Pulmonary arteriovenous malformations

Patient selection.

Patients were referred to our center when they had clinical evidence of HHT or radiologic evidence of a PAVM. Routine screening included a chest radiograph (CXR) and arterial oxygen measurement (PaO_{2). Those with abnormally low PaO2} levels and a normal CXR underwent thoracic CT scan. When a PAVM was suggested on CXR or thoracic CT and PaO₂ was <92 mm Hg, patients were admitted for diagnostic pulmonary angiography and possible therapeutic PAVM occlusion. A diagnosis of HHT was given if patients satisfied clinically accepted criteria.13

Pulmonary evaluation.

Digital subtraction angiography was performed by selective injection of contrast material into each pulmonary artery according to standard techniques.10 Angiograms were reviewed independently by two interventional radiologists. Diameters of the PAVM feeding arteries (FA) were measured at the site of proposed occlusion, according to the methods described in a previous publication.10 The maximum diameter of the aneurysmal sac connecting the pulmonary artery to the pulmonary vein was also measured. All measurements were made by comparison with the reference diameter of the catheter and performing standard calculations to correct for magnification. When only one lung was injected, it was assumed that there was no PAVM in the contralateral lung if no abnormality was present on CXR or CT and if postocclusion arterial PaO₂ levels were normal.

Patients were included in this study if they had single or multiple PAVM. Patients with single PAVM were defined as having a solitary PAVM with an FA diameter of ≥3 mm (figure). Patients with multiple PAVM were defined as having two or more PAVM with an FA diameter of ≥3 mm. The 3-mm value was selected based on our previously published experience and our empirical clinical observations of no cerebral ischemic events in patients with PAVM FA diameters below that size.9,10,14-16⇓⇓⇓⇓

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Figure. Pulmonary angiogram demonstrates a single arteriovenous malformation comprising an aneurysmal dilation (A), a feeding artery (FA), and two draining veins (DV).

Neurologic evaluation.

During hospitalization, patients were interviewed and examined by a neurologist. The interview focused on the potential neurologic complications of HHT, and all available medical records were used to supplement the patient history. All available cerebral imaging studies were reviewed.

Patient history and medical records were used to determine the prevalence of migraines and seizures. History and cerebral imaging, MRI and CT, were used to determine the prevalence of abscesses and intracranial hemorrhages. The prevalence of CVM was based on history and MRI.

Assessment of cerebral ischemia.

Cerebral ischemic events were defined as clinical symptoms or deficits or imaging abnormalities due to ischemia at any location in the hemispheres or posterior fossa. All clinical events or radiologic lesions due to migraine, seizure, abscess, hemorrhage, or CVM were excluded from this analysis.

Infarcts on imaging studies were categorized according to location as cortical or subcortical, as superficial cortical infarctions are most likely caused by emboli whereas deep subcortical infarctions are more commonly caused by local vasculopathy due to lipohyalinosis or microatheromatous disease of the small penetrating vessels.17 Cortical infarctions pertained to lesions in the cortex of the hemispheres or cerebellum as determined on MRI or CT, as their sensitivity is similar for detecting this pathology. Distinctive small subcortical infarcts in the hemispheres or posterior fossa were determined exclusively by MRI, given its greater sensitivity.18 Small subcortical infarcts were defined as being ≤1.5 cm in diameter and were distinguished from larger subcortical (striatocapsular) infarcts that are commonly embolic in etiology. Therefore, a cortical infarction on MRI or CT was considered the most sensitive indicator of cerebral embolization and was the primary endpoint used in determining the prevalence of paradoxical embolization.

Clinical cerebral ischemic events were similarly divided into cortical and subcortical groups by a neurologist according to the presence or absence of cortical symptoms and deficits.

Patients with accepted or possible risk factors for cerebral vascular disease (hypertension, diabetes, hypercholesterolemia, atrial fibrillation, coronary artery disease, mitral valve disease, tobacco use) were not excluded from analysis, but the risk factors were noted.

Data analysis.

For all outcomes analyzed, single PAVM was considered as lower risk and multiple PAVM as greater risk. The SAS (PC version 6.12) (SAS Data Corporation, Cary, NC) procedure PROC FREQ was used to determine OR, their 95% CI, and p values for comparing odds. OR were calculated using frequency values according to the following equation: OR = [(single PAVM without disease) × (multiple PAVM with disease)]/[(single PAVM with disease) × (multiple PAVM without disease)]. The 95% CI was listed for each OR. The p values associated with each OR presented were determined by the χ² method if all four values were >5 or by Fisher’s exact test (two-tailed) if any of the four values was <5. Wilcoxon scores (rank sums) for FA diameters in infarct and noninfarct cases were determined by the SAS (PC version 6.12) (SAS Data Corporation, Cary, NC) procedure PROC NPAR1WAY with option WILCOXON and used to determine their distribution differences.

Patients.

Seventy-five patients had PAVM with an FA diameter of ≥3 mm. HHT was clinically present in 72 (96%) of patients. Baseline demographics and evaluations are detailed in table 1 .

Pulmonary evaluation.

Twenty-six patients (35%) had a single PAVM and 49 (65%) had multiple PAVM. Two patients had a unilateral angiogram only, but they had a normal CXR of the contralateral lung and normal postocclusion PaO₂.

Patients with a single PAVM had a mean FA diameter of 6.6 mm and a median diameter of 5.2 mm (range 3 to 16.1 mm). The mean aneurysmal sac maximum diameter in this group was 30.4 mm and the median diameter was 25.5 mm (range 9.5 to 90.5 mm). One patient with single PAVM had no PAVM aneurysm but only a fistula. Five patients with single PAVM (19%) had one additional minor PAVM (<1 mm FA), and one patient (4%) had two minor PAVM.

Neurologic evaluation.

A complete neurologic evaluation was performed at our institution on 58 (77%) patients, and the remainder had an outside evaluation. The prevalence and type of neurologic manifestations are summarized in table 2 . The prevalence of abscesses and seizures in patients with multiple PAVM was at least twice that of patients with single PAVM, but the differences were not significant. Seizures in patients with multiple PAVM were closely related to the presence of abscesses and cortical infarctions. Four patients had abscesses, four had cortical infarctions, one had a cortical infarct and a vascular malformation, and one had no obvious focal lesion on MRI. No patients had intracranial hemorrhage. The overall prevalence of clinical ischemic events and radiologic infarctions is also included in table 2.

Cerebral ischemia.

The prevalence of imaging lesions in patients with single and multiple PAVM is summarized in table 3 . OR of cortical and subcortical infarctions for patients with multiple PAVM were generally on a magnitude of at least two. The difference in prevalence of any infarction between patients with single and multiple PAVM was significant. No patients had large subcortical (striatocapsular) infarcts. The prevalence of clinical ischemic events is also listed in table 3. Of patients with complete records, ∼64% (29/45) of patients with multiple PAVM and 29% (6/21) of patients with a single PAVM had clinical or radiologic evidence of ischemic involvement (OR = 4.5, 95% CI 1.47 to 14, p = 0.008).

Among patients with a single PAVM, FA diameters tended to be larger in those who did not have cortical infarctions. The mean FA diameter for patients with cerebral infarction was 4.2 mm and the median was 4.3 mm (range 3.5 to 4.9 mm). In patients without cerebral infarction, the mean FA diameter was 6.9 mm and the median was 6 mm (range 3 to 16.1 mm). As determined by Wilcoxon scores (rank sums), the distributions of FA diameters in infarct and noninfarct cases were not significantly different.

Aneurysmal sac sizes were also larger in patients who did not have cortical infarctions. The range, median, and mean aneurysmal maximum diameters for infarct patients were 16.2 to 22, 21.6, and 19.9 mm. The corresponding dimensions for noninfarct patients were 9.5 to 90.5, 27.6, and 31.9 mm.

The distribution of cerebrovascular risk factors is provided in table 4 . A similar frequency of risk factors was present in the single and multiple PAVM groups. When patients with vascular risk factors were excluded from the analysis, the prevalence of radiologic cortical infarctions became 11% (2/18) in patients with a single PAVM and 22% (8/36) in patients with multiple PAVM. If only patients with hypertension or diabetes were excluded, the prevalence of small deep subcortical infarctions was 27% (4/15) and 41% (13/32) in the single and multiple PAVM groups.