Diagnostic Value of the “Insular Knife‐Cut” Sign in Patients With Suspected Herpes Simplex Virus Encephalitis

Background: The “insular knife-cut” sign is a sharp demarcation between hyperintense insular lesions on fluid-attenuated inversion recovery axial images and the basal ganglia, detected on brain MRI. This sign has been associated with herpes simplex virus encephalitis (HSVE); however, its specificity remains unknown. We assessed the frequency and specificity of the insular knife-cut sign in a real-life cohort of patients with suspected HSVE. Methods: We retrospectively identified patients admitted for suspected HSVE over the past 10 years at three Neurology Units in Italy. Inclusion criteria were cerebrospinal fluid (CSF) tested for HSV-1/2 PCR and acute brain MRI available. Results: A total of 188 patients were included: HSVE, 44; alternative diagnoses, 144 (autoimmune encephalitis, 51; infectious encephalitis, 22; other acute encephalopathies, 71). The insular knife-cut sign was present on the initial brain MRI in 23/44 (52.3%) HSVE patients and 1/144 (0.7%) patients with alternative diagnoses (p < 0.001). The specificity and sensitivity of the sign were 99.3% (95% CI, 96–100) and 52% (95% CI, 38–66), respectively. In eight HSVE patients, the insular knife-cut sign appeared on subsequent MRIs obtained acutely, raising the sensitivity to 70.5% (95% CI, 56–82). On multivariate regression, the insular knife-cut sign was the strongest independent predictor (odds ratio [95% CI]) of HSVE (68.9 [11.42–415.54]), followed by temporal pole involvement (8.44 [2.06–34.6]), and CSF pleocytosis (6 [1.7–21.18]). Conclusions: In patients with suspected encephalitis, the insular knife-cut sign on MRI strongly predicts a diagnosis of HSVE. Its detection should prompt consideration of HSVE, even when other diagnostic tests are equivocal/unavailable.