To assess the frequency and specificity of the insular knife-cut sign in patients with suspected herpes simplex virus encephalitis (HSVE).

A total of 188 patients were included: HSVE, 44; alternative diagnoses, 144 (autoimmune/paraneoplastic encephalitis, 51; infectious encephalitis, 22; acute encephalopathies of other etiologies, 71). The two groups were similar in (median [range]) age at symptoms onset (66 [56-73] vs 64 [52-74] years) and days from onset to the first brain MRI (5 [4-9] vs 4.5 [1-13]).The insular knife-cut sign was present on the initial brain MRI in 23/43 (53%) HSVE patients and 1/95 (1%) 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). In eight HSVE patients, the insular knife-cut sign appeared on subsequent MRIs, raising the sensitivity to 70.45% (95%CI, 56-82). Multivariate regression identified the insular knife-cut sign as the strongest independent predictor of HSVE (OR:42.4, 95%CI, 7.3-486.4), followed by temporal pole involvement (OR:12.86, 95%CI, 3.7-54.6), abnormal brain MRI (OR:7.4, 95%CI, 1.6-34.3), and CSF pleocytosis (OR:4.9, 95%CI, 1.4-19.4).

The insular knife-cut sign is a common and highly specific MRI finding in patients with HSVE. Its detection in clinical practice might aid HSVE diagnosis and treatment, especially when other tests are equivocal/unavailable.