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Kiel University

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Frank Leypoldt

University Hospital Schleswig-Holstein

Fabián A. Michelangeli

New York Botanical Garden

María Alexandra García-Amado

Instituto Venezolano de Investigaciones Científicas

Jan Lewerenz

Universität Ulm

Mónica Contreras

Instituto Venezolano de Investigaciones Científicas

Roberto Romero

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Harald Prüß

Charité - Universitätsmedizin Berlin

Nelson Reyes

Universidad Del Este

Péter Körtvélyessy

Humboldt-Universität zu Berlin

Leslie Vargas‐Saturno

Universidad Bernardo O'Higgins

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University of Lübeck

University Hospital Schleswig-Holstein

Instituto Venezolano de Investigaciones Científicas

Universität Hamburg

University of Würzburg

University Medical Center Hamburg-Eppendorf

Charité - Universitätsmedizin Berlin

Universitätsklinikum Würzburg

Inserm

German Center for Neurodegenerative Diseases

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Distinct movement disorders in contactin-associated-protein-like-2 antibody-associated autoimmune encephalitis

Brain (2022)

Felix Gövert Ligia Abrante Jos S. Becktepe Bettina Balint Christos Ganos

Autoimmune encephalitis can be classified into antibody-defined subtypes, which can manifest with immunotherapy-responsive movement disorders sometimes mimicking non-inflammatory aetiologies. In the elderly, anti-LGI1 and contactin associated protein like 2 (CASPR2) antibody-associated diseases compose a relevant fraction of autoimmune encephalitis. Patients with LGI1 autoantibodies are known to present with limbic encephalitis and additionally faciobrachial dystonic seizures may occur. However, the clinical spectrum of CASPR2 autoantibody-associated disorders is more diverse including limbic encephalitis, Morvan's syndrome, peripheral nerve hyperexcitability syndrome, ataxia, pain and sleep disorders. Reports on unusual, sometimes isolated and immunotherapy-responsive movement disorders in CASPR2 autoantibody-associated syndromes have caused substantial concern regarding necessity of autoantibody testing in patients with movement disorders. Therefore, we aimed to systematically assess their prevalence and manifestation in patients with CASPR2 autoimmunity. This international, retrospective cohort study included patients with CASPR2 autoimmunity from participating expert centres in Europe. Patients with ataxia and/or movement disorders were analysed in detail using questionnaires and video recordings. We recruited a comparator group with anti-LGI1 encephalitis from the GENERATE network. Characteristics were compared according to serostatus. We identified 164 patients with CASPR2 autoantibodies. Of these, 149 (90.8%) had only CASPR2 and 15 (9.1%) both CASPR2 and LGI1 autoantibodies. Compared to 105 patients with LGI1 encephalitis, patients with CASPR2 autoantibodies more often had movement disorders and/or ataxia (35.6 versus 3.8%; P < 0.001). This was evident in all subgroups: ataxia 22.6 versus 0.0%, myoclonus 14.6 versus 0.0%, tremor 11.0 versus 1.9%, or combinations thereof 9.8 versus 0.0% (all P < 0.001). The small group of patients double-positive for LGI1/CASPR2 autoantibodies (15/164) significantly more frequently had myoclonus, tremor, 'mixed movement disorders', Morvan's syndrome and underlying tumours. We observed distinct movement disorders in CASPR2 autoimmunity (14.6%): episodic ataxia (6.7%), paroxysmal orthostatic segmental myoclonus of the legs (3.7%) and continuous segmental spinal myoclonus (4.3%). These occurred together with further associated symptoms or signs suggestive of CASPR2 autoimmunity. However, 2/164 patients (1.2%) had isolated segmental spinal myoclonus. Movement disorders and ataxia are highly prevalent in CASPR2 autoimmunity. Paroxysmal orthostatic segmental myoclonus of the legs is a novel albeit rare manifestation. Further distinct movement disorders include isolated and combined segmental spinal myoclonus and autoimmune episodic ataxia.

Autoimmune encephalitis

Limbic Encephalitis

Movement Disorders

Neuromyotonia

10.1093/brain/awac276

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Heterogeneity of cag genotypes of Helicobacter pylori in the esophageal mucosa of dyspeptic patients and its relation to histopathological outcomes

International Journal of Infectious Diseases (2014)

Mónica Contreras Ligia Abrante Víctor Salazar Nelson Reyes María Alexandra García-Amado

BackgroundA high prevalence of Helicobacter pylori in the esophageal mucosa of dyspeptic Venezuelan patients has been reported. We aimed to assess the genetic composition of the cag genotypes of H. pylori and its relation to histopathological outcomes in the gastroesophageal mucosa.MethodsThe presence of cagA, cagE, and virB11 cag pathogenicity island (PAI) genes was detected by PCR in 80 of 150 H. pylori-positive dyspeptic patients in both mucosae. Alterations of the gastroesophageal mucosa were assessed by histological techniques.ResultsThe frequency of intact, partial, and deleted cag-PAI genes in the stomach of dyspeptic patients was found to be 57.5%, 21.3%, and 21.3%, respectively, whereas in the esophagus, frequencies were 33.8%, 33.8%, and 32.5% respectively. The genetic composition in the stomach was 57.5% cagA-positive, 20.0% cagA-negative, 75.0% cagE, and 77.5% virB11, whereas in the esophagus the distribution was 36.3% cagA-positive, 30.0% cagA-negative, 61.3% cagE, and 63.8% virB11. The gene with the largest difference between the two mucosae was cagA, with 58.8% in the stomach and 37.5% in the esophagus; cagE and virB11 were less variable. The correlation among single and/or mixed cag genotypes with histopathological outcomes in both mucosae from the same patient was higher for intact single cag-PAI genotypes, showing severe alterations.ConclusionsH. pylori may coexist in similar proportions without dominance of one cag genotype, suggesting a heterogeneous distribution in the esophagus. The cagE and virB11 genes can be used as markers of cag-PAI in the esophagus. The single cag-PAI genotype in both mucosae confers an increased risk of developing histological damage.

CagA

10.1016/j.ijid.2014.03.1387

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[Diagnosis of Helicobacter pylori infection by PCR in gastric juice and gastroesophageal biopsies from dyspeptic patients].

PubMed (2012)

Ligia Abrante Nelson Reyes María Alexandra García-Amado Paula Suárez Roberto Romero

Helicobacter pylori is the main bacterial agent implicated in human gastroduodenal inflammatory pathologies; being one of the most common bacterial pathogens, with a high prevalence in Venezuela. The diagnosis of H. pylori infection is performed primarily in gastric biopsies through PCR; however, string-absorbed gastric juice and esophageal biopsies could be also used as alternative specimens to determine the infection. In this study the H. pylori infection was assessed in different specimens of the upper tract digestive of dyspeptic patients, though the detection by PCR of essential genes (glmM and ureA) and genes encoding virulence factors (cagA). Of 104 patients studied, H. pylori was found in 53.8, 69,2 and 58,7% of gastric juice, and gastric and esophageal biopsies, respectively; with predominance of the strains type I (cagA+) in juice and gastric biopsies, and strains type II (cagA-) in esophageal biopsies. The detection of H. pylori in gastric juice and esophageal biopsies showed high sensitivity and specificity, in comparison with the detection in gastric biopsies, suggesting that both types of specimens may be used efficiently for a secure diagnosis of H. pylori infection.

CagA

Gastric biopsy

Spirillaceae

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Amyloid‐Aβ Peptide in Olfactory Mucosa and Mesenchymal Stromal Cells of Mild Cognitive Impairment and Alzheimer's Disease Patients

Brain Pathology (2014)

Carlos A. Ayala‐Grosso Rosalinda Pieruzzini Dylana Diaz‐Solano Olga Wittig Ligia Abrante

Patients with mild cognitive impairment (MCI) or Alzheimer's disease (AD) might develop olfactory dysfunction that correlates with progression of disease. Alteration of olfactory neuroepithelium associated with MCI may be useful as predictor of cognitive decline. Biomarkers with higher sensitivity and specificity would allow to understand the biological progression of the pathology in association with the clinical course of the disease. In this study, magnetic resonance images, apolipoprotein E (ApoE) load, Olfactory Connecticut test and Montreal Cognitive Assessment (MoCA) indices were obtained from noncognitive impaired (NCI), MCI and AD patients. We established a culture of patient-derived olfactory stromal cells from biopsies of olfactory mucosa (OM) to test whether biological properties of mesenchymal stromal cells (MSC) are concurrent with MCI and AD psychophysical pathology. We determined the expression of amyloid Aβ peptides in the neuroepithelium of tissue sections from MCI and AD, as well as in cultured cells of OM. Reduced migration and proliferation of stromal (CD90(+) ) cells in MCI and AD with respect to NCI patients was determined. A higher proportion of anosmic MCI and AD cases were concurrent with the ApoE ε4 allele. In summary, dysmetabolism of amyloid was concurrent with migration and proliferation impairment of patient-derived stem cells.

Olfactory mucosa

Apolipoprotein E

Amyloid (mycology)

Neuroepithelial cell

10.1111/bpa.12169

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Neuropathic pain and distinct CASPR2 autoantibody IgG subclasses drive neuronal hyperexcitability

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Margarita Habib Anna-Lena Wiessler Patrik Greguletz Michéle Niesner Mareike Selcho

Abstract Patients with autoantibodies (aAbs) against the contactin-associated protein-like 2 (CASPR2) suffer from a variety of clinical syndromes including neuropathic pain, in some patients even as the only symptom. CASPR2 is an adhesion protein of the neurexin IV family and part of the voltage-gated potassium channel complex (VGKC) in neurons of dorsal root ganglia (DRG). The subsequent pathological mechanisms following the binding of CASPR2 aAbs and their association with pain are only partially understood. CASPR2 aAbs are mainly of the IgG4 subclass. Previous studies have neglected subclass-dependent effects. Here we investigated 49 subclassified patient serum samples positive for CASPR2 aAbs. To unravel underlying molecular mechanisms, we used a combination of super-resolution lattice structural illumination microscopy (SIM 2 ) and functional readouts by calcium imaging and electrophysiological recordings. CASPR2-positive patient sera subclassified in IgG4 together with at least one other IgG subclass (IgGX) and patients with only IgG4 were further subdivided into the pain and no pain group. Patient subclassification shed further light on the pathological mechanisms of CASPR2 aAbs. A decrease of CASPR2 expression after long-term exposure to CASPR2 aAbs was only observed for the patient group without pain. Upon withdrawal of the CASPR2 aAbs, CASPR2 expression returned to normal level. Structural alterations were obtained by increased distances between CASPR2 and associated potassium channels along DRG axons using high-resolution lattice SIM 2 microscopy but only following binding of CASPR2 aAbs from patients with pain. Similarly, CASPR2 aAbs of patients with pain significantly increased overall neuronal excitability of cultured DRG neurons as measured by calcium imaging. Patch-clamp recordings revealed significantly decreased current amplitudes of voltage-gated potassium (Kv) channels after incubation with all four CASPR2 aAbs subclassifications with the most prominent effect of serum samples harboring IgG4 aAbs. Notably, a patient serum sample lacking IgG4 did not alter Kv channel function. Withdrawal of aAbs rescued Kv channel function to normal levels suggesting that the affected potassium channel function is rather due to a functional block of the VGKC rather than altered structural integrity of the VGKC. Taken together, we found IgG4 aAbs to be a major modifier of potassium channel function. The increase in DRG excitability is primarily due to impaired Kv channel conductance as a consequence of CASPR2 aAbs binding but additional and so far unidentified signal pathways contribute to this process in patients with neuropathic pain.

10.1101/2024.09.04.611282

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Fatal PCR-negative herpes simplex virus-1 encephalitis with GABA _A receptor antibodies

Neurology Neuroimmunology & Neuroinflammation (2019)

S. Schuster Ligia Abrante Jakob Matschke Marc Lütgehetmann Brigitte Holst

Herpes simplex virus-1 encephalitis (HSVE) is the most common cause of fatal sporadic encephalitis worldwide. Recently, post-HSVE relapses due to autoimmune encephalitis with NMDA receptor antibodies and other synaptic autoantibodies have been reported in up to 27% of patients within 1–2 months after HSVE.1,2 We report an unusual case of a patient with refractory status epilepticus due to HSVE with antibodies against GABAA receptors (GABAAR).

Autoimmune encephalitis

10.1212/nxi.0000000000000624

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Citations (9)