Contactin-2 associated protein (CASPR2) autoimmune neurological conditions: Detailed clinical phenotype and antibody quantification
0
Citation
0
Reference
10
Related Paper
Keywords:
Neuromyotonia
Autoimmune encephalitis
Limbic Encephalitis
Clinical phenotype
Antibodies against CASPR2 (Contactin-2 Associated Protein), a neuroglial cell-adhesion protein, have been described in at least three neurological syndromes: autoimmune limbic encephalitis, acquired neuromyotonia (or Isaacs' syndrome) and Morvan syndrome. However, the clinical phenotype associated with anti-CASPR2 antibodies is not yet completely understood. In addition, some authors consider that instead of specific syndromes, anti-CASPR2 antibodies associate with a set of core symptoms that combine randomly in the patients. Last, the pathophysiologic factors underpinning clinical variability in the anti-CASPR2 antibodies patients are unknown. In this PhD project, we use a nationwide, retrospective cohort of anti-CASPR2 antibodies patients, in order to address the issue of the clinical characterization of anti-CASPR2 antibodies patients. We aimed at describing the clinical presentation of CASPR2 encephalitis and Morvan syndrome, studying the outcomes of CASPR2 encephalitis, and analyzing the repartition of the patients' symptoms in order to assess if the symptoms are distributed randomly or if instead they form distinct clinical patterns. The present PhD project is divided into three studies. In the first study, we analyze clinical presentations and outcomes of anti-CASPR2 antibodies patients with limbic encephalitis. We observe that most patients were males from 50 to 75 years old, and frequently had extra-limbic symptoms, such as cerebellar ataxia. In addition, response to immunotherapy was good, even though 25% of the patients did not return to baseline and were left with residual symptoms, including cognitive disturbances, epilepsy, and cerebellar ataxia. In the second study, we describe the first reported cases of autoimmune episodic ataxia, a novel symptom that so far has been found only in anti-CASPR2 antibody associated autoimmune limbic encephalitis patients. It consists in transient episodes of paroxysmal ataxia, and is reminiscent of hereditary episodic ataxia. Interestingly, we found in two patients rare variants of CACNA1A and KCNA1, two genes involved in the main types of hereditary episodic ataxia. While the impact of these variants on ion channel functions is unknown, it raises the question of the role of the genetic background in phenotype determination in anti-CASPR2 antibodies patients. In the third study, we use a statistical cluster analysis to assess anti-CASPR2 antibodies patients' symptoms combinations. We found that the symptoms do not form random combinations, but that instead clinical patterns can be identified, which correspond to patients with limbic encephalitis, Morvan syndrome, and neuromyotonia. In addition, we confirm the expansive clinical presentation of limbic encephalitis, since more than a third of the patients had non-limbic symptoms such as cerebellar ataxia, dysautonomia, weight loss, and movement disorders. Notably, less than ten percent of the patients had a combination of neuromyotonia and limbic symptoms. Finally, the Morvan syndrome patients had severe peripheral nerve hyperexcitability features, severe dysautonomia, severe insomnia, weight loss, and frequently had a malignant thymoma. This clinical classification into three specific syndromes is supported by differences in term of autoantibody specificities, as limbic encephalitis patients tended to have higher anti-CASPR2 antibodies levels and were more frequently cerebrospinal fluid-positive, and by the genetic background, since the Morvan syndrome patients did not have the HLA DRB1*1101 association that is found in limbic encephalitis patients. In conclusion, the present PhD project supports the view that anti-CASPR2 antibodies patients can be classified into three specific syndromes, autoimmune limbic encephalitis, neuromyotonia, and Morvan syndrome. Differences in etiopathogeny likely account for the clinical variability observed in anti-CASPR2 antibodies patients
Neuromyotonia
Limbic Encephalitis
Autoimmune encephalitis
Cerebellar ataxia
Cite
Citations (0)
Neuromyotonia
Limbic Encephalitis
Peripheral Nervous System
Cite
Citations (0)
The description of VGKC antibodies detected by radioimmunoassay (RIA) led to mischaracterizing as autoimmune an extensive number of syndromes in many patients who in fact did not have autoimmune disorders. We now know that VGKC antibodies demonstrated by RIA have no clinical value, unless the presence of LGI1 and CASPR2 antibodies are demonstrated by cell-based assays. Limbic encephalitis is by far the most frequent disorder associated with LGI1 antibodies. It usually occurs in the elderly (median age ~65 years) and ~65% are male. Anti-LGI1 encephalitis is frequently preceded by faciobrachial dystonic seizures that are very characteristic of this disorder and should prompt early-onset immunotherapy to prevent the development of memory and cognitive deficits. Most patients do not have cancer or other types of tumours, with the exception of thymoma in a few cases. Patients with CASPR2 antibodies may present with symptoms of encephalitis or peripheral nervous system hyperexcitability (neuromyotonia), and sometimes they develop Morvan syndrome. This disorder is characterized by a severe sleep dysfunction named agrypnia excitata, along with hallucinations, cognitive decline, dysautonomia, and neuromyotonia. Up to 50% of patients with Morvan syndrome have an underlying thymoma. As with other encephalitis associated with antibodies against neuronal surface antigens, patients with encephalitis associated with LGI1 and CASPR2 antibodies usually respond to immunotherapy.
Neuromyotonia
Limbic Encephalitis
Autoimmune encephalitis
Dysautonomia
Cite
Citations (0)
Twenty years since the discovery of voltage-gated potassium channel (VGKC)-related autoimmunity; it is currently known that the antibodies are not directed at the VGKC itself but to two closely associated proteins, anti-leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (Caspr2). Antibodies to LGI1 and Caspr2 give well-described clinical phenotypes. Anti-LGI1 encephalitis patients mostly have limbic symptoms, and anti-Caspr2 patients have variable syndromes with both central and peripheral symptoms. A large group of patients with heterogeneous symptoms are VGKC positive but do not have antibodies against LGI1 or Caspr2. The clinical relevance of VGKC positivity in these 'double-negative' patients is questionable. This review focusses on these three essentially different subgroups.The clinical phenotypes of anti-LGI1 encephalitis and anti-Caspr2 encephalitis have been described in more detail including data on treatment and long-term follow-up. A specific human leukocyte antigen (HLA) association was found in nontumor anti-LGI1 encephalitis, but not clearly in those with tumors. There has been increasing interest in the VGKC patients without LGI1/Caspr2 antibodies questioning its relevance in clinical practice.Anti-LGI1 encephalitis and anti-Caspr2 encephalitis are separate clinical entities. Early recognition and treatment is necessary and rewarding. The term VGKC-complex antibodies, lumping patients with anti-LGI1, anti-Caspr2 antibodies or lacking both, should be considered obsolete.
Limbic Encephalitis
Autoimmune encephalitis
Neuromyotonia
Clinical Significance
Cite
Citations (63)
Biochemical biomarkers are important candidates for the diagnosis and prognosis of neurological diseases of autoimmune etiology, since they may reflect the presence, nature and intensity of certain immune responses caused by both genetic and environmental processes. Different body fluids such as cerebrospinal fluid (CSF), serum, urine, and tears have been used to identify useful biomarkers. Autoimmune neurological diseases associated with pathology of cell surface structures such as myasthenia gravis, Lambert-Eaton myasthenic syndrome, neuromyotonia, stiff person syndrome, limbic encephalitis, Guillain-Barré syndrome (GBS), and neuromyelitis optica (NMO) are amenable to serum antibody tests which can be used to support the diagnosis. In several of these disorders, new specific autoantibodies have been detected that are directed against proteins complexed with potassium channels in both the central and peripheral nervous system such as contactin-2 associated protein (Caspr2) or the protein leucine-rich, glioma-inactivated 1 (LGI1). Recently, a number of central nervous system disorders like limbic encephalitis and multiple sclerosis (MS) have also been associated with the presence of specific serum autoantibodies. In MS and GBS CSF analysis is still essential to support the diagnosis and to rule out other diseases. We provide an overview over the widening field of autoimmune diseases of the central and peripheral nervous system and discuss the current state of biomarker research and its relevance for clinical practice. Keywords: Biochemical markers, cerebrospinal fluid, myasthenia, neuromyotonia, stiff person syndrome, limbic encephalitis, Guillain-Barre syndrome, neuromyelitis optica, multiple sclerosis, cerebrospinal fluid (CSF).
Limbic Encephalitis
Neuromyotonia
Autoimmune encephalitis
Neuromyelitis Optica
Acute disseminated encephalomyelitis
Demyelinating Disorder
Cite
Citations (14)
Abstract Since its first recognition in 2001, hundreds of patients have been identified with autoimmune limbic encephalitis (LE) associated with antibodies that immunoprecipitate voltage-gated potassium channel (VGKC)-complex proteins. Preliminary epidemiology suggests that it is more common in men (2:1) and that the median age at onset is 65 years. The phenotype has been recognized mainly in patients over the age of 18 years at onset. The classic presentation is with subacute onset of short-term memory loss, seizures, disorientation, with psychological disturbance or hallucinations. Additional features that may occur are sleep disturbance, autonomic dysfunction, and neuromyotonia, but these would be more typical of Morvan’s syndrome.
Neuromyotonia
Limbic Encephalitis
Autoimmune encephalitis
Cite
Citations (0)
Limbic Encephalitis
Neuromyotonia
Peripheral Nervous System
Cite
Citations (1)
Continuous muscle activity, Morvan's syndrome and limbic encephalitis: ionic or non ionic disorders?
The early pathophysiologic study showed increasing evidence that autoimmunity is implicated in the pathogenesis of neuromyotonia. Antibodies to voltage gated potassium channel were detected in the serum of patients who had peripheral nerves hyperexcitability and also Morvan's disease or limbic encephalitis. These discoveries offered new approaches to treatments. Recently, antibodies previously attributed to VGKC recognise 2 surface antigens LGI1 and CASPR2 into the VGKC complex. Finally, VGKC antibodies are directed to 2 proteins the first one is a key hippocampic protein containing pre and post synaptic proteins. The second one CASPR2 is an hippocampic and paranodal protein. There clinical significance is different: hyperexcitability, limbic encephalitis without thymoma for LGI1, hyperexcitability, Morvan limbic encephalitis and frequent thymoma for CASPR2. In conclusion, the term NMT--LE--VGKC should be changed to NMT--LE with LGII and CASPR2 antibodies and classified as auto immune synaptic disorders. Mutations in genes encoding both these proteins are found in hereditary epilepsy and other syndromes. Various potassium channelopathies are closely linked to Morvan's syndromes. A new classification of antibodies will be necessary.
Neuromyotonia
Limbic Encephalitis
Autoimmune encephalitis
Myokymia
Cite
Citations (6)
Limbic encephalitis (LE) with antibodies against leucine-rich glioma inactivated protein 1 (LGI1) is an autoimmune disease with variable clinical features, including seizures, cognitive disorders, psychiatric disturbances, and hyponatremia. The majority of these patients present faciobrachial dystonic seizures (FBDS), which are regarded as a characteristic symptom. A few cases have reported pilomotor seizures as the main manifestation of anti-LGI1 encephalitis. Here, we described a Chinese woman with frequent pilomotor seizures who was finally diagnosed as having anti-LGI1 encephalitis. Our report emphasizes the possible significance of pilomotor seizures in anti-LGI1 encephalitis.
Limbic Encephalitis
Autoimmune encephalitis
Cite
Citations (11)
The early pathophysiologic study showed increasing evidence that autoimmunity is implicated in the pathogenesis of neuromyotonia. Antibodies to voltage gated potassium channel were detected in the serum of patients who had peripherical nerves hyperexcitability and also Morvan's disease or limbic encephalitis. These discoveries offered new approaches to treatments.
Recently, antibodies previously attributed to VGKC recognise 2 surface antigens LGI1 and CASPR2 into the VGKC complex. Finally, VGKC antibodies are directed to 2 proteins the first one is a key hippocampic protein containing pre and post synaptic proteins. The second one CASPR2 is an hippocampic and paranodal protein. There clinical significance is different: hyperexcitability limbic encephalitis without thymoma for LGI1, hyperexcitability Morvan limbic encephalitis and frequent thymoma for CASPR2.
In conclusion, the term NMT - LE - VGKC should be changed to NMT- LE with LGI1 and CASPR2 antibodies and classified as auto immune synaptic disorders.
Limbic Encephalitis
Neuromyotonia
Voltage-gated potassium channel
Cite
Citations (0)