Genetic mutations of sporadic hemiplegic migraine (SHM) are mostly unknown. SHM pathophysiology relies on cortical spreading depression (CSD), which might be responsible for ischemic brain infarction. Cystic fibrosis (CF) is caused by a monogenic mutation of the chlorine transmembrane conductance regulator (CFTR), possibly altering brain excitability. We describe the case of a patient with CF, who had a migrainous stroke during an SHM attack. A 32‐year‐old Caucasian male was diagnosed with CF, with heterozygotic delta F508/unknown CFTR mutation. The patient experiences bouts of coughing sometimes triggering SHM attacks with visual phosphenes, aphasia, right‐sided paresthesia, and hemiparesis. He had a 48‐hour hemiparesis triggered by a bout of coughing with hemoptysis, loss of consciousness, and severe hypoxia‐hypercapnia. MRI demonstrated transient diffusion hyperintensity in the left frontal‐parietal‐occipital regions resulting in a permanent infarction in the primary motor area. Later, a brain perfusion SPECT showed persistent diffuse hypoperfusion in the territories involved in diffusion‐weighted imaging alteration. Migrainous infarction, depending on the co‐occurrence of 2 strictly related phenomena, CSD and hypoxia, appears to be the most plausible explanation. Brain SPECT hypoperfusion suggests a more extensive permanent neuronal loss in territories affected by aura. CF may be then a risk factor for hemiplegic migraine and stroke since bouts of coughing can facilitate brain hypoxia, triggering auras.

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