Location-atypical lesions in non-ketotic hyperglycemic epilepsy: expanding the clinico-radiographic phenotype

Non-ketotic hyperglycemia (NKH) is associated with a spectrum of symptoms and radiographic findings due to poorly-controlled diabetes mellitus. These lesions, which predominantly affect the parieto-occipital cortex, are commonly missed by neurologists and neuroradiologists due to their subtle hypointense appearance on T2-based imaging. We report four atypical cases of this syndrome to highlight its subtle, protean presentation in order to aid timely diagnosis. Based on our institutional case series, we describe four cases of NKH with atypical presentation and lesion burden affecting the anterior cortex. We review the clinical presentations, laboratory abnormalities, neuroimaging, and corresponding electroencephalography. Four patients with atypical NKH were characterized in our series. Presenting symptoms ranged from rhythmic hand-tapping to generalized tonic-clonic status epilepticus. Laboratory values were notable for marked hyperglycemia (range: 447 - 627 mg/dL), mild pseudo-hyponatremia (range: 127 - 136 mmol/L), and elevated hemoglobin A1C levels (range: 10.9 - 16.1%). All patients were found to have the classically described pattern of T2-based hypointensity; three with atypical distributions involving the "anterior" cortex. These lesions corresponded to the electrographic nidus of seizure burden. During follow-up, both seizures and T2-based hypointensity resolved within weeks of serum glucose normalization. Our series of four NKH patients with atypical findings of T2-based signal abnormalities expands the clinico-radiographic phenotype revealing a more protean distribution than previously described. Knowledge of these atypical imaging features will aid both the neurologist and radiologist in timely diagnosis and care of these patients.

Neurokinin B induces c-fos transcription via protein kinase C and activation of serum response factor and Elk-1 in immortalized GnRH neurons.

Mutations in neurokinin B (NKB) and its receptor, NK3R, were identified in human patients with hypogonadotropic hypogonadism, a disorder characterized by lack of puberty and infertility. Further studies have suggested that NKB acts at the level of the hypothalamus to control GnRH neuron activity, either directly or indirectly. We recently reported that treatment with senktide, a NK3R agonist, induced GnRH secretion and expression of c-fos mRNA in GT1-7 cells. Here, we map the responsive region in the murine c-fos promoter to between -400 and -200 bp, identify the signal transducer and activator of transcription (STAT) (-345) and serum response element (-310) sites as required for induction, a modulatory role for the Ets site (-318), and show that induction is protein kinase C dependent. Using gel shift and Gal4 assays, we further show that phosphorylation of Elk-1 leads to binding to DNA in complex with serum response factor at serum response element and Ets sites within the c-fos promoter. Thus, we determine molecular mechanisms involved in NKB regulation of c-fos induction, which may play a role in modulation of GnRH neuron activation.