We hereby report a puzzling case of multiple sclerosis (MS) relapse presenting as Takotsubo syndrome (TTS). Female, 42-years old, who presented herself to the Emergency Room of University Hospital "ASST Spedali Civili" of Brescia, Italy, for a severe headache and a non-ST-segment elevation acute coronary syndrome. Coronary angiogram showed no signs of coronary atherosclerosis. Upon further neurological evaluation, a diagnosis of MS relapse, related to TTS, was made, and treatment was started accordingly. The patient was discharged after 12 days after the admission, free of symptoms, and without signs of neurological and cardiological active disease. A hallmark of TTS is its association with a preceding stressful event. It may also be connected to a wide variety of diseases, including neurological ones, such as stroke, intracranial bleeding, head trauma, migraine, and seizures. However, up to our knowledge, only few cases of MS-induced TTS were previously described. Whether it is plausible to consider TTS as an uncommon extra-neurological manifestation of MS is still debated, however all the evidence points in that direction, considering the central role of catecholamines in TTS pathogenesis. With this case report the authors hope to encourage research on this field and on the intricate topic of brain-heart connections.