Autoimmune Encephalitis Resembling Dementia Syndromes

Abstract

Objective: As autoimmune encephalitis (AIE) can resemble neurodegenerative dementia syndromes, and patients do not always present as encephalitis, this study evaluates how frequently AIE mimics dementia and provides red flags for AIE in middle-aged and older patients.

Methods: In this nationwide observational cohort study, patients with anti-leucine-rich glioma-inactivated 1 (LGI1), anti-NMDA receptor (NMDAR), anti-gamma-aminobutyric acid B receptor (GABA_BR), or anti-contactin-associated protein-like 2 (CASPR2) encephalitis were included. They had to meet 3 additional criteria: age ≥45 years, fulfillment of dementia criteria, and no prominent seizures early in the disease course (≤4 weeks).

Results: Two-hundred ninety patients had AIE, of whom 175 were 45 years or older. Sixty-seven patients (38%) fulfilled criteria for dementia without prominent seizures early in the disease course. Of them, 42 had anti-LGI1 (48%), 13 anti-NMDAR (52%), 8 anti-GABA_BR (22%), and 4 anti-CASPR2 (15%) encephalitis. Rapidly progressive cognitive deterioration was seen in 48 patients (76%), whereas a neurodegenerative dementia syndrome was suspected in half (n = 33). In 17 patients (27%; 16/17 anti-LGI1), subtle seizures had been overlooked. Sixteen patients (25%) had neither inflammatory changes on brain MRI nor CSF pleocytosis. At least 1 CSF biomarker, often requested when dementia was suspected, was abnormal in 27 of 44 tested patients (61%), whereas 8 had positive 14-3-3 results (19%). Most patients (84%) improved after immunotherapy.

Conclusions: Red flags for AIE in patients with suspected dementia are: (1) rapidly progressive cognitive decline, (2) subtle seizures, and (3) abnormalities in ancillary testing atypical for neurodegeneration. Physicians should be aware that inflammatory changes are not always present in AIE, and that biomarkers often requested when dementia was suspected (including 14-3-3) can show abnormal results. Diagnosis is essential as most patients profit from immunotherapy.

Figure 1. Patient Inclusion

In total, 290 patients with autoimmune encephalitis were identified. At disease onset, 175 of the patients had an age of ≥45 years. Sixty-seven patients fulfilled the dementia criteria including the additional condition that no prominent seizures were present at early disease course (≤4 weeks). *Percentage of the patients ≥45 years of age. AIE = autoimmune encephalitis; CASPR2 = contactin-associated protein-like 2; GABA_BR = gamma-aminobutyric acid B receptor; LGI1 = leucine-rich glioma-inactivated 1; NMDAR = NMDA receptor.

Figure 2. Cognitive Domains in Autoimmune Encephalitis

For patients with anti-LGI1, anti-NMDAR, and anti-GABA_BR encephalitis, cognitive symptoms were divided into 5 cognitive domains. The domains for memory and behavior were divided into 4 categories (not present, mildly present, present, and prominent), and the speech, visuospatial, and executive domains were divided into 3 categories (not present, present, and prominent). ***p < 0.0001 and **p = 0.001 between anti-NMDAR and, respectively, anti-LGI1 and anti-GABA_BR. GABA_BR = gamma-aminobutyric acid B receptor; LGI1 = leucine-rich glioma-inactivated 1; NMDAR = NMDA receptor.

Figure 3. Dementia Biomarkers in Patients With Autoimmune Encephalitis

Dementia CSF biomarkers in 44 patients with autoimmune encephalitis cutoff values to be considered abnormal were (A) t-tau > 400 pg/mL, (B) p-tau > 64 pg/mL, (C) a t-tau/p-tau ratio of >30, (D) Aβ42 < 500 pg/mL, and (E) a t-tau/Aβ42 ratio of >0.52. (F) A positive 14-3-3 is abnormal. Two patients with t-tau values of 14,720 and 2,800 were maximized at 2001. Five patients with a positive 14-3-3 had been tested by RT-QuIC, all negative. Filled diamond symbols represent abnormal results, and half-filled symbols represent normal results. Aβ42 = amyloid-beta-42; CASPR2 = contactin-associated protein-like 2; GABA_BR = gamma-aminobutyric acid B receptor; LGI1 = leucine-rich glioma-inactivated 1; NMDAR = NMDA receptor; p-tau = phosphorylated tau; RT-QuIC = real‐time quaking-induced conversion; t-tau = total tau.