Prezentujeme kazuistiku 61letého muže s rychlým rozvojem epileptických záchvatů, encefalopatie, deliria, syndromu periferní hyperexcitability a dysautonomie, u kterého byly prokázány anti-Caspr2 protilátky a jehož stav se rychle upravil po léčbě vysokými dávkami kortikosteroidů. Následně uvádíme krátký přehled patofyziologie anti-Caspr2 syndromů, přehled klinického spektra obtíží s důrazem na typický Morvanův syndrom, diagnostiku a terapii těchto syndromů.

We present a case report of a 61-year-old man with an acute onset of epileptic seizures, encephalopathy, delirium, peripheral nerve hyperexcitability syndrome and dysautonomy with indentified anti-Caspr2 antibodies whose clinical status has promptly improved after a high dose of corticosteroids. Subsequently a short review of anti-Caspr2 pathophysiology, spectrum of clinical manifestation with emphasis put on a typical Morvan syndrome, diagnostics and treatment of these conditions is presented.

• Klíčová slova
• anti-Caspr2, Morvanův syndrom,
• MeSH
• autoimunitní nemoci nervového systému * diagnóza   terapie   MeSH
• encefalitida * diagnóza   terapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Contactin-associated protein-like 2 (CNTNAP2) encodes for CASPR2, a multidomain single transmembrane protein belonging to the neurexin superfamily that has been implicated in a broad range of human phenotypes including autism and language impairment. Using a combination of biophysical techniques, including small angle x-ray scattering, single particle electron microscopy, analytical ultracentrifugation, and bio-layer interferometry, we present novel structural and functional data that relate the architecture of the extracellular domain of CASPR2 to a previously unknown ligand, Contactin1 (CNTN1). Structurally, CASPR2 is highly glycosylated and has an overall compact architecture. Functionally, we show that CASPR2 associates with micromolar affinity with CNTN1 but, under the same conditions, it does not interact with any of the other members of the contactin family. Moreover, by using dissociated hippocampal neurons we show that microbeads loaded with CASPR2, but not with a deletion mutant, co-localize with transfected CNTN1, suggesting that CNTN1 is an endogenous ligand for CASPR2. These data provide novel insights into the structure and function of CASPR2, suggesting a complex role of CASPR2 in the nervous system.

• MeSH
• difrakce rentgenového záření MeSH
• HEK293 buňky MeSH
• hipokampus cytologie   metabolismus   MeSH
• kontaktin 1 metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• maloúhlový rozptyl MeSH
• mapy interakcí proteinů MeSH
• membránové proteiny chemie   metabolismus   ultrastruktura   MeSH
• molekulární modely MeSH
• myši inbrední C57BL MeSH
• proteiny nervové tkáně chemie   metabolismus   ultrastruktura   MeSH
• terciární struktura proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

BACKGROUND AND OBJECTIVES: Patients with ongoing seizures are usually not allowed to drive. The prognosis for seizure freedom is favorable in patients with autoimmune encephalitis (AIE) with antibodies against NMDA receptor (NMDAR), leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and the gamma-aminobutyric-acid B receptor (GABABR). We hypothesized that after a seizure-free period of 3 months, patients with AIE have a seizure recurrence risk of <20% during the subsequent 12 months. This would render them eligible for noncommercial driving according to driving regulations in several countries. METHODS: This retrospective multicenter cohort study analyzed follow-up data from patients aged 15 years or older with seizures resulting from NMDAR-, LGI1-, CASPR2-, or GABABR-AIE, who had been seizure-free for ≥3 months. We used Kaplan-Meier (KM) estimates for the seizure recurrence risk at 12 months for each antibody group and tested for the effects of potential covariates with regression models. RESULTS: We included 383 patients with NMDAR-, 440 with LGI1-, 114 with CASPR2-, and 44 with GABABR-AIE from 14 international centers. After being seizure-free for 3 months after an initial seizure period, we calculated the probability of remaining seizure-free for another 12 months (KM estimate) as 0.89 (95% confidence interval [CI] 0.85-0.92) for NMDAR, 0.84 (CI 0.80-0.88) for LGI1, 0.82 (CI 0.75-0.90) for CASPR2, and 0.76 (CI 0.62-0.93) for GABABR. DISCUSSION: Taking a <20% recurrence risk within 12 months as sufficient, patients with NMDAR-AIE and LGI1-AIE could be considered eligible for noncommercial driving after having been seizure-free for 3 months.

• MeSH
• autoprotilátky * krev   MeSH
• dospělí MeSH
• encefalitida * imunologie   MeSH
• Hashimotova nemoc imunologie   krev   MeSH
• intracelulární signální peptidy a proteiny * imunologie   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové proteiny * imunologie   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• následné studie MeSH
• proteiny nervové tkáně * imunologie   MeSH
• proteiny imunologie   MeSH
• receptory GABA-B * imunologie   MeSH
• receptory N-methyl-D-aspartátu imunologie   MeSH
• recidiva * MeSH
• retrospektivní studie MeSH
• senioři MeSH
• záchvaty etiologie   imunologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

Úvod: Protilátky proti membránovým a synaptickým antigenům jsou přímo patogenní protilátky sdružené s pestrou paletou neurologických syndromů. Různorodost příznaků komplikuje stanovení dia­gnózy, a tím i včasné zahájení imunoterapie. Cíl: Cílem práce bylo popsat klinické charakteristiky pa­cientů s pozitivitou uvedených protilátek. Metodika a soubor: V období dvou let jsme zjišťovali přítomnost protilátek proti membránovým a synaptickým antigenům u 224 pa­cientů. Metodou nepřímé imunofluorescence byly vyšetřeny protilátky proti N‑metyl‑D‑aspartátovému receptoru (anti‑NMDAR), α‑amino‑3-hydroxy‑5-metyl‑4-izoxazolepropionátovému receptoru (anti‑AMPAR 1 a 2), B‑receptoru kyseliny γ‑aminomáselné (anti‑GABABR), proti leucin‑rich‑glioma‑inactivated proteinu‑1 (anti‑LGI1) a proti contactin‑associated proteinu‑2 (anti‑CASPR2). U pozitivních pa­cientů byly retrospektivně zhodnoceny klinické projevy, nálezy pomocných metod a vývoj onemocnění. Pa­cienti s pozitivitou anti‑NMDAR protilátek nebyli do hodnocení zahrnuti. Výsledky: Autoprotilátky byly prokázány v séru 11 pa­cientů (medián 58 let, sedm mužů) – u šesti pa­cientů anti‑LGI1, u čtyř anti‑CASPR2, u dvou anti‑AMPAR1 (u jednoho pa­cienta současně anti‑AMPAR1 a anti‑CASPR2). Příznaky zahrnovaly epilepsii (n = 5), subakutní encefalopatii (n = 5), doprovázenou ve čtyřech případech epileptickými záchvaty, a mozečkový syndrom s doprovodným kognitivním deficitem (n = 1). U dvou pa­cientů byly současně přítomny dobře charakterizované onkoneurální protilátky (anti‑Hu, anti‑Ma2). Nádor (malobuněčný karcinom plic) byl zjištěn u jedné pa­cientky (anti‑AMPAR1). U osmi pa­cientů došlo po podání imunosuprese k remisi nebo částečnému zlepšení klinického stavu. Závěr: Přítomnost protilátek proti membránovým antigenům je sdružena nejčastěji s limbickou encefalitidou nebo fokální epilepsií, vzácněji s jinými neurologickými syndromy. Efekt imunoterapie závisí na jejím časném podání.

Background: Neuronal surface antibodies are associated with numerous neurological symptoms. Better knowledge of these symptoms may improve identification of potential candidates for immunotherapy. Aim: Characterize clinical signs in patients with neuronal surface antibodies positivity. Methods: We detected neuronal surface antibodies in 11/2011–12/2013 in 224 patients (224 in serum and 37 in cerebrospinal fluid). We investigated anti-NMDAR, anti-AMPAR1, anti-AMPAR2, anti-GABABR, anti-LGI1, anti-CASPR2 using cell-based assays for indirect immunofluorescence (Euroimmun AG). We retrospectively analyzed clinical characteristics of patients with positive neuronal surface antibodies in serum or cerebrospinal fluid other than anti-NMDAR positive patients. Results: Neuronal surface antibodies were detected in 11 patients (seven males, median age 58). Six patients had anti-LGI1, four anti-CASPR2 and two anti-AMPAR1 antibodies (one patient had both anti-CASPR2 and anti-AMPAR1 antibodies). Clinical symptoms included chronic epilepsy (n = 5), acute encephalopathy (n = 5) accompanied by epileptic seizures in four patients and one patient presented with cerebellar syndrome and cognitive deficit. Two patients had coincidence of paraneoplastic antibodies (anti-Hu, anti-Ma2). Tumor (small cell lung carcinoma) was diagnosed in one patient (anti-AMPAR1). Eight patients improved following immunotherapy (corticosteroids, IVIG). Early immunotherapy was associated with better outcome. Conclusion: NS-Abs were mostly associated with limbic encephalitis and chronic temporal lobe epilepsy. Immunotherapy had better effect when applied early in the disease course. Key words: autoimmune diseases – encephalitis – antibodies to cell-surface proteins – limbic encephalitis The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manu­script met the ICMJE “uniform requirements” for biomedical papers.

• MeSH
• autoimunitní nemoci MeSH
• autoprotilátky * krev   MeSH
• dospělí MeSH
• elektroencefalografie MeSH
• encefalitida s protilátkami proti NMDA receptorům krev   MeSH
• epilepsie parciální diagnóza   farmakoterapie   MeSH
• fluorescenční protilátková technika nepřímá MeSH
• glutamátové receptory analýza   MeSH
• imunosupresiva aplikace a dávkování   MeSH
• kognitivní poruchy etiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• limbická encefalitida * diagnóza   farmakoterapie   MeSH
• magnetická rezonanční tomografie MeSH
• membránové proteiny * krev   MeSH
• mozek radiografie   MeSH
• nemoci mozku * krev   radiografie   MeSH
• poruchy paměti etiologie   MeSH
• proteiny nervové tkáně analýza   MeSH
• proteiny analýza   MeSH
• receptory GABA-B analýza   MeSH
• receptory N-methyl-D-aspartátu analýza   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH

Autoimmune disease associated with anti-CASPR2 antibodies is a relatively rare neurological illness characterized by the presence of anti-CASPR2 antibodies in serum and/or CSF. It manifests with a variety of symptoms - from the central nervous system (cognitive impairment, epilepsy and cerebellar symptoms), from the peripheral nervous system (peripheral nerve hyperexcitability and neuropathic pain), and from the autonomic nervous system (autonomic dysfunction, insomnia and weight loss). Case report: The 61-year-old patient was admitted to the intensive care unit of our neurological department with myoclonic abdominal muscle twitching with intermittent generalization and right upper limb myoclonus, associated with behavioral change, cognitive deterioration, intermittent disorientation and aggression, bulbar syndrome, dysarthria, and dysautonomia (hypersalivation, bronchial hypersecretion, and circulatory instability). Due to progressive hypercapnia and loss of consciousness, the patient had to be intubated and connected to artificial pulmonary ventilation. EMG investigation demonstrated axonal motor polyneuropathy of both upper and lower limbs. Several unspecific gliotic lesions located in the white matter adjacent to the left cerebral ventricle were described on the brain MRI. Significant anti-CASPR2 antibody positivity was found both in serum and cerebrospinal fluid. Treatment with i.v. methylprednisolone and intravenous immunoglobulins was applied. With this treatment, the patient's neurological status gradually improved to the ability of verticalization. However, his cachectization, which was already present on admission, progressed despite the maximal effort in nutrition therapy. Also, repeated episodes of respiratory insufficiency resulting in transitory impairment of consciousness occurred. One such episode resulted in cardiac arrest followed by successful cardiopulmonary resuscitation. However, myoclonic jerks reappeared afterward and the patient's overall condition worsened. At this stage, it was decided not to further escalate and extend the treatment. Palliative treatment was commenced. The patient died during the following episode of respiratory failure. Comment: This case report of a patient with autoimmune disease associated with anti-CASPR2 antibodies highlights its multiple and often disease-unspecific clinical symptoms on the one hand, and on the other, its severe and ultimately fatal clinical course despite the initial effect of immunotherapy. Early diagnosis and early and aggressive immunomodulatory treatment are crucial in patients with this disorder.

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• MeSH
• autoimunitní nemoci nervového systému * diagnóza   farmakoterapie   imunologie   patologie   MeSH
• autoprotilátky analýza   imunologie   MeSH
• elektroencefalografie metody   MeSH
• elektromyografie metody   MeSH
• glukokortikoidy aplikace a dávkování   terapeutické užití   MeSH
• imunohistochemie metody   MeSH
• intravenózní imunoglobuliny aplikace a dávkování   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• limbická encefalitida diagnóza   farmakoterapie   imunologie   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

PURPOSE: Epileptic seizures are a common manifestation of autoimmune encephalitis, but the role of neural antibodies in long-term epilepsy remains unclear. The aim of this study was to assess the prevalence of neural-surface antibodies (NSAbs) and antibodies against glutamic acid decarboxylase (GAD) in patients with chronic temporal lobe epilepsy (TLE). METHOD: Patients with an electro-clinical diagnosis of TLE and a disease duration longer than one year were included. NSAbs (LGI1, CASPR2, AMPAR1/2, NMDAR, GABABR) and antibodies against GAD were detected. Only patients with significant antibody levels in serum, and/or positivity in CSF (according to antibody subtype), were enrolled in the seropositive group. Cohorts of seropositive and seronegative patients were compared regarding clinical and imaging data. RESULTS: Significant serum levels of antibodies were detected in eight out of 163 (5%) TLE patients (CASPR2 n = 2, GAD n = 3, LGI1 n = 2, and GABABR n = 1). In four of them, antibodies were detected in the CSF as well (CASPR2 in one, GAD in three). Five seropositive patients had uni- or bilateral temporal lobe lesions on MRI and three patients were non-lesional. All seropositive patients had TLE of unknown cause. Seropositive patients had higher age at epilepsy onset and autoimmune comorbidity, but did not differ in other clinical, EEG or neuroimaging characteristics. Response to immunotherapy (seizure reduction >50%) was observed in three of the six patients treated. CONCLUSIONS: Besides older age at epilepsy onset and autoimmune comorbidity, seropositive patients cannot be distinguished from seronegative patients on the basis of clinical, EEG or neuroimaging data.

• MeSH
• autoimunitní nemoci komplikace   epidemiologie   MeSH
• autoprotilátky krev   MeSH
• chronická nemoc MeSH
• dospělí MeSH
• epilepsie temporálního laloku komplikace   epidemiologie   patofyziologie   terapie   MeSH
• glutamát dekarboxyláza imunologie   MeSH
• imunoterapie MeSH
• komorbidita MeSH
• lidé středního věku MeSH
• lidé MeSH
• prevalence MeSH
• prospektivní studie MeSH
• proteiny nervové tkáně imunologie   MeSH
• senioři MeSH
• věk při počátku nemoci MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

We assessed the outcome of patients with drug resistant epilepsy and neuronal antibodies who underwent epilepsy surgery. Retrospective study, information collected with a questionnaire sent to epilepsy surgery centers. Thirteen patients identified, with antibodies to GAD (8), Ma2 (2), Hu (1), LGI1 (1) or CASPR2 (1). Mean age at seizure onset: 23 years. Five patients had an encephalitic phase. Three had testicular tumors and five had autoimmune diseases. All had drug resistant temporal lobe epilepsy (median: 20 seizures/month). MRI showed unilateral temporal lobe abnormalities (mainly hippocampal sclerosis) in 9 patients, bilateral abnormalities in 3, and was normal in 1. Surgical procedures included anteromesial temporal lobectomy (10 patients), selective amygdalohippocampectomy (1), temporal pole resection (1) and radiofrequency ablation of mesial structures (1). Perivascular lymphocytic infiltrates were seen in 7/12 patients. One year outcome available in all patients, at 3 years in 9. At last visit 5/13 patients (38.5%) (with Ma2, Hu, LGI1, and 2 GAD antibodies) were in Engel's classes I or II. Epilepsy surgery may be an option for patients with drug resistant seizures associated with neuronal antibodies. Outcome seems to be worse than that expected in other etiologies, even in the presence of unilateral HS. Intracranial EEG may be required in some patients.

• MeSH
• autoprotilátky krev   MeSH
• biologické markery krev   MeSH
• dítě MeSH
• dospělí MeSH
• epilepsie temporálního laloku komplikace   diagnostické zobrazování   imunologie   chirurgie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mozek diagnostické zobrazování   imunologie   patologie   chirurgie   MeSH
• následné studie MeSH
• prognóza MeSH
• průzkumy a dotazníky MeSH
• refrakterní epilepsie komplikace   diagnostické zobrazování   imunologie   chirurgie   MeSH
• retrospektivní studie MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Geografické názvy
• Evropa MeSH
• Spojené státy americké MeSH

• Klíčová slova
• antineuronální protilátky, CASPR2, LGI1, nepřímá imunohistochemie,
• MeSH
• antigeny povrchové imunologie   MeSH
• autoprotilátky * imunologie   krev   MeSH
• encefalitida s protilátkami proti NMDA receptorům * diagnóza   imunologie   patofyziologie   MeSH
• imunohistochemie metody   MeSH
• imunologické techniky metody   MeSH
• lidé MeSH
• limbická encefalitida * diagnóza   imunologie   patofyziologie   MeSH
• membránové proteiny imunologie   MeSH
• paraneoplastické neurologické syndromy diagnóza   imunologie   MeSH
• proteiny nervové tkáně imunologie   MeSH
• receptory GABA-B imunologie   MeSH
• receptory N-methyl-D-aspartátu imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH