Retrograde Amnesia in LGI1 and CASPR2 Limbic Encephalitis: Two Case Reports and a Systematic Literature Review

Abstract

Background: Both anterograde and retrograde amnesia can typically co-occur in limbic autoimmune encephalitis (LAE), including the forms associated with antibodies to CASPR2/LGI1, two protein complexed with the voltage-gated potassium channel (VGKC). However, isolated retrograde amnesia is very rare, and it has never been described in LAE.

Methods: We report two patients with CASPR2 LAE who showed isolated retrograde amnesia, without other significant cognitive impairments. A systematic literature review was performed in accordance with the PRISMA guidelines on patients with LAE, antibodies to the VGKC complex (including LGI1, CASPR2, or the VGKC), and memory impairment.

Results: We identified 467 patients from 29 studies. Fourteen/467 had retrograde amnesia (2.9%), which co-occurred with anterograde amnesia in 12 with VGKC antibodies (7 with LGI1 LAE-like clinical phenotypes). Our two cases with CASPR2 LAE (2/469, 0.4%) were the only ones with isolated retrograde amnesia, which was actively investigated in only 56/467 patients. Thirteen/14 patients, including the two with isolated retrograde amnesia, had partial or poor cognitive improvement.

Conclusions: Retrograde amnesia is rare but likely under-recognized in VGKC-complex antibodies LAE and associates with poor recovery. When isolated, it adds to the spectrum of CASPR2 LAE. These findings promote insights into retrograde amnesia pathophysiology, deserving investigation across the whole spectrum of AE.

Keywords: CASPR2 encephalitis; LGI1 encephalitis; VGKC encephalitis; autoimmune encephalitis; retrograde amnesia.

FIGURE 1

Flowchart of the search process based on the PRISMA systematic review of the literature. LAE, limbic autoimmune encephalitis. * PubMed, Scopus, and Embase databases analyzed with and without MeSH terms in the search strings.

FIGURE 2

Timeline of neurological symptoms of our two CASPR2 LAE patients. The results of AMI (autobiographical incidents and personal semantic schedules, at baseline and 2‐year follow‐up); AMI scores were defined as follows; “Acceptable”: ±1 SD of the mean derived from literature data on healthy controls (dotted green line); “borderline”: All the values falling between 1 SD and 2 SD below the mean; “probably abnormal”: > 2 SD below the mean (dotted orange line; not always assessed); “definitely impaired”: Scores at or below the lowest score among the healthy controls (red line) (Kopelman et al. 1989 [20]). Brain MRI, case 1 (A) and case 2 (F): coronal sections showing bilateral hippocampal hyperintensity (on the left) and swelling on Fluid‐attenuated‐inversion‐recovery (FLAIR) and T2 sequences (on the right). CASPR2 antibody detection assays (case 1, B–E; case 2, G–L). Serum of patient 1 (B–E) and of patient 2 (F–L) did not bind to untrasfected HEK293 cells (B, G), but provided membrane surface staining on fixed cell‐based assay (CBA, green, anti‐human IgG), and on live CBA (D, I; red, anti‐human IgG; green, EGFP tag) on CASPR2‐transfected HEK293 cells. Blue: DAPI. The presence of CASPR2 antibodies was confirmed on IHC on lightly fixed rat brain slices showing neuropilar staining patterns compatible with CASPR2 antibody reactivity (E, case 1; L, case 2; brown: anti‐human IgG). Staining intensity on both CBAs and IHC in case 1 was more intense than in case 2. AE, autoimmune encephalitis; AMI, autobiographical memory interview; IHC, immunohistochemistry; LAE, limbic AE; MRI, magnetic resonance imaging; NS, non‐significant; TC, tonic‐clonic; TGRA, temporally graded retrograde amnesia; TuGRA, temporally ungraded retrograde amnesia; yr, years.

FIGURE 3

Results of the systematic review: VGKC, LGI1 and CASPR2 Limbic Autoimmune Encephalitis with memory impairment.