Autoimmune limbic encephalitis can be associated with different neural-specific autoantigens, of which autoantibodies against the voltage-gated potassium channels (VGKC) are the most common [
1,
2]. These can target any of the three subunits of the VGKC complex including leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and contactin-2. Encephalitis related to anti-LGI-1 antibody is more common than these three types, and was first described in 2010 [
2,
3]. Although it can be a paraneoplastic phenomenon, anti-LGI-1 encephalitis is mostly unrelated to tumors [
4]. It mostly affects males in their 60s [
5,
6], and can manifest as subacute memory decline, cognitive impairment, psychiatric disturbances, refractory seizures, hyponatremia, and, in some cases, dysautonomia and sleep disturbances [
1,
2,
6]. The most common presenting symptoms are seizures (53%) or cognitive disorders (42%). Faciobrachial dystonic seizures (FBDS), if present, are the characteristic seizure type for this disease [
3,
4]. The diagnosis is primarily made on the basis of the clinical presentation (mainly subacute refractory seizures otherwise unexplained) and evidence of neurally directed inflammation. The diagnosis is confirmed by finding the anti-LGI-1 antibody and after excluding other possible causes of encephalitis. All the same, underdiagnosis is not uncommon, owing to ambiguous clinical presentation or absence of distinguishing findings. Many of these patients are initially diagnosed with nonorganic psychogenic disorders until the first undeniable generalized tonic–clonic seizure happens [
7]. Therefore, several diagnostic tools have been developed in recent years, such as the Antibody Prevalence in Epilepsy and Encephalopathy (APE2) and Response to Immunotherapy in Epilepsy and Encephalopathy (RITE2) scores to help facilitate the detection of the disease and consequently accelerate treatment [
8]. Neuroimaging findings are usually more illuminating in the acute phase, whereas changes in cerebrospinal fluid (CSF) analysis are less frequent [
6,
9]. In the end, detection of anti-LGI1 antibodies in serum or CSF is needed to confirm the diagnosis [
2]. Seizures are commonly refractory to usual antiseizure medications. But, fortunately, they have been eliminated dramatically by immunotherapy, especially steroids. This feature also helps the physician to diagnose the disease [
4,
9].
Here, we aim to introduce two patients with different clinical manifestations and distinct localization of brain involvement. Through these two interesting cases, we can split the diagnostic process into four steps: recognizing the spectrum of the clinical presentation, finding the evidence of neurally directed inflammation, excluding other differential diagnosis, and how to proceed with treatment.