Beyond Non-specific White Matter Abnormalities – Is There a Causal Relationship with Patent Foramen Ovale?
Bade Gulec1, Merve Hazal Ser1, Elif Everest3, Özgür Selim Ser4, Eser Durmaz2, Derya Uluduz1, Melih Tutuncu1, Ugur Uygunoglu1, Sabahattin Saip1, Aksel Siva1
1Neurology, 2Cardiology, Istanbul University Cerrahpasa School of Medicine, 3National Institutes of Health, 4Cardiology, Istanbul Cemil Tascıoglu City Hospital
Objective:
To investigate the potential relationship between nonspecific white matter abnormalities (NSWMA) and right-to-left shunt (RLS) detected by transcranial Doppler ultrasound (TCD), and to explore the role of patent foramen ovale (PFO) in the pathogenesis of these lesions.
Background:
NSWMAs are frequently encountered on brain MRI, often in patients presenting with headache. NSWMA is defined by: 1) small (<3 mm), nodular white matter lesions, 2) non-ovoid morphology without a central vein sign, 3)predominant localization in subcortical regions, 4) a semi-symmetric distribution, 5) absence of gadolinium enhancement, 6) absence of radiological features typical of demyelinating etiologies. The pathogenesis of NSWMA remains uncertain, with proposed mechanisms including microvascular ischemia, inflammatory processes, and paradoxical embolism via patent foramen ovale (PFO).
Design/Methods:
Patients aged 18–55 years with MRI findings fulfilling NSWMA criteria were included. All participants underwent contrast-enhanced TCD to evaluate for RLS, and transthoracic and/or transesophageal echocardiography to confirm PFO. MRI findings were retrospectively evaluated for lesion size, morphology, and distribution.
Results:
Among 104 patients (mean age 44.4±9.7 years; 86.5% female), 51.9% were TCD-positive. Headache was significantly more frequent among TCD-positive patients (p=0.0048), who also demonstrated higher PFO positivity (p<0.0001) and closure rates (p=0.0003). In contrast, TCD-negative patients exhibited a greater lesion burden, including higher numbers of periventricular and juxtacortical lesions (p<0.05 for all), more frequent symmetric/semi-symmetric patterns (p=0.02), and larger lesion sizes (p=0.03). None of the patients displayed infratentorial or spinal cord involvement.
Conclusions:
The significant association between PFO-related shunting and headache supports a possible embolic or vasoactive contribution to certain NSWMA presentations. However, the higher lesion load in TCD-negative patients suggests that NSWMA represents a heterogeneous, non-demyelinating entity with multifactorial origins, with the possibility of a genetic origin. These findings emphasize the importance of recognizing NSWMA as a distinct radiological pattern requiring careful differential diagnosis in patients with incidental white matter findings.
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