Basal Ganglia T1 Hyperintensity in Hereditary Hemorrhagic Telangiectasia

Discussion

In this study, basal ganglia T1 hyperintensity was present in >23% of patients with definite HHT. There was a statistically significant association between this imaging finding and increased patient age, hepatic vascular malformations, hepatic dysfunction, and elevated cardiac output. There was no significant association with sex, genetic mutation status, cerebral AVMs, or gross neuropsychiatric derangement. These findings are in accordance with the prevailing hypothesis that intracranial deposition of paramagnetic manganese in the presence of hepatic AVMs is responsible for basal ganglia hyperintensity, a phenomenon that has been described in other disease processes in which hepatic metabolism of manganese is impaired or bypassed.¹² Moreover, these findings are important because they suggest that the degree of shunting required to produce basal ganglia hyperintensity appears to be associated with hepatic dysfunction and increased cardiac output, both of which may entail further metabolic derangements and a worse prognosis.

The prevalence of basal ganglia hyperintensity in the present investigation was less than the rate described in a recent study of 139 patients (23% versus 38%); this prevalence may reflect the lower overall rate of hepatic AVMs in our cohort (30% versus 45%).¹³ This could be due to a difference in the prevalence of ENG versus ALK1 mutations in each study population, with hepatic AVMs and the high cardiac output state being much more common in those with the ALK1 mutation. Older age, higher cardiac output, and increased prevalence of hepatic dysfunction in the bright basal ganglia group merit further discussion. Hepatic vascular involvement in HHT results in shunting involving portal vein to hepatic vein, hepatic artery to portal vein, or hepatic artery to hepatic vein. It is the hepatic artery–hepatic vein shunting that results in a high cardiac output state. A recent large nationwide study of patients with HHT in the United States found that most (∼75%) patients with a high cardiac output state were older than 60 years of years of age.³ Similarly, almost 60% of patients with cirrhosis were also older than 60 years of age in that study. Thus, the finding of high cardiac output and liver dysfunction among older patients in our study in the bright basal ganglia group is not a surprise.

Predicting liver disease in HHT is an important topic because substantial liver disease can often be present in otherwise asymptomatic patients. In a multivariate prediction model, Singh et al¹⁴ reported that increasing age, female sex, higher alkaline phosphatase levels, and lower hemoglobin levels were all predictive of clinically significant liver disease among patients with HHT. Our study confirms these findings, with older age and higher alkaline phosphatase levels being more common in the bright basal ganglia group. Thus, it appears that bright basal ganglia occur more frequently in the same group of patients previously shown to have higher rates of clinically significant HHT-related liver disease. These congruent findings further validate our study hypothesis and results.

Manganese deposition has been associated with neurotoxicity in certain at-risk populations. In a recent study of workers with occupational exposure to manganese, Shin et al¹⁵ found a dose-response relationship between T1 signal intensity and serum manganese levels and further described an inverse relationship between signal and neurobehavioral performance, positing that signal intensity may predict performance in workers exposed to the element. In the present study, increased basal ganglia signal intensity was not associated with gross neurologic disturbances, though subclinical neurologic dysfunction may have existed at the time of imaging. Given the absence of overt neurologic manifestations, however, the association between basal ganglia T1 hyperintensity and liver dysfunction and elevated cardiac output highlights the importance of screening MR imaging.

Current guidelines recommend Doppler sonography or CT screening of adult patients with abnormal hepatic enzymes or clinical features suggestive of hepatic vascular malformations (ie, high output cardiac failure, liver failure, intestinal ischemia, or hepatic encephalopathy).¹⁶ Our findings suggest that basal ganglia hyperintensity on screening brain MR imaging may be the only evidence of a subclinical hepatic AVM. In this setting, it may be appropriate to raise this possibility and recommend additional imaging and diagnostic studies to determine the presence of liver AVMs along with hepatic dysfunction and a high cardiac output state. Each of these entities worsens prognosis in patients with HHT and requires specific decisions with regard to follow-up and treatment options.² Most important, early detection of potentially consequential yet preclinical hepatic vascular malformations may facilitate timely intervention and ultimately lead to improved patient outcomes.