Early-Stage Contactin-Associated Protein-like 2 Limbic Encephalitis: Clues for Diagnosis

Abstract

Background and objectives: Previous studies suggested that autoimmune limbic encephalitis with antibodies against contactin-associated protein-like 2 (CASPR2-encephalitis) is clinically heterogeneous and progresses slowly, preventing its early recognition. We aimed to describe the onset and progression of CASPR2-encephalitis and to assess long-term outcomes.

Methods: We retrospectively analyzed the medical records of all patients whose CSF tested positive for anti-CASPR2 antibodies in our center between 2006 and 2020. Standardized telephone interviews of all available patients and relatives were conducted, assessing long-term functional independence using the Functional Activity Questionnaire (FAQ) and quality of life using the 36-Item Short-Form Survey (SF36).

Results: Forty-eight patients were included (98% males; median age 64 years), and 35 participated in telephone interviews (73%). At onset, 81% had at least 1 neurologic symptom among the following: limbic (54%), peripheral nerve hyperexcitability (PNH; 21%), and/or cerebellar symptoms (17%). Most of the patients (75%) had initially symptoms of only one of these categories. Limbic symptoms at onset included mostly seizures (33%), while memory disturbances were less frequent (10%). PNH signs were mostly neuropathic pain (9/10 patients). Other symptoms seen at onset included asthenia (33%), mood disorders (25%), and insomnia (21%); 19% of patients did not show any limbic, peripheral, or cerebellar symptom at onset but only asthenia (15%), mood disorders (6%), weight loss (8%), dysautonomia (4%), and/or insomnia (2%). The peak of the disease was attained in median 16.7 months after onset. Over the study period (median follow-up, 58.8 months, range 10.6-189.1), 77% of patients developed ≥3 core CASPR2 symptoms and 42% fulfilled the diagnostic criteria for autoimmune limbic encephalitis, although all patients ultimately developed limbic symptoms. At the last visit, most interviewed patients (28/35 patients, 80%; median, 5 years after onset) had recovered functional independence (FAQ <9) while only the vitality subscore of the SF36 was lower than normative data (mean 49.9 vs 58.0, p = 0.0369).

Discussion: CASPR2-encephalitis has a progressive course and is highly heterogeneous at the early stage. In men older than 50 years, otherwise unexplained seizures, cerebellar ataxia, and/or neuropathic pain are suggestive of early-stage CASPR2-encephalitis, especially if they coincide with recent asthenia, mood disorders, or insomnia.

Figure 1. Flowchart of the Study

Figure 2. Progression of CASPR2-Encephalitis

(A) An overlap of the 3 main categories of neurologic symptoms in the patients: limbic (generalized or temporal lobe seizures, behavioral change, and/or memory impairment), peripheral nerve hyperexcitability (PNH), and cerebellar symptoms at the studied time points between onset and peak of the disease; and (B) over the entire study period (left panel) and at the last visit (right panel). The values represent the number of patients in each category. Patients who did not have symptoms of limbic encephalitis, cerebellar ataxia, or peripheral nerve hyperexcitability at 1 time point are not represented in the corresponding diagram. CASPR2 = contactin-associated protein-like 2.

Figure 3. Fulfilment of the Graus Criteria for Definite Autoimmune Limbic Encephalitis and Completion of ≥3 and ≥4 of Van Sonderen CASPR2 Core Symptoms, Over Disease Course

There was no missing value. CASPR2 = contactin-associated protein-like 2.

Figure 4. Outcomes of Patients With CASPR2-Encephalitis

(A) Progression of neurologic disability as assessed by the modified Rankin scale (mRS) score. There was no missing value. (B) Spider chart showing the medians of the 8 subscores of the SF-36 scale for quality of life, at the last visit. Thirty-five patients were included in this cross-sectional analysis, and their scores were compared with normative data from a French population of men older than 55 years. The axis represents the absolute values of the SF36 subscales, from the minimal to the maximal value of both our cohort and normative data, for each subscale. CASPR2 = contactin-associated protein-like 2; SF36 = 36-Item Short-Form Survey.