining 5-10% of the succinylcholine dose acts as an acetylcholine receptor agonist at the neuromuscular junction, causing prolonged depolarization of the postsynaptic junction of the motor-end plate. This depolarization initially triggers fasciculation of skeletal muscle. As a result of prolonged depolarization, endogenous acetylcholine released from the presynaptic membrane of the motor neuron does not produce any additional change in membrane potential after binding to its receptor on the myocyte. Flaccid paralysis of skeletal muscles develops within 1 minute.

In normal subjects, skeletal muscle function returns to normal approximately 5 minutes after a single bolus injection of succinylcholine as it passively diffuses away from the neuromuscular junction. Pseudocholinesterase deficiency can result in higher levels of intact succinylcholine molecules reaching receptors in the neuromuscular junction, causing the duration of paralytic effect to continue for as long as 8 hours.

This condition is recognized clinically when paralysis of the respiratory and other skeletal muscles fails to spontaneously resolve after succinylcholine is administered as an adjunctive paralytic agent during anesthesia procedures.

Epidemiology

Frequency

International

Pseudocholinesterase deficiency is most common in people of European descent; it is rare in Asians.

History

A personal or family history of an adverse drug reaction to one of the choline ester compounds, such as succinylcholine, mivacurium, or cocaine, may be the only clue suggesting pseudocholinesterase deficiency.

Physical

No characteristic physical examination findings correlate with the presence of pseudocholinesterase deficiency.

Causes

Most clinically significant causes of pseudocholinesterase deficiency are due to one or more inherited abnormal alleles that code for the synthesis of the enzyme.

• These abnormal alleles may result in a failure to produce normal amounts of the enzyme or in production of abnormal forms of pseudocholinesterase with altered structure and lacking full enzymatic function, as described below.
• Patients with only partial deficiencies of inherited pseudocholinesterase enzyme activity often do not manifest clinically significant prolongation of paralysis following administration of succinylcholine unless a concomitant acquired cause of pseudocholinesterase deficiency is present. The acquired causes of pseudocholinesterase deficiency include a variety of physiologic conditions, pathologic states, and medications listed below.

Inherited causes

Inherited causes of pseudocholinesterase deficiency include the following:

The gene that codes for the pseudocholinesterase enzyme is located at the E1 locus on the long arm of chromosome 3, and 96% of the population is homozygous for the normal pseudocholinesterase genotype, which is designated as EuEu.

The remaining 4% of the population carries one or more of the following atypical gene alleles for the pseudocholinesterase gene in either a heterozygous or homozygous fashion.

Table 1. Atypical Gene Alleles for the Pseudocholinesterase Genotype

In individuals with an inherited form of pseudocholinesterase deficiency, only a single atypical allele is carried in a heterozygous fashion, resulting in a partial deficiency in enzyme activity, which manifests as a slightly prolonged duration of paralysis, longer than 5 minutes but shorter than 1 hour, following administration of succinylcholine. Less than 0.1% of the general population carries 2 pseudocholinesterase gene allele mutations that will produce clinically significant effects from succinylcholine lasting longer than 1 hour.

One rare variant allele of the pseudocholinesterase gene, designated the C5 variant, actually has higher than normal enzyme activity, resulting in relative resistance to the paralytic effects of succinylcholine.

The dibucaine-resistant genetic variant form of pseudocholinesterase is identified by the percent inhibition of hydrolysis of benzyl choline caused by the addition of dibucaine to the pseudocholinesterase enzymatic assay. The dibucaine number is the percent inhibition of hydrolysis of benzyl choline by dibucaine added to the plasma sample. The normal dibucaine number for the homozygous typical genotype (EuEu) is 80%. Individuals homozygous for the atypical dibucaine resistant genotype (EaEa) have a dibucaine number of 20%, which correlates with a marked prolongation of the paralytic effect of standard doses of succinylcholine to well over 1-hour duration. Heterozygotes (EuEa) have intermediate dibucaine numbers and modest prolongation of muscle paralysis with succinylcholine. The EuEa heterozygous genotype is found in 2.5% of the general population, making it more common than all other abnormal pseudocholinesterase genotypes combined.

The fluoride-resistant pseudocholinesterase enzyme variant is identified by its percent inhibition of benzyl choline hydrolysis when fluoride is added to the assay. The fluoride number (percentage inhibition of enzyme activity in the presence of fluoride) is 60% for the EuEu genotype and is 36% for the EfEf genotype. This homozygous fluoride-resistant genotype exhibits mild to moderate prolongation of succinylcholine-induced paralysis. The heterozygous fluoride-resistant genotype usually is clinically insignificant unless accompanied by a second abnormal allele or by a coexisting acquired cause of pseudocholinesterase deficiency.

The most severe form of inherited pseudocholinesterase deficiency occurs in only 1 in 100,000 individuals who are homozygous for the silent Es genotype, with no detectible pseudocholinesterase enzyme activity. These individuals may exhibit prolonged muscle paralysis for as long as 8 hours following a single dose of succinylcholine. Gene mutations that produce silent alleles are caused by frameshift or stop codon mutations, resulting in no functional pseudocholinesterase enzyme synthesis.

Acquired causes

Acquired causes of pseudocholinesterase deficiency include the following:

People, such as neonates, elderly individuals, and pregnant women, with certain physiologic conditions may have lower plasma pseudocholinesterase activity.

Pathologic conditions that may lower plasma pseudocholinesterase activity include the following:

• Chronic infections (tuberculosis)
• Extensive burn injuries
• Liver disease
• Malignancy
• Malnutrition
• Organophosphate pesticide poisoning
• Uremia

Iatrogenic causes

Iatrogenic causes of lower plasma pseudocholinesterase activity include plasmapheresis and medications such as the following:

• Anticholinesterase inhibitors
• Bambuterol
• Chlorpromazine
• Contraceptives
• Cyclophosphamide
• Echothiophate eye drops
• Esmolol
• Glucocorticoids
• Hexafluorenium
• Metoclopramide
• Monoamine oxidase inhibitors
• Pancuronium
• Phenelzine
• Tetrahydroaminacrine
   

  Laboratory Studies

  Diagnosis of pseudocholinesterase deficiency is made by plasma assays of pseudocholinesterase enzyme activity.

  • A sample of the patient's plasma is incubated with the substrate butyrylthiocholine along with the indicator chemical 5,5'-dithiobis-(2-nitrobenzoic acid), which will produce a colored product that is assayed using spectrophotometry. The resulting amount of spectrophotometric absorption is proportionate to the pseudocholinesterase enzyme activity that is present in the patient's plasma sample.
  • Because succinylcholine metabolites can interfere with this assay, plasma samples should be collected after muscle paralysis has completely resolved.
  • The dibucaine and fluoride numbers can be determined by repeating this assay in the presence of standard aliquots of either dibucaine (0.03 mmol/L) or fluoride (4 mmol/L) in the reaction mixture to determine the percent inhibition of enzyme activity caused by these agents.

  A simplified screening test of pseudocholinesterase enzyme activity can be performed using the Acholest Test Paper. When a drop of the patient's plasma is applied to the substrate-impregnated test paper, a colorimetric reaction occurs. The time it takes the exposed Acholest Test Paper to turn from green to yellow is inversely proportional to the pseudocholinesterase enzyme activity in the plasma sample.

  Table 2. Reaction Times for Acholest Test Paper 

  Reaction Time	Pseudocholinesterase Enzyme Activity
  < 5 min	Above normal
  5-20 min	Normal
  20-30 min	Borderline low
  >30 min	Below normal

  Imaging Studies

  No imaging studies aid in the diagnosis of pseudocholinesterase deficiency.

  Other Tests

  The complete DNA sequence and amino acid structure of both the normal pseudocholinesterase protein and most of its abnormal variants have now been identified. However, molecular genetic techniques such as polymerase chain reaction (PCR) amplification with allele-specific oligonucleotide probes for identifying abnormal pseudocholinesterase genotypes presently are available only in a limited number of research laboratories and are not in routine clinical use.

  Histologic Findings

  No characteristic alteration in liver histology is associated with genetic mutations in pseudocholinesterase enzyme synthesis.

  
  

  Medical Care

  • Pseudocholinesterase deficiency is a clinically silent condition in individuals who are not exposed to exogenous sources of choline esters.
  • Patients with prolonged paralysis following administration of succinylcholine can be treated in the following ways:

    • Prophylactic transfusion of fresh frozen plasma can augment the patient's endogenous plasma pseudocholinesterase activity. This practice is not recommended because of the risk of iatrogenic viral infectious complications. However, perioperative transfusion of fresh frozen plasma administered to correct a coagulopathy may mask an underlying pseudocholinesterase deficiency.
    • Mechanical ventilatory support is the mainstay of treatment until respiratory muscle paralysis spontaneously resolves. Recovery eventually occurs as a result of passive diffusion of succinylcholine away from the neuromuscular junction.
    • Administration of cholinesterase inhibitors, such as neostigmine, is controversial for reversing succinylcholine-related apnea in patients who are pseudocholinesterase deficient. The effects may be transient, possibly followed by intensified neuromuscular blockade.

  Consultations

  • Consultation with a geneticist may help to identify the specific atypical genotype alleles contributing to pseudocholinesterase deficiency.
  • Because the DNA sequence of the pseudocholinesterase gene and its amino acid structure is known, atypical alleles now can be identified by PCR amplification studies using DNA extracted from leukocytes in a blood sample.
     

    Complications

    • The main complication resulting from pseudocholinesterase deficiency is the possibility of respiratory failure secondary to succinylcholine or mivacurium-induced neuromuscular paralysis.
    • Individuals with pseudocholinesterase deficiency also may be at increased risk of toxic reactions, including sudden cardiac death, associated with recreational use of cocaine.

    Prognosis

    • Prognosis for recovery following administration of succinylcholine is excellent when medical support includes close monitoring and respiratory support measures.
    • In nonmedical settings in which subjects with pseudocholinesterase deficiency are exposed to cocaine, sudden cardiac death can occur.

    Patient Education

    • Patients with known pseudocholinesterase deficiency may wear a medic-alert bracelet that will notify healthcare workers of increased risk from administration of succinylcholine.
    • These patients also may notify others in their family who may be at risk for carrying one or more abnormal pseudocholinesterase gene alleles.