The classical triad-ophthalmoplegia, cerebellar dysfunction, and altered mental state-in addition to bilateral symmetrical periventricular lesions are actually common to see, and clinicians tend to associate that with Wernicke's encephalopathy (WE). The diagnosis is strengthened with a likely deficiency of thiamine. We herein describe a malnourished patient with clinical triad and hyperintensities in the circumventricular regions, and she turned out to have neuromyelitis optica spectrum disorder (NMOSD) after many twists and turns. Despite totally different pathogenic mechanisms, NMOSD can mimic WE, sometimes even exhibiting radiological features similar to that of WE, thereby complicating the diagnosis. Our case highlights how similar these two diseases could be and the importance of differential diagnosis in clinical practice, which are so far rarely reported. Some clinical and radiological differences of these two diseases are summarized to help establish a prompt diagnosis.