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ObjectiveAntibodies against contactin-associated protein-like 2 (CASPR2-Abs) have been described in acquired neuromyotonia, limbic encephalitis (LE) and Morvan syndrome (MoS). However, it is unknown whether these constitute one sole spectrum of diseases with the same immunopathogenesis or three distinct entities with different mechanisms.MethodsA cluster analysis of neurological symptoms was performed in a retrospective cohort of 56 CASPR2-Abs patients. In parallel, immunological features and human leucocyte antigen (HLA) were studied.ResultsCluster analysis distinguished patients with predominant limbic symptoms (n=29/56) from those with peripheral nerve hyperexcitability (PNH; n=27/56). In the limbic-prominent group, limbic features were either isolated (LE/−; 18/56, 32.1%), or combined with extralimbic symptoms (LE/+; 11/56, 19.6%). Those with PNH were separated in one group with severe PNH and extralimbic involvement (PNH/+; 16/56, 28.6%), resembling historical MoS descriptions; and one group with milder and usually isolated PNH (PNH/−; 11/56, 19.6%). LE/− and LE/+ patients shared immunogenetic characteristics demonstrating a homogeneous entity. HLA-DRB1*11:01 was carried more frequently than in healthy controls only by patients with LE (94.1% vs 18.3%; p=1.3×10−10). Patients with LE also had serum titres (median 1:40 960) and rates of cerebrospinal fluid positivity (93.1%) higher than the other groups (p<0.05). Conversely, DRB1*11:01 association was absent in PNH/+ patients, but only they had malignant thymoma (87.5%), serum antibodies against leucine-rich glioma-inactivated 1 protein (66.7%) and against netrin-1 receptor deleted in colorectal carcinoma (53.8%), and myasthenia gravis (50.0%).InterpretationSymptoms’ distribution supports specific clinical phenotypes without overlap between LE and MoS. The distinct immunogenetic characteristics shared by all patients with LE and the particular oncological and autoimmune associations of MoS suggest two very different aetiopathogenesis.

Contactin-associated protein-like 2 (CASPR2) and leucine-rich glioma-inactivated 1 (LGI1) are essential components of the voltage-gated Kv1 potassium channel complex and are extensively expressed in both central and peripheral nervous system. Autoimmune CASPR2 and LGI1 disorders commonly present with Morvan syndrome (Mos) and/or limbic encephalitis, but whether Guillain–Barré syndrome (GBS) is a specific clinical phenotype is unknown. Here, we first reported an adult patient with dual CASPR2 and LGI1 antibodies in both serum and cerebrospinal fluid, who initially presented with a GBS-like syndrome and developed a typical MoS and respiratory paralysis, with a rapid resolution of his neurological symptoms and disappearance of autoantibodies after treatment with plasma exchange. Additionally, we also provided an overview of the previously reported GBS cases associated with CASPR2 or LGI1 antibodies. These cases expand the phenotypic spectrum of CASPR2 and LGI1 autoimmune syndromes, implying that these two antigens, especially CASPR2, are likely to participate in the etiology of GBS as a potential new target antigen, which deserves further exploration.

Background Contactin-associated protein-like 2 (CASPR2) autoantibody disease has a variable clinical phenotype. We present a case report and performed a systematic review of the literature to summarize: (1) the clinical phenotype of patients with CASPR2 antibodies, (2) the findings in neurological investigations, and (3) the associated neuroimaging findings. Methods A chart review was performed for the case report. A systematic review of the medical literature was performed from first available to June 13, 2018. Abstracts were screened, and full-text peer-reviewed publications for novel patients with CASPR2 positivity in serum or cerebrospinal fluid (CSF) were included. Selected publications were reviewed, and relevant information was collated. Data were analyzed to determine overall frequency for demographic information, clinical presentations, and investigation findings. Results Our patient was a previously healthy 61-year-old male with both serum and CSF CASPR2 antibodies who presented with limbic encephalitis and refractory epilepsy. He was successfully treated with immunosuppression. For our systematic review, we identified 667 patients from 106 studies. Sixty-nine percent were male. Median age was 54 years (IQR 39–65.5). Median disease duration was 12 months (IQR 5.6–20). Reported overall clinical syndromes were: autoimmune encephalitis [69/134 (51.5%)], limbic encephalitis [106/274 (38.7%)], peripheral nerve hyperexcitability [72/191 (37.7%)], Morvan syndrome [57/251 (22.7%)], and cerebellar syndrome [24/163 (14.7%)]. Patients had positive serum [642/642 (100%)] and CSF [87/173 (50.3%)] CASPR2 antibodies. MRI was reported as abnormal in 159/299 patients (53.1%), and the most common abnormalities were encephalitis or T2 hyperintensities in the medial temporal lobes, or hippocampal atrophy, mesial temporal sclerosis, or hippocampal sclerosis. FDG-PET was abnormal in 30/35 patients (85.7%), and the most common abnormality was temporomesial hypometabolism. The most commonly associated condition was myasthenia gravis (38 cases). Thymoma occurred in 76/348 patients (21.8%). Non-thymoma malignancies were uncommon [42/397 (10.6%)]. Conclusions Most patients have autoimmune or limbic encephalitis and corresponding abnormalities on neuroimaging. Other presentations include peripheral nerve hyperexcitability or Morvan syndromes, cerebellar syndromes, behavioral and cognitive changes, and more rarely movement disorders. The most commonly associated malignancy was thymoma and suggests a role for thymoma screening in CASPR2-related diseases.

Abstract Study Objectives Rapid eye movement (REM) sleep behavior disorder (RBD) and other sleep disturbances are frequent in leucine-rich, glioma inactivated protein 1-IgG (LGI1) and contactin-associated protein 2-IgG (CASPR2) autoimmunity, yet polysomnographic analyses of these disorders remain limited. We aimed to characterize clinical presentations and analyze polysomnographic manifestations, especially quantitative REM sleep without atonia (RSWA) in LGI1/CASPR2-IgG seropositive (LGI/CASPR2+) patients. Methods We retrospectively analyzed clinical and polysomnographic features and quantitative RSWA between LGI1+/CASPR2+ patients and age-sex matched controls. Groups were compared with Wilcoxon rank-sum and chi-square tests. Combined submentalis and anterior tibialis (SM + AT) RSWA was the primary outcome. Results Among 11 (LGI1+, n = 9; CASPR2+, n = 2) patients, Morvan syndrome sleep features were present in seven (63.6%) LGI1+/CASPR2+ patients, with simultaneous insomnia and dream enactment behavior (DEB) in three (27.3%), and the most common presenting sleep disturbances were DEB (n = 5), insomnia (n = 5), and sleep apnea (n = 8; median apnea-hypopnea index = 15/hour). Median Epworth Sleepiness Scale was nine (range 3–24; n = 10), with hypersomnia in four (36.4%). LGI1+/CASPR2+ patients had increased N1 sleep (p = .02), decreased REM sleep (p = .001), and higher levels of SM + AT any RSWA (p < .001). Eight of nine (89%) LGI1+ exceeded RBD RSWA thresholds (DEB, n = 5; isolated RSWA, n = 3). RSWA was greater in AT than SM. All 10 LGI1+/CASPR2+ patients treated with immunotherapy benefitted, and 5/10 had improved sleep disturbances. Conclusions LGI1/CASPR2-IgG autoimmunity is associated with prominent dream enactment, insomnia, RSWA, sleep apnea, and shallower sleep. Polysomnography provides objective disease markers in LGI1+/CASPR2+ autoimmunity and immunotherapy may benefit associated sleep disturbances.

Morvan syndrome is a rare autoimmune disorder characterized by peripheral nerve hyperexcitability with autonomic and central nervous system involvement, most commonly associated with antibodies against contactin-associated protein-like 2 (CASPR2). Acute motor and sensory axonal neuropathy (AMSAN) is an axonal variant of Guillain-Barré syndrome linked to anti-ganglioside antibodies and often manifests as severe limb weakness. Their concurrent presentation is unusual and raises the possibility of shared immune targets within peripheral nerve microdomains. A 70-year-old man presented with a relapsing course of progressive lower-limb weakness accompanied by widespread muscle twitching, severe insomnia with nocturnal hyperarousal, and refractory constipation. He had a prior episode diagnosed as AMSAN that improved after immunotherapy but relapsed four months after treatment was discontinued. Neurological examination demonstrated bilateral lower-limb weakness with reduced tendon reflexes. Moreover, electrophysiological studies confirmed diffuse multifocal peripheral nerve injury with superimposed peripheral nerve hyperexcitability. In addition, immunologic testing revealed serum anti-GM1 antibodies and anti-CASPR2 IgG in both serum and cerebrospinal fluid. Collectively, these findings supported a diagnosis of recurrent AMSAN coexisting with CASPR2-associated Morvan syndrome. Combined immunotherapy with corticosteroids and intravenous immunoglobulin, alongside symptomatic management, resulted in marked clinical improvement. This case report describes a rare overlap of relapsing AMSAN and Morvan syndrome. This antibody-defined coexistence is hypothesis-generating and may reflect synergistic immune injury involving nodal and paranodal regions. This case underscores the importance of recognizing overlapping phenotypes to guide diagnostic profiling and immunomodulatory therapy.

The disorders of the central nervous system associated with cancer by remote immune-mediated mechanisms are a heterogeneous group. These disorders encompass the classic paraneoplastic disorders and the recently recognized autoimmune encephalitis associated with antibodies against neuronal cell surface or synaptic proteins that occur with or without cancer association. In the last decade, the new surge of interest in neuronal diseases associated with anti-neuronal antibodies led to the rapid discovery of new forms of disease that have different manifestations and were not previously suspected to be immune mediated. The recognition of these syndromes is important because it may lead to early detection of an underlying malignancy and prompt initiation of treatment, improving chances for a better outcome.

Background Contactin-associated protein-like 2 (CASPR2) antibody-related neurological syndrome is well defined in adults, while data in children is rare. We perform this case series and literature review to ascertain the clinical features of this disorder in children. Case presentations We describe three cases who were diagnosed with CASPR2 antibody-related neurological syndrome, and then systematically characterized clinical features, therapeutic responses, and outcomes in 64 patients in literature. Among the 67 patients, the median age was 8.4 years (range 0.5–18), with a male predominance (65.7%). The most characteristic symptoms of CASPR2 antibody-related neurological syndrome include psychiatric abnormalities (68.7%), sleep disorders (55.2%), dysautonomia (44.8%), movement disorders (43.3%), seizures (41.8%), neuropathic pain (34.3%), and cognitive disturbances (31.3%). Autoimmune encephalitis (AE, 62.7%) was most frequent, followed by Morvan syndrome (MoS, 26.9%) and peripheral nerve hyperexcitability (PNH, 7.5%). CASPR2 antibodies are typically detected in serum (85.1%), but rarely in CSF exclusively (3.0%). Investigations revealed abnormalities in CSF analysis (22.9%; 13 AE, 5 MoS), brain MRI (24.1%; 11 AE, 3 MoS), and EEG (67.3%; 26 AE, 7 MoS). Neoplasm was not found in our case series and literature review. Regarding treatment, 46 patients received first-line immunotherapy alone, while 5 required second-line treatment. Immunotherapy demonstrated highly effective, with 95.8% achieving a favorable outcome (mRS score ≤ 2) and a low recurrence rate of 5.1%. Conclusions We therefore recommend that all children presenting with new-onset psychiatric abnormalities, sleep disorders, dysautonomia, movement disorders, seizures, neuropathic pain, and cognitive disturbances should be suspected of having CASPR2 antibody-related neurological syndrome. Neoplastic processes are rare in pediatric patients. Early recognition of the disease is important because it responds well to immunotherapy.

Morvan syndrome is a rare subtype of autoimmune encephalitis, primarily characterized by increased peripheral nerve excitability, autonomic dysfunction, and severe insomnia. This report presents a 28-year-old female patient who sought medical attention due to widespread pain, refractory insomnia, limb sensory abnormalities, and low mood, initially diagnosed as \"anxiety disorder\". Neurological examination revealed muscle twitching in the limbs. Electromyography indicated increased peripheral nerve excitability, with serum testing showing weak positivity for anti-Leucine-rich Glioma Inactivated 1 (LGI-1) IgG antibodies and strong positivity for anti-Contactin-associated Protein-like 2 (CASPR2) IgG antibodies. Cerebrospinal fluid Pandy's test was weakly positive. The final diagnosis was Morvan syndrome complicated by anxiety disorder. Following treatment, the patient's symptoms significantly improved. This case highlights the diagnostic challenges of Morvan syndrome, particularly when patients present with prominent psychiatric symptoms that mimic functional disorders. It underscores the critical importance of screening for subtle organic signs-specifically fasciculations and widespread pain-in patients with refractory anxiety to prevent misdiagnosis and facilitate timely immunotherapy.

Anti-contactin-associated protein-like 2 (CASPR2) is classically associated with limbic encephalitis (LE), Morvan syndrome and peripheral nerve hyperexcitability (PNH). Additional clinical features have been previously recognized. To describe a cohort of patients with anti-CASPR2-associated neurological syndromes from a tertiary referral centre. Retrospective analysis of patients with positive serum anti-CASPR2 antibodies in the period between 2014 and 2021. Nineteen patients were identified, 11 (57.9%) male, with a median age at symptom onset of 49.0 (31.3–63.0) years and a median time to diagnosis of 1.0 (0.0–1.8) years. The most common clinical syndromes were LE (7 cases, 36.8%), Morvan syndrome (4, 21.1%) and PNH (2, 10.5%). Six patients presented with atypical phenotypes (31.6%), comprising dysautonomia (orthostatic hypotension and Adie’s Pupil), motor tics/stereotypies, obsessive-compulsive disorder, and brainstem involvement. The most common presenting symptoms were seizures (31.6%), PNH (21.1%) and cognitive dysfunction (15.8%). One LE patient had a disease duration of 2,5 years and was initially diagnosed with dementia. CSF was normal in most cases. Brain MRI showed temporal lobe hyperintensities in 4 LE cases (57.1%). All PNH cases had myokymic discharges of fasciculations in the electromyography. Two patients had associated thymoma and 1 had lung adenocarcinoma. Eight patients (42.1%) received treatment during the acute phase and 26.3% maintenance treatment. Approximately half of the treated cases improved or stabilised, with 4 (21.1%) deaths in the whole cohort. Anti-CASPR2-associated neurological disorders may present with isolated atypical phenotypes, a slowly progressive clinical course, and with normal CSF or imaging findings. •The most syndromes were limbic encephalitis (36.8%), Morvan syndrome (21.1%) and peripheral nerve hyperexcitability (10.5%).•Six patients presented with atypical phenotypes (31.6%), including motor tics/stereotypies and obsessive-compulsive disorder.•Patients may present with a slowly progressive clinical course and normal cerebrospinal fluid or imaging findings.