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Moreno-Martínez et al. Rare Dis Orphan Drugs J 2024;3:9 https://dx.doi.org/10.20517/rdodj.2023.51 Page 9 of 16

Pulvinar sign
The symmetric hyperintensity of the lateral pulvinar nucleus on unenhanced T1-weighted brain MRI is
known as the pulvinar sign (PS). The pathogenesis of the PS in FD is still unclear and may represent
dystrophic calcifications, likely due to chronic regional hyperperfusion [92,93] . It has been initially described as
a common neuroradiologic sign in patients with FD [92,94] ; nevertheless, PS is not a specific finding and it has
been reported in other conditions, including metabolic disorders (Krabbe or Tay-Sachs disease), Fahr
disease, disturbances of the calcium-phosphorus metabolism, central nervous system infections, or after
[95]
chemoradiation therapy . In a recent study, PS was detected in only 4 of 133 patients with FD (3.0%); all
the patients were adult males with chronic renal failure on enzyme replacement therapy (ERT) . These
[95]
results suggest that the true incidence of PS is considerably lower than previously thought. In addition, the
PS has a low sensitivity for the diagnosis of FD, is not modified by ERT, and is not associated with any
specific FD genotype [94,95] .

Vertebrobasilar artery involvement
Alterations of the posterior circulation system include tortuosity, diffuse ectasia, elongation, and/or focal
aneurismal dilatation involving the vertebral and basilar arteries [Figure 2D] . The underlying mechanisms
[96]
of such abnormal vessel dilatation have been described in the corresponding section of this review. It is
worth noting that the prevalence of vertebrobasilar dolichoectasia has also been described in young patients
with other uncommon causes of acute strokes .
[97]
Recommended MRI sequences
MRI sequences suggested include T1-weighted fluid-attenuated inversion recovery (FLAIR) and
T2-weighted sequences to quantify chronic WMH load and to identify lacunar and territorial strokes; T2*
MRI (gradient echo, susceptibility-weighted imaging) to identify macro and microbleeds; diffusion-
weighted imaging to assess stroke and time-of-flight sequences to evaluate the diameter of cerebral vessels
without using contrast .
[55]

In adults with FD, due to the higher prevalence of strokes in comparison to the general population and the
presence of silent lesions, a consensus guideline proposes to perform a brain MRI every three years in all
[98]
males at baseline and in females over 30 years old . By contrast, given the rarity of stroke in the pediatric
population with FD, the latest consensus guidelines advise against performing a brain MRI as baseline
practice in children, except in cases with neurological symptoms .
[99]
Computed tomography scans may be used in the acute setting or when MRI is contraindicated.

Advanced imaging techniques
Quantitative volumetric MRI studies evaluate the presence of brain-tissue volume loss in FD patients with
mild-to-moderate central nervous system involvement. Reduced grey matter density has been recently
reported at the level of the thalami and hippocampus, bilaterally, reflecting direct neuronal involvement
independent from vascular pathology .
[100]

Diffusion tensor imaging has been shown to detect brain tissue alterations, allowing for an accurate
quantification of microstructural white matter changes. FD patients, including those without white matter
lesions seen on conventional MRIs, may present an elevated total brain parenchymal diffusion constant
compared to controls. Increased mean diffusivity values in FD patients were found in the temporal, frontal,
and parietal lobes. This increase, presumably due to an elevated water content of brain tissue, may be
identified independently from white matter lesions and could be interpreted as a biomarker of early stages
of microvascular injury [101,102] .