4.1 Diagnosis of Anti-CASPR2 Encephalitis
CASPR2 is expressed in the central and peripheral nervous systems as a transmembrane protein. CASPR2 presents with central nervous system symptoms, such as cognitive dysfunction, seizures, psychiatric disorders, and changes in consciousness, and peripheral nervous system symptoms, such as neuralgia and peripheral hyperexcitability. Previous studies also demonstrated the presence of cerebellar ataxia, dyskinesia, autonomic nervous dysfunction, weight loss, and insomnia [14–17].
The diagnostic criteria for all patients with autoimmune encephalitis [13] in this study were: Part 1 (clinical criteria): with subacute onset (rapid progression of fewer than three months) of working memory deficits (short-term memory loss), altered mental status, or psychiatric symptoms. Six patients had subacute onset, and two had subjective working memory deficits (short-term memory loss). However, all six patients showed a decline in cognitive function and changes in mental status or mental disorders. Part 2: with at least one of the following: 1. New focal CNS findings; 2. Seizures not related to a previously known seizure disorder; 3. CSF pleocytosis (white blood cell count > five cells per mm³); 4. MRI features suggestive of encephalitis. Five patients had seizures. The CSF white blood cell count was normal in all patients, and MRI showed no changes in encephalitis. Part 3: other possible diseases, such as metabolism, poisoning, special pathogen infection, and other diseases, were excluded in each of the six patients.
Serological criteria: six patients with positive serum anti-CASPR2 antibody. Three of five patients with positive serum antibodies were tested using TBA, which showed no abnormality. In addition, one patient had a positive antibody to anti-CASPR2 in CSF, and another had positive oligonclonal bands. All patients responded well to the immunotherapy.
Besides the diagnostic criteria, psychiatrists have reported that the presentation of a rapidly evolving psychotic syndrome in a person without a history of psychiatric disorder and/or substance use, in addition to poor response to standard treatment with antipsychotics, should prompt a high suspicion for AE [18].
4.2 Demographic characteristics of Anti-CASPR2 Encephalitis patients with depression
Anti-CASPR2 encephalitis occurs in males (90%) at 60–70 years, but the onset in females may be earlier [19], which is consistent with the average age of onset of participants in this study at 56.3 years. Anti-CASPR2 encephalitis with depressive onset occurs mainly in females, inconsistent with previous reports that anti-CASPR2 encephalitis is more common in males [20].
4.3 EEG and MRI Features of Anti-CASPR2 Encephalitis in patients with Depression
Qin et al. [16] reviewed the clinical features of 25 patients with anti-CASPR2 encephalitis and found that approximately 65% of the patients reported abnormal EEG findings, including slow background activity and epileptic patterns. In this study, abnormal EEG reached 50% (3/6), in which epileptic waves were found in two patients and slow-wave background increased in one patient. This finding indicated an abnormal boundary, which was consistent with the results of Qin et al. Previous studies [21–22] found MRI abnormalities (80% and 55.6%) in the brains of patients with anti-CASPR2 encephalitis, showing T2- weighted FLAIR images of temporal lobe hyper signal and hippocampal atrophy. In this study, brain MRI of patients showed no high signal in the temporal lobe; only four patients with age-matched small ischaemic lesions were found, and two patients with hippocampal atrophy, which may be related to immunoglobulin and complement deposition in the neurons and cell degeneration in the hippocampus [23].
4.4 Examination of a Single Low Titer Serum Antibody to CASPR2 for diagnosis of Anti-CASPR2 Encephalitis
Two-thirds of the antibodies against CASPR2 encephalitis are produced in the peripheral blood, and the CSF is insensitive [14, 16, 24]. Moreover, previous studies also found that CASPR2 antibodies are undetected in the CSF of patients with neuromyotonia or Morvan syndrome [21]. Eoin P’s [25] demonstrated that autoimmune encephalitis in adults is easily misdiagnosed because it is latent rather than subacute onset, cannot be examined using MRI or CSF to indicate inflammation, and serum nonspecific antibodies can be over-interpreted. They believed that only high antibody titres could be used to diagnose autoimmune encephalitis. Bien [24] et al. revealed that patients with non-encephalitis MRI, having serum titres of anti-CASPR2 antibody ≥ 1:1000, are 70% more likely to develop autoimmune encephalitis. Low titres of anti-CASPR2 antibodies potentially cause destructive processes in several inflammatory, degenerative, and neuropsychiatric diseases.
4.5 Relationship between a single low titer serum antibody to CASPR2 and anti-CASPR2 encephalitis
This study found that previous serum antibody titres for anti-CASPR2 encephalitis mostly fluctuated at 1:10 − 1:320, and patients showed typical anti-CASPR2 encephalitis symptoms, such as seizures, cognitive impairment, and psychiatric abnormalities [14, 16]. Although CSF and MRI showed no inflammatory changes, all six patients presented with a subacute onset pattern. Comprehensive examinations, such as systemic autoantibody examination, cognitive function, and tumors, did not support patients with other systemic immune, neurodegenerative, and tumor diseases. In addition, immunotherapy was effective, and the serum antibody titre was negative, consistent with the change in the patient's symptoms. Therefore, low serum titre antibody CASPR2 was considered as the antibody responsible for patients presenting with symptoms.
Several studies found that the severity of depressive symptoms and depression-like behavior positively correlates with autoantibody titres [26]. In this study, the degree of depression was relatively mild (5/6), potentially because of the low serum antibody titres.
4.6 The Classification of Depression
According to the DSM-5 diagnostic criteria, depression is divided into subtypes with anxiety-distress, atypical, depressive, and psychotic features. In this study, the first symptom was a depression in the six patients; four had anxiety and distress. Among the patients not included in the study may be patients with depression as the first symptom. However, emotional disorders in the patients may be ignored due to their treatment in the neurology department or other departments.
Previous studies found that anxiety-distress develops later and is more common in women [27–28], consistent with our findings. Meanwhile, several studies found that anxiety-distress has a slow onset, often accompanied by suicidal thoughts, more severe depression, and a delayed response to anti-depression treatment [28–30]. This finding differs from our study findings, in which the six patients showed subacute onset: three patients had prolonged anxiety and depression, even more than one year. Despite this change, symptoms presented an episodic-remitting-relapsing (aggravating) state. We hypothesized that the three patients were not correctly identified at the early stage of the disease. Therefore, AE was not considered until the patients developed new symptoms with poor efficacy and delayed conditions.
4.7 Mechanisms of Depression in Autoimmune Encephalitis
Previous studies [10–12] found that depression may occur during anti-CASPR2 encephalitis but can be easily misdiagnosed as a psychiatric disease. All patients in this study had symptoms of depression initially, accompanied by anxiety such as worry, tension, fear, and insomnia, consistent with previous findings [12]. Planaguma [31] et al. used animal experiments to validate that anti-NMDA encephalitis produces depression-like symptoms. They suggested that depression results from underlying biological mechanisms related to immune activation rather than a response to stress [26]. The study found that autoantibodies can cause central nervous system diseases in several ways: (1) Autoantibodies form immune complexes deposited in the brain, activating the classical complement pathway. (2) Autoantibody-driven caspase-induced apoptosis via calcium influx. (3) Autoantibody-mediated decline in neurotransmitter receptors and monoamine concentrations. (4) Autoantibody-mediated interference with nutrient absorption. Collectively, these processes result in disturbed neurotransmitter synthesis, endocrine dysfunction, changes in peripheral tissue, synaptic dysfunction, the generation of a proinflammatory environment and oxygen free radicals, and altered neurotrophin synthesis, ultimately resulting in depressive-like symptoms [26].
In a study by Nishimura et al. [32], functional near-infrared spectroscopy was employed to investigate patients with anxiety. Results showed that anxiety symptoms are related to the right lateral prefrontal cortex. Depressive symptoms negatively correlate with activation of the right lateral prefrontal lobe [33]. The gene encoding CASPR2, contact protein-like II genes (CNTNAP2), is highly expressed throughout the brain and spinal cord. CNTNAP2 is highly expressed in the frontal lobe, prefrontal lobe, striatum, and dorsal thalamus during human brain development. This expression pattern forms the cortico-striatum-thalamus circuit. This circuit regulates higher cognitive functions, including speech, language, reward, and the frontal lobe's executive functions [34]. This study demonstrated that the symptoms of depression and anxiety in patients with anti-CASPR2 encephalitis, with depression as the first symptom, are related to the expression of CNTNAP2 in the frontal lobe. Depressed patients with anti-CASPR2 encephalitis were susceptible to cognitive dysfunction, especially significant impairment in the wiring test in the MoCA, which may be related to a decline in executive functions of the frontal lobe. Simultaneously, such patients often present autonomic nervous disorders, possibly related to anti-CASPR2 encephalitis's ease of imitating neurodegenerative diseases [18].
4.8 Treatment of Anti-CASPR2 Encephalitis
Patients with anti-CASPR2 encephalitis respond well to immunotherapy. The commonly used first-line treatments are steroids, IVIG, plasma exchange, or both. Second-line therapies such as rituximab, cyclophosphamide, or other drugs can be selected if their efficacy remains poor [13]. Monoclonal antibodies and interleukin-6 receptor antagonist medication are effective when first - and second-line drug therapies fail [18]. Electroconvulsive therapy is a possible alternative to immunotherapy in anti-NMDA encephalitis with significant psychiatric symptoms, but its efficacy is unclear in anti-CASPR2 encephalitis [35].
All patients in this study attended psychiatry or neurology department for depression in the past and were diagnosed with a primary psychiatric disease. Depression in several patients was alleviated after receiving mood-regulating drugs, which may be related to the regulation of neurotransmitter and monoamine concentrations by SSRIs or SNRIs. Although the patients were in remission, they were not completely cured. After receiving immunotherapy, five out of six patients fully recovered, and only one had residual symptoms. No patient was treated with SSRIs or SNRIs. No recurrence was observed during follow-up for 24 weeks after discharge, and the serum anti-CASPR2 antibodies were negative upon re-examination.