Widening the Neuroimaging Features of Adenosine Deaminase 2 Deficiency

DISCUSSION

In this series, we identified a wide spectrum of neuroimaging abnormalities associated with DADA2, including 2 novel imaging patterns. All patients presented a vascular phenotype, as expected in most patients harboring missense mutations,⁵ but none had hematologic disorders besides hypogammaglobulinemia. Neurologic involvement at presentation was common (33% of cases). As previously shown,^2,14 small, multiple ischemic infarcts in the nucleocapsular and mesencephalic or thalamic regions were the most frequent MR imaging abnormality, being present in 75% of our patients and reflecting the prevalent involvement of deep perforators. Before treatment with anti-TNF, thalidomide, or both, new ischemic lesions developed in half of patients at follow-up studies.^4,7,13,15 Conversely, no new neurologic events or MR imaging lesions were noticed afterward, except for 2 recurrences shortly after introduction of anti-TNF or temporary discontinuation of thalidomide. Of note, the prevalence of ischemic strokes in our cohort was similar to that reported by Bulut et al¹⁴ in patients with DADA2-related vasculopathy and was expectedly higher than that described in a review also including patients with purely hematologic phenotypes (around 40%).⁶ Interestingly, some patients presented with small lacunar strokes clearly depicted on DWI at clinical onset that were difficult to distinguish from enlarged perivascular spaces in follow-up examinations probably because of their small size and progressive gliotic “healing” changes. This suggests a possible underestimation of these subtle findings if brain MR imaging studies are not performed in the acute stage or with high spatial resolution sequences. As previously identified in a few patients with DADA2,^14,15 we found an additional small ischemic medullary infarct at the cervical level in 1 patient. Of note, spinal cord involvement in individuals with DADA2 might also be underrated because only a minority of patients underwent a spinal MR imaging in both the current and in Bulut et al’s series.¹⁴

Intracranial hemorrhagic strokes are additional complications of DADA2,^1,2,6,11,12 involving nearly 12% of cases in a recent review⁶ and 17% in our cohort. These hemorrhages may occur in isolation^1,12 or in association with ischemic strokes,^2,12 as seen in our patients. In most published cases, no underlying causes were found. Conversely, 2 intracranial aneurysms were detected in 1 of our patients presenting with diffuse subarachnoid hemorrhage and a history of peripheral intracranial aneurysm and lobar hematoma. Of note, CNS aneurysms have been described only once in a patient with DADA2¹ and in a few patients with PAN who had unknown ADA2 status.^16⇓-18 These aneurysms are multiple, small (<5 mm), and peripheral, arising in nonbranching sites or rupturing even when small.^16⇓-18 Additionally, they can cause cranial nerve compression or infarction because of occlusion of the parental vessel.¹⁷ Their management is controversial, with both medical and surgical and interventional treatments proposed.¹⁷ In our case, early follow-up studies demonstrated spontaneous aneurysmal thrombosis with total exclusion from circulation and no new intracranial aneurysms after 5 years. Of note, no visceral aneurysms were found in this patient and in the other investigated patients.

In their series, Bulut et al¹⁴ described brain atrophy in more than 50% of cases, without further information regarding the temporal evolution of this imaging finding. Similarly, we found mild diffuse enlargement of CSF spaces, including the ventricular system, the cortical cerebral sulci, or both, in 42% of patients at first brain MR imaging. However, none of the patients with available follow-up studies presented signs of progressive atrophy.

The first novel finding in this series was the detection of small parenchymal foci of susceptibility effect in 2 patients with DADA2, likely corresponding to brain microhemorrhages. The latter have been shown to correlate with hemosiderin-laden perivascular macrophages and have been associated with progressive aging and multiple neurologic conditions, including small-vessel disease and CNS vasculitis.¹⁹ Another patient presented a similar focal susceptibility effect located in the interpeduncular fossa, likely in a vessel wall, that could have the same origin, considering the absence of intracranial aneurysms and subarachnoid hemorrhage.

Different from Bulut et al,¹⁴ we did not identify any parenchymal area of enhancement after gadolinium injection. However, in one-third of patients, we found another novel feature, which was the presence of irregular, contrast-enhancing tissue in the interpeduncular fossa, crural cistern, and inner auditory canal, surrounding the basilar, posterior cerebral arteries and AICA, respectively. Eccentric vessel wall thickening and enhancement were noted in all patients, more pronounced at the origin of brain stem perforators, leading to progressive arterial stenosis in 1 patient. This pattern slightly differs from the concentric smooth arterial wall involvement typically seen in cerebral vasculitis caused by inflammation-related endothelial or vasa vasorum leakage.²⁰ On the other hand, in 2 patients, this new finding was associated with acute ischemic infarcts in the territory of the posterior perforators, reflecting an active disease phase and suggesting an inflammatory origin. Ac-cordingly, after anti-TNF treatment, there was total tissue regression in all patients and normalization in caliber of the stenosed artery at 1-year follow-up. As in the present series, most skin and bowel biopsy specimens of patients with DADA2 either reveal a PAN-like or a leukocytoclastic type of vasculitis.^1,2,10 However, histologic proof of CNS vasculitis was not obtained so far.² Therefore, the precise mechanism of DADA2-related intracranial vasculopathy remains unknown and awaits further research. Interestingly, most of our patients presented unremarkable angiographic findings. Indeed, abnormalities of intra-cranial vessels have been only occasionally described in DADA2,^14,21 probably caused by predominant involvement of medium- and small-sized vessels, frequently beyond the current resolution of lumen-based angiographic studies, including DSA. Accordingly, with the exception of the infarcted tissues, we did not find brain perfusion abnormalities on arterial spin-labeling.

Finally, we identified 2 DADA2-related PRES events in our cohort. PRES has been occasionally reported in patients with DADA2,^11,14 as well as in patients with PAN with unknown ADA2 status.²² Both our cases occurred during childhood and manifested with seizures associated with typical neuroimaging patterns.²³ These events occurred in the context of arterial hypertension, a complication of DADA2⁶ and a well-known risk factor for PRES²³; none of the patients was under anti-TNF treatment. Of note, ADA2 is an endothelial growth factor.² Therefore, patients with DADA2 may be intrinsically more prone to endothelial dysfunction, which is the presumed key-role mechanism of PRES.²³