A 33-year-old Kuwaiti woman, with no relevant past medical or psychiatric history, presented to our clinic with a 6-month history of progressive memory loss. Initially, the patient developed subacute onset of short-term memory loss that was mainly noticed by her family and coworkers. The condition was associated with depressed mood, insomnia, crying attacks and back pain, with no other associated neurological complaints. She was evaluated by a local psychiatrist who diagnosed her with major depressive disorder (MDD), and started her on antidepressant medication (vortioxetine 10 mg/day). Within the next month, the dose was increased to 20 mg per day and a benzodiazepine (alprazolam 0.5 mg/day) was added. The depressed mood and insomnia showed improvement, but her memory loss progressed. The patient was referred to a neurologist 3 months after onset. Her neurological examination was reported as normal apart from short-term memory loss. Her Mini-Mental State Examination (MMSE) score was 23/30. Magnetic resonance imaging (MRI) of the brain was requested and showed a bilateral asymmetric hyperintense signal of both hippocampi on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images, without contrast enhancement. Cerebrospinal fluid (CSF) analysis revealed lymphocytic pleocytosis with glucose and protein within the normal range. Virology screening for herpes simplex virus (HSV) was negative. However, the patient received acyclovir 10 mg/kg intravenously every 8 hours for 14 days with no improvement. We evaluated the patient 6 months after symptoms onset. Her memory loss had progressed since her last evaluation. However, she had not developed any seizures or other neurological or psychological manifestations. Her vital signs and general examination were normal. Her neurological examination showed a conscious and oriented patient with normal speech. Her memory assessment showed severe anterograde, and to a lesser extent retrograde, short-term memory loss, with MMSE of 20/30 and a Montreal Cognitive Assessment (MoCA) score of 21/30. Otherwise, her motor, sensory and cerebellar examination were normal. A follow-up brain MRI showed bilateral hyperintensity and hypertrophy of the head, body and tail of the bilateral hippocampi (more on the left side), and amygdala bilaterally. There was no associated contrast enhancement or restriction in diffusion-weighted image (DWI) sequences. However, there was a focal increase in the regional cerebral blood flow (rCBF) on the left side in perfusion imaging, and an increase in the choline peak (increased choline/N-acetylaspartate [Cho/NAA] ratio) on magnetic resonance spectroscopy (MRS). Electroencephalography (EEG) showed electrographic seizure activity manifested as temporal intermittent rhythmic delta activity (TIRDA) appearing from the right inferior, frontal and opercular regions, with frequent right anterior–mid-temporal spikes and spike-wave discharges. A comprehensive blood workup showed normal complete blood count (CBC), renal and liver function, serum electrolytes, inflammatory markers (erythrocyte sedimentation rate [ESR], C-reactive protein), serum vitamins B1, B6, B12 and folate, protein electrophoresis, immunoglobulin essay, thyroid function and antithyroid autoantibodies. Serology for HSV, hepatitis B and C, human immunodeficiency virus (HIV), Lyme disease, syphilis and Toxoplasma were negative. A panel for vasculitis including rheumatoid factor (RF), antinuclear antibody (ANA), anti-double-stranded DNA antibody (anti-dsDNA), extractable nuclear antigen (ENA) and antineutrophil cytoplasmic antibodies (ANCA) was also negative. Extensive workup for autoimmune antibodies associated with LE was performed including anti-N-methyl-d-aspartate (NMDA) receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, voltage-gated potassium channels (VGKC), leucine-rich glioma-inactivated protein 1 (LGI-1), contactin-associated protein-like 2 (CASPR2), gamma-aminobutyric acid-B (GABA-B), glutamic acid decarboxylase (GAD) and dipeptidyl peptidase-like protein-6 (DPPX) antibodies, and it yielded negative results. A paraneoplastic workup including anti-Yo, anti-Hu, anti-Ri, anti Ma1/2, CEA19.9, CA125, CA15.3 and anti-amphiphysin, collapsin response-mediator protein-5 (CRMP5) was also negative. Lumbar puncture was repeated, and CSF analysis showed lymphocytic pleocytosis (17 cells/mm3) with normal glucose (4.25 mol/L) and protein (362 mg/L). Polymerase chain reaction virology screening for neurotropic viruses (HSV, varicella-zoster virus, Epstein–Barr virus, cytomegalovirus) was negative. It also tested negative for bacterial, fungal or mycobacterial infection. Anti-VGKC, NMDA and AMPA receptor antibodies were negative, but oligoclonal bands (OCB) were positive. Computed tomography of the chest, abdomen and pelvis, and whole-body positron emission tomography (PET) were performed and showed no evidence of malignancy. The patient received a diagnosis of “seronegative LE” and was treated with a course of intravenous methylprednisolone 1000 mg per day for 5 days, followed by 1000 mg once weekly for 8 weeks. Lacosamide 50 mg twice daily was added after the abnormal EEG findings. A follow-up brain MRI was performed after 2 months of therapy, and showed decreased hyperintensity and hypertrophy of the limbic structures. She was maintained on oral prednisolone (60 mg/day) that was tapered gradually over 6 months. The patient showed subjective and objective improvement in her memory. MMSE score was 23/30 after 1 month, 25/30 after 3 months and 27/30 after 6 months. A timeline of the clinical course is highlighted in Fig..