Dark white matter is a subcortical MRI marker in seizures and systemic disorders: A narrative review

Recognizing subcortical white matter hypointensities on magnetic resonance imaging (MRI), particularly in patients with seizures, has led to identifying a novel radiological phenomenon known as the dark white matter (DWM), or subcortical low intensity on T2/fluid-attenuated inversion recovery brain-MRI. Initially described in non-ketotic hyperglycemia (NKH) and peri-ictal states, DWM serves as a potentially valuable marker of seizure-related subcortical dysfunction and other non-epileptic conditions. This narrative review seeks to synthesize current knowledge on the DWM sign by discussing its radiological features, etiology, hypothesized mechanisms, and potential clinical applications as a functional neuroimaging biomarker. We expand on the original observational study, introducing the DWM concept, and incorporate findings from a thorough literature review on DWM-related MRI abnormalities, particularly on metabolic, autoimmune, and structural epilepsies. DWM typically appears as a T2/fluid-attenuated inversion recovery hypointensity localized to juxtacortical white matter, mostly temporally and anatomically associated with seizure activity. It has been found across various etiologies, including NKH, autoimmune encephalitis, and seizures. Suggested mechanisms include glial water depletion, axoglial energetic failure, and cortical-subcortical functional coupling. DWM may act as a dynamic biomarker of recent seizures, especially in diagnostically challenging situations, such as in non-convulsive status epilepticus. DWM is commonly encountered in NKH, encephalitis, moyamoya disease, genetic causes, and subdural hematoma. Seizures were associated with NKH in almost every case in our previous systematic work, and the occipital lobe was the most commonly affected. Looking only at patients with seizures, DWM indicated NKH in 51.4 % of cases and encephalitis in 26.4 %. Myelin oligodendrocyte glycoprotein antibody-associated disorder was the most frequently associated encephalitis with DWM. In conclusion, DWM is a reproducible and potentially underdiagnosed MRI finding that reflects transient subcortical dysfunction during or after seizures. Integrating it into clinical and research frameworks could enhance diagnostic accuracy, clarify the contributions of white matter to epileptogenesis, and foster new translational insights into brain excitability, ultimately improving therapeutic approaches.