Arteriovenous Malformations of the Central Nervous System

Etiology

Though the exact mechanism of AVM formation is not fully understood, they are believed to form secondary to an abnormal arrest during embryologic vascular development. Approximately 5% of AVMs are identified in patients with inherited disorders such as autosomal dominant hereditary hemorrhagic telangiectasia, also known as Osler-Weber-Rendu syndrome.[6][7] Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is a more recently described systemic disorder of autosomal dominant inheritance with multiple small AVMs in the limbs and face.[7] 

Multiple genetic mutations have been noted in patients with sporadic AVMs, including somatic activating KRAS mutations, the stop-gain mutation in SMAD9, and an increase in Notch-3 receptor expression.[8][9][10] Increased KRAS activity leads to increased MAPK/ERK pathway activity with downstream elevations in Notch signaling and angiogenesis factors.[8] A significantly lower level of SMAD9 in AVM vessels was observed, as well as a decrease in SMAD4 phosphorylation. SMAD4 is a downstream factor in the MAPK/ERK pathway.[9] In 2015, Hill-Fellberg et al discovered a significant increase in Notch-3 receptor expression in AVM vasculature compared to brain samples without AVM. In addition, they found a significant decrease in Notch-1 and an increase in Notch-4 receptors.[10] More recently, in 2020, Hauer et al evaluated genetic alterations in AVMs via next-generation RNA sequencing of 12 AVMs compared to 16 healthy controls. Over 700 genes were upregulated in the AVM samples, including those involved in transforming growth factor-β (TGF-β) signaling, the extracellular matrix composition, inflammation, and the angiotensin-Tie pathway.[11]

AVMs also occur within the spinal canal, comprising 3% to 4% of all space-occupying spinal lesions and 5% to 9% of all central nervous system vascular malformations.[12] Patients with hereditary hemorrhagic telangiectasia are also predisposed to spinal AVMs.[5] Other genetic syndromes with a predisposition to spinal AVMs are Klippel-Trenaunay syndrome, Parkes-Weber Syndrome, and the spinal arteriovenous metameric Cobb Syndrome.[4]

Epidemiology

Up to 88% of intracranial AVMs are asymptomatic. Of those symptomatic, 45% present with hemorrhage.[13] The A Randomized Trial of Unruptured Brain AVMs (ARUBA) trial identified a 2.2% annual risk of hemorrhage for unruptured cerebral AVMs.[14] The incidence of AVMs is 1.12 to 1.34 per 100,000 persons, which is significantly lower than cerebral aneurysms and other cerebral vascular malformations.[15] There is no significant sex predisposition in adults.[6] A meta-analysis by Gross and Du published in 2013 reported the average age at presentation was 33.7 years old, with 36% to 38% of initial presentations in the form of a first-time hemorrhage.[16] 

There is a 0.02% incidence of intracranial AMVs in the pediatric population without sex predilection. Pediatric spinal AVMs occur at 10% the rate of cerebral AVMs and have a five-fold predilection for boys.[4][5] Spinal AVMs commonly present clinically in the third decade, but patients aged less than 16 years comprise 20% of cases.[4]

Pathophysiology

Arteriovenous malformations are abnormal arterial to venous structural connections without capillaries or intervening cortical tissue. AVMs demonstrate nonphysiological hemodynamics, which affects the structure of the vessels within; they are typically high-flow, low-resistance shunts. Elevated hydrostatic pressure is a postulated contributing risk to hemorrhage.[13] Cerebral AVM rupture can lead to significant intraparenchymal hemorrhage or seizures secondary to microhemorrhages, resulting in cortical irritation. Spinal AVMs may rupture due to vascular instability. Arterialized venous architecture leads to vascular hypertension, which then exerts a mass effect on surrounding neural tissues and ischemic injury, leading to progressive myelopathy, paresthesias, motor deficits, or bowel or bladder dysfunction.[17]

Histopathology

Histopathological examination may reveal a wide range of vascular wall composition, from mature arterial and venous structures to immature, thin, and hyalinized walls. Focal regions of wall hyalinization may protrude into vessel lumens. Intimal and smooth muscle layers are often malformed or disrupted.[6] Capillary architecture and intervening normal cortical tissue are not seen. Hemosiderin staining from prior microhemorrhages is very common, even without clinical symptoms.[6]

History and Physical

Intracranial hemorrhage can result from a variety of pathologies, including chronic hypertension, amyloid angiopathy, vascular malformations, and trauma. Vascular malformations such as aneurysms and AVMs are more likely in patients presenting without trauma, aged second through sixth decades of life, with significant smoking history, and the simultaneous presence of other vascular malformations. The family history may include hereditary hemorrhagic telangiectasia or multiple vascular malformations. 

The physical examination findings of a patient with an AVM are highly dependent on the location of the intracranial or spinal AVM and the presence or absence of acute hemorrhage. Intracranial AVMs in adults most commonly present with acute hemorrhage. Acute intracranial AVM hemorrhage may lead to weakness, sensory changes, cranial nerve palsies, seizures, or an altered level of consciousness, depending on location and mass effect. AMVs are responsible for 33% of intracranial hemorrhage in patients in the third and fourth decades of life; seizures are the second-most common presenting sign and are seen in 27% of patients.[2] Seizure presentation is more common with AVMs within the temporal lobes. Other less common presentations include focal neurologic deficits from mass effect, headaches, and vascular steal phenomena. 

Two different symptomologies are typically seen in patients with spinal AVMs. An acute hemorrhage presenting with the sudden onset of severe back pain may be accompanied by lower extremity motor weakness, sensory deficits such as paresthesias and numbness, and bladder or bowel dysfunction. Alternatively, an unruptured spinal AVM may present with chronic progressive low back pain or lower extremity neurologic deficits secondary to progressive mass effect on the spinal cord.[18] Foix-Alajouanine syndrome has a characteristic presentation, defined as an acute or subacute onset of myelopathy secondary to spinal cord venous thrombosis that induces spinal cord ischemic injury and necrosis.[5] 

Evaluation

Imaging studies are essential in the evaluation of intracranial and spinal AVMs. Patients presenting with headaches or neurologic deficits should undergo initial imaging via computed tomography (CT) of the head without contrast. A noncontrast head CT can reveal acute intraparenchymal hemorrhage, subarachnoid hemorrhage, or intraventricular hemorrhage and rule out ischemic injury, lesions, masses, and other nonhemorrhagic pathologies. A noncontrast head CT may demonstrate only a subtle hyperdensity in a patient with an unruptured AVM, making detection difficult.[19] 

CT angiography provides excellent spatial resolution of vascular architecture. Valuable information about the AVM nidus structure, deep draining veins, possible aneurysms within the AVM, and significant feeding arteries can be visualized with CT angiography.[19] A study by Gross et al demonstrated that CT angiography detected 90% of cerebral AVMs, as opposed to magnetic resonance angiography (MRA), which was only 74% sensitive.[20] Digital subtraction catheter cerebral angiogram (DSA) is the gold standard for vascular imaging, with higher spatial and temporal sensitivity than noninvasive imaging modalities.[21] 

Magnetic resonance imaging (MRI) of the cervical, thoracic, and lumbar spine, with and without contrast, is the recommended initial diagnostic imaging evaluation for spinal AVMs. MRI can also exclude mass lesions, infectious pathology, spinal cord injury, discogenic mass effect, and epidural fluid collections.[18] Contrast-enhanced MRA provides significant spatial resolution and is a valuable adjunct before DSA for evaluating feeding vessels.[22] The gold standard for spinal vascular evaluation is spinal DSA, which provides a substantially more detailed view of vascular anatomic architecture and shows temporal flow through feeding and draining vessels.  

In addition to imaging modalities, an initial laboratory evaluation must be performed to determine patient coagulation status, renal function before contrast use in imaging modalities, and overall health status before considering possible interventions. These laboratory studies include but are not limited to a complete blood count with differential, comprehensive metabolic panel, internationalized normal ratio (INR), prothrombin time (PT), partial thromboplastin time (PTT), and type and screen for possible blood transfusion. 

Treatment / Management

Spetzler-Martin Arteriovenous Malformation Grading System

The primary treatment modalities for intracranial and spinal AVMs include surgical resection, endovascular embolization, stereotactic radiosurgery, or conservative management. The Spetzler-Martin AVM Grading System was developed in 1986 to determine the risk of morbidity and mortality of open surgical resection of intracranial AVMs. The grading system requires a correlation between neuroimaging and cerebral angiographic findings. Graded neuroimaging findings include the size and site of the nidus, and graded angiographic findings include the size of the nidus and the pattern of venous drainage. Points are assigned for each finding, and a grade is calculated.[23] The assigned grade is equal to the sum of points from 3 categories; the minimum is Grade I (1 point), and the maximum is Grade V (5 points).[23] There is an additional special designation of Grade VI.[23]

• Size of Nidus
  • small, < 3 cm = 1 point
  • medium, 3 to 6 cm = 2 points
  • large, > 6 cm = 3 points
• Venous Drainage
  • superficial veins only = 0 points
  • deep veins = 1 point
• Eloquence of Adjacent Brain
  • noneloquent = 0 points
  • eloquent = 1 point

The areas of the brain considered eloquent are the sensory, motor, language, or visual cortex; internal capsule; hypothalamus and thalamus; brainstem; superior, middle, and inferior cerebellar peduncles; and deep cerebellar nuclei.[23] Venous drainage is considered deep if any drainage is to the deep cerebral veins or cerebellar hemispheric veins unless they drain into the straight or transverse sinuses.[23] 

Interventions for Intracranial Arteriovenous Malformations

Indications for urgent intervention include symptomatic or progressive neurologic deficits and intractable seizures not amenable to medical management. Often, surgical resection if preferred for superficial lesions, while radiosurgery is preferred for locations in the deep brain including the basal ganglia, thalamus and brainstem.[24]

The risk of perioperative morbidity and mortality increases with increasing Spetzler-Martin grade. This grading system does not necessarily correlate with risks associated with endovascular embolization or stereotactic radiosurgery. However, Spetzler-Martin grades I and II AVMs are usually managed with open surgical resection, grade III with endovascular embolization, and grades IV and V with stereotactic radiosurgery.[25] Endovascular embolization can be used to decrease the AVM nidus volume prior to stereotactic radiosurgery.[21] The ultimate goal of intervention is to obliterate the AVM nidus and all arteriovenous shunt locations. Grade VI AVMs are considered inoperable.[23] 

The risk of AVM rupture was evaluated in the A Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA) trial. This study revealed a decreased risk of stroke and mortality in patients managed conservatively versus patients who underwent interventional therapy.[13]  The ARUBA trial compared medical management alone to medical management with prophylactic intervention, be it surgical, endovascular, radiosurgical, or a combination thereof. Out of 223 patients with a mean follow-up of 33.3 months, the primary endpoint of death from any cause or stroke occurred in 11 of 109 (10.1%) patients in the medical group, compared with 35 of 114 (30.7%) in the interventional group. These data led to the discontinuation of the study after 6 years.[15] This study may overestimate the risk of surgery and underestimate the risk of medical management as surgical complications are usually evident in the short-term, while the risks of medical management are related to the long-term risks of rupture or mass effect.(B2)

Interventions for Spinal Arteriovenous Malformations

Treatment of spinal AVMs involves surgical resection, endovascular embolization, or a combination of methods. The main goal of treatment is to halt the progression of neurologic deficits secondary to mass effect or vascular steal phenomenon, as well as minimize permanent deficits.[5] Gross et al found a 10% annual rate of spinal AVM repeat hemorrhage, which has led to significant consideration for a more urgent intervention timeline.[26] Neurologic deficits after acute hemorrhage often improve with time, though some may have fixed neurologic deficits. In some cases, occlusion of an AVM may prevent the worsening of the current neurologic deficits.[27] (A1)

Differential Diagnosis

Intracranial AVMs can be diagnosed after symptomatic presentation, such as hemorrhage, mass effect, or seizures. Intracranial AVMs are also frequently diagnosed in asymptomatic patients undergoing cranial imaging for an unrelated evaluation. The differential diagnosis of a patient presenting with an acute intracranial hemorrhage includes AVM, ruptured aneurysm, dural arteriovenous fistula, cerebral amyloid angiopathy, hemorrhagic tumor, lacunar hemorrhage secondary to hypertensive lipohyalinosis, and traumatic injury. For patients presenting with seizures, the differential diagnosis includes pathologies that lead to cerebral edema, such as AVM, tumor, abscess, meningitis, and hydrocephalus, or neurologic etiologies of seizure disorders, including focal cortical dysplasia, mesial temporal sclerosis, and hereditary seizure disorders. 

For patients with a spinal AVM who present with acute or progressive neurologic deficits and back pain, the differential diagnosis includes mass effect secondary to spinal cord tumor, disc herniation, osteomyelitis, diskitis, pathologic fractures, degenerative disk disease, acute traumatic injury, and vascular malformations. The majority of patients with spinal AVMs present after chronic progressive neurologic decline.[5] 

Radiation Oncology

The Spetzler-MartinAVM Grading System is an essential tool for determining the appropriate management of intracerebral AVMs, be it open surgical resection, endovascular treatment, or a radiosurgical approach. AVMs smaller than 3cm in diameter with deep draining veins within the eloquent cortex are ideal for stereotactic radiosurgery as the morbidity and mortality of open surgical resection of these lesions are the highest. Stereotactic radiosurgery (SRS) can achieve a 70% to 90% obliteration rate in appropriately selected patients. The standard single dose in these cases is 22 Gy (50% isoline dose).[28] Radiosurgical treatment for AVMs measuring greater than 10 cm in diameter is still under investigation; multiple dose fractions are needed to deliver adequate radiation dose and minimize adjacent cerebral edema. The complications of SRS for AVM treatment include seizure and hemorrhage. The primary consideration of SRS in AVM management is that obliteration and radiation effects take 2 to 3 years to occur.[28] 

Prognosis

The prognosis of an intracranial AVM is dependent on a history of rupture. Unruptured AVMs have a 2.2% annual risk of rupture, and previously ruptured AVMs have a 4% annual risk.[28] In 2019, Fengali et al introduced a predictive index to stratify the risk of hemorrhage, called the R2eED AVM Score. Factors that increased risk were a small nidus size, non-White ethnicity, deep location, the presence of a single arterial feeder, and deep venous drainage.[29] The volume and location of rupture determine residual neurologic deficit burden and functional recovery. 

Complications

There is debate over the management of intracranial AVMs, as the risk of surgical treatment complications must be weighed against the risk of lesion rupture or repeat rupture. Surgical complications include stroke, intracranial hemorrhage, seizure, and death. The ARUBA trial evaluated the cumulative outcomes of intervention for unruptured AVMs compared to outcomes of observation, with a significantly increased rate of death from any cause or stroke in the intervention group.[14] Other complications of intracranial AVMs include the vascular steal phenomenon and mass effect.

Complications of spinal AVMs include rupture with subsequent hemorrhage and neurologic deficits secondary to progressive mass effect.