Whole-brain metabolic pattern analysis in patients with anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis.

BACKGROUND AND PURPOSE: Faciobrachial dystonic seizures (FBDS) and hyponatremia are the distinct clinical features of autoimmune encephalitis (AE) caused by antibodies against leucine-rich glioma-inactivated 1 (LGI1). The present study aims to explore the pathophysiological patterns and neural mechanisms underlying these symptoms. METHODS: We included 30 patients with anti-LGI1 AE and 30 controls from a retrospective observational cohort. Whole-brain metabolic pattern analysis was performed to assess the pathological network of anti-LGI1 AE, as well as the symptom networks associated with FBDS. Logistic regression was applied to explore independent predictors of FBDS. Finally, we used a multiple regression model to investigate the hyponatremia-associated brain network and its effect on serum sodium levels. RESULTS: The pathological network of anti-LGI1 AE involved hypermetabolism in the cerebellum, subcortical structures and Rolandic area, as well as hypometabolism in the medial prefrontal cortex. The symptom network of FBDS included hypometabolism in the cerebellum and Rolandic area (pFDR <0.05). Hypometabolism in the cerebellum was an independent predictor of FBDS (p < 0.001). Hyponatremia-associated network highlighted a negative effect on the caudate nucleus, frontal and temporal white matter. The metabolism of the hypothalamus was negatively associated with (Pearson's R = -0.180, p = 0.342), while not the independent predictor for serum sodium level (path c' = -7.238, 95% confidence interval = -30.947 to 16.472). CONCLUSIONS: Our results provide insights into the whole-brain metabolic patterns of patients with anti-LGI1 AE, including the symptom network associated with FBDS and the hyponatremia-associated brain network. The findings help us to understand the neural mechanisms underlying anti-LGI1 AE and to evaluate the progress of this disease.

Comprehensive B-Cell Immune Repertoire Analysis of Anti-NMDAR Encephalitis and Anti-LGI1 Encephalitis.

Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) and anti-leucine-rich glioma-inactivated 1 encephalitis (anti-LGI1E) are the two most common types of antibody-mediated autoimmune encephalitis. We performed a comprehensive analysis of the B-cell immune repertoire in patients with anti-NMDARE (n = 7) and anti-LGI1E (n = 10) and healthy controls (n = 4). The results revealed the presence of many common clones between patients with these two types of autoimmune encephalitis, which were mostly class-switched. Additionally, many differences were found among the anti-NMDARE, anti-LGI1E, and healthy control groups, including the diversity of the B-cell immune repertoire and gene usage preference. These findings suggest that the same adaptive immune responses occur in patients with anti-NMDARE and anti-LGI1E, which deserves further exploration.

Role of LGI1 protein in synaptic transmission: From physiology to pathology.

Leucine-Rich Glioma Inactivated protein 1 (LGI1) is a secreted neuronal protein highly expressed in the central nervous system and high amount are found in the hippocampus. An alteration of its function has been described in few families of patients with autosomal dominant temporal lobe epilepsy (ADLTE) or with autoimmune limbic encephalitis (LE), both characterized by epileptic seizures. Studies have shown that LGI1 plays an essential role during development, but also in neuronal excitability through an action on voltage-gated potassium Kv1.1 channels, and in synaptic transmission by regulating the surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-R). Over the last decade, a growing number of studies investigating LGI1 functions have been published. They aimed to improve the understanding of LGI1 function in the regulation of neuronal networks using different animal and cellular models. LGI1 appears to be a major actor of synaptic regulation by modulating trans-synaptically pre- and post-synaptic proteins. In this review, we will focus on LGI1 binding partners, "A Disintegrin And Metalloprotease (ADAM) 22 and 23", the complex they form at the synapse, and will discuss the effects of LGI1 on neuronal excitability and synaptic transmission in physiological and pathological conditions. Finally, we will highlight new insights regarding N-terminal Leucine-Rich Repeat (LRR) domain and C-terminal Epitempin repeat (EPTP) domain and their potentially distinct role in LGI1 function.

Hypothalamic Inflammation as a Potential Pathophysiologic Basis for the Heterogeneity of Clinical, Hormonal, and Metabolic Presentation in PCOS.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age. It is a heterogeneous condition characterized by reproductive, endocrine, metabolic, and psychiatric abnormalities. More than one pathogenic mechanism is involved in its development. On the other hand, the hypothalamus plays a crucial role in many important functions of the body, including weight balance, food intake, and reproduction. A high-fat diet with a large amount of long-chain saturated fatty acids can induce inflammation in the hypothalamus. Hypothalamic neurons can sense extracellular glucose concentrations and participate, with a feedback mechanism, in the regulation of whole-body glucose homeostasis. When consumed nutrients are rich in fat and sugar, and these regulatory mechanisms can trigger inflammatory pathways resulting in hypothalamic inflammation. The latter has been correlated with metabolic diseases, obesity, and depression. In this review, we explore whether the pattern and the expansion of hypothalamic inflammation, as a result of a high-fat and -sugar diet, may contribute to the heterogeneity of the clinical, hormonal, and metabolic presentation in PCOS via pathophysiologic mechanisms affecting specific areas of the hypothalamus. These mechanisms could be potential targets for the development of effective therapies for the treatment of PCOS.

Metabolic Imaging Patterns on 18F-FDG PET in Acute and Subacute LGI1 Autoimmune Limbic Encephalitis.

Autoimmune encephalitis is a diverse group of neuropsychiatric disorders, which are difficult to diagnose clinically. The disorder presents acutely or subacutely with alteration of consciousness, cognitive decline, seizures, and abnormal movements. Autoantibodies are directed against intracellular antigens or extracellular domains of cell surface proteins, critical for neuronal excitability. F-FDG PET/CT has been used to diagnose the metabolic derangement in the brain due to various antibodies. Here we describe a case where acute and subacute phase of disease was visualized on serial F-FDG PET/CT.

Encefalitis límbica asociada a anti-Caspr2: contribución del análisis visual ayudado de las imágenes PET con 18F-FDG mediante comparación con una base de datos de normalidad / Caspr2 antibody-associated limbic encephalitis: contribution of visual aided analysis of 18F-FDG PET images using normal database comparison

Un inicio temprano de la inmunoterapia es fundamental para mejorar el pronóstico de los pacientes con encefalitis aguda de origen autoinmune (EAI). Se ha propuesto un nuevo abordaje clínico para el diagnóstico temprano basado en aspectos clínicos y pruebas complementarias, pero estas pueden tener una sensibilidad limitada principalmente en las primeras semanas. Mientras que las formas más comunes de EAI (anti-LGI-1 y anti-NMDAR), muestran frecuentemente patrones de PET con 18Flúor-fluordeoxiglucosa (PET-FDG) consistentes, las anti-Caspr2 son menos frecuentes y los patrones de PET-FDG no están establecidos. En nuestra experiencia la PET-FDG en la EAI anti-Caspr2 presenta un hipermetabolismo temporal medial y un déficit difuso cortical, incluso con pruebas complementarias negativas. No obstante, es necesaria la estandarización del análisis de las imágenes PET mediante métodos basados en vóxeles con comparación con bases de datos de normalidad para definir con claridad las áreas de metabolismo alterado que pueden pasar desapercibidas al análisis visual

Early immunotherapy is of paramount importance for a positive outcome in patients suffering acute encephalitis of autoimmune origin (AIE). A new approach for early diagnosis based on clinical presentation and complementary tests has been proposed, but not all these tests show positive findings in the first weeks. While common forms of AIE (anti-LGI-1 and anti-NMDAR antibodies) exhibit consistent 18Fluor-fluorodeoxiglucose (FDG-PET) patterns in many cases, the anti-Caspr2 form of AIE is infrequent and FDG-PET patterns have not been well characterized. In our experience, FDG-PET in anti-Caspr2 limbic encephalitis shows medial temporal hypermetabolism and diffuse cortical hypometabolism, even in the absence of findings in these tests. However, it is necessary to standardize PET image analysis by means of visual and voxel-based methods compared to normal databases to define the areas of pathological metabolism that may go unnoticed when using visual analysis exclusively

Primary DQ effect in the association between HLA and neurological syndromes with anti-GAD65 antibodies.

The primary cause of neurological syndromes with antibodies against glutamic acid decarboxylase 65 (GAD65-Ab) is unknown, but genetic predisposition may exist as it is suggested by the co-occurrence in patients and their relatives of other organ-specific autoimmune diseases, notably type 1 diabetes mellitus (T1DM), and by the reports of a few familial cases. We analyzed the human leukocyte antigen (HLA) in 32 unrelated patients and compared them to an ethnically matched sample of 137 healthy controls. Four-digit resolution HLA alleles were imputed from available Genome Wide Association data, and full HLA next-generation sequencing-based typing was also performed. HLA DQA1*05:01-DQB1*02:01-DRB1*03:01 was the most frequent class II haplotype in patients (13/32, 41%). DQB1*02:01 was the only allele found to be significantly more common in patients than in controls (20/137, 15%, corrected p = 0.03, OR 3.96, 95% CI [1.54-10.09]). There was also a trend towards more frequent DQA1*05:01 among patients compared to controls (22/137, 16%; corrected p = 0.05, OR 3.54, 95% CI [1.40-8.91]) and towards a protective effect of DQB1*03:01 (2/32, 6% in patients vs. 42/137, 31% in control group; corrected p = 0.05, OR 0.15, 95% CI [0.02-0.65]). There was no significant demographic or clinical difference between DQ2 and non-DQ2 carriers (p > 0.05). Taken together, these findings suggest a primary DQ effect on GAD65-Ab neurological diseases, partially shared with other systemic organ-specific autoimmune diseases such as T1DM. However, it is likely that other non-HLA loci are involved in the genetic predisposition of GAD65-Ab neurological syndromes.

Caspr2 antibody-associated limbic encephalitis: contribution of visual aided analysis of 18F-FDG PET images using normal database comparison. / Encefalitis límbica asociada a anti-Caspr2: contribución del análisis visual ayudado de las imágenes PET con 18F-FDG mediante comparación con una base de datos de normalidad.

Early immunotherapy is of paramount importance for a positive outcome in patients suffering acute encephalitis of autoimmune origin (AIE). A new approach for early diagnosis based on clinical presentation and complementary tests has been proposed, but not all these tests show positive findings in the first weeks. While common forms of AIE (anti-LGI-1 and anti-NMDAR antibodies) exhibit consistent 18Fluor-fluorodeoxiglucose (FDG-PET) patterns in many cases, the anti-Caspr2 form of AIE is infrequent and FDG-PET patterns have not been well characterized. In our experience, FDG-PET in anti-Caspr2 limbic encephalitis shows medial temporal hypermetabolism and diffuse cortical hypometabolism, even in the absence of findings in these tests. However, it is necessary to standardize PET image analysis by means of visual and voxel-based methods compared to normal databases to define the areas of pathological metabolism that may go unnoticed when using visual analysis exclusively.

Identification of adenylate kinase 5 antibodies during routine diagnostics in a tissue-based assay: Three new cases and a review of the literature.

Antibodies against adenylate kinase 5 (AK5) have been described in patients with non-paraneoplastic limbic encephalitis, mainly in men around 70 years of age. Routine testing with specific cell-based assays is not yet available. Three patients with episodic anterograde memory problems and depression had extensive limbic lesions and developed severe atrophy, mainly of the medial temporal lobes. The antibodies were identified in serum and CSF based on the typical staining pattern of AK5 antibodies on a tissue-based assay (here, unfixed mouse brain). Subsequently, they were confirmed by a research laboratory through a cell-based assay.

Autoimmune encephalitis associated with glutamic acid decarboxylase antibodies: a case series.

Antibodies against glutamic acid decarboxylase (GAD) are associated with various neurologic conditions described in patients including stiff person syndrome, cerebellar ataxia, refractory epilepsy, limbic and extralimbic encephalitis. GAD antibodies-related limbic encephalitis cases are well described; reports of extralimbic involvement are limited. We describe four cases of GAD antibody-related autoimmune encephalitis. Three of them had extralimbic involvement and only one had limbic encephalitis.

From VGKC to LGI1 and Caspr2 encephalitis: The evolution of a disease entity over time.

A wide variety of clinical syndromes has been associated with antibodies to voltage-gated potassium channels (VGKCs). Six years ago, it was discovered that patients do not truly have antibodies to potassium channels, but to associated proteins. This enabled the distinction of three VGKC-positive subgroups: anti-LGI1 patients, anti-Caspr2 patients and VGKC-positive patients lacking both antibodies. Patients with LGI1-antibodies have a limbic encephalitis, often with hyponatremia, and about half of the patients have typical faciobrachial dystonic seizures. Caspr2-antibodies cause a more variable syndrome of peripheral or central nervous system symptoms, almost exclusively affecting older males. Immunotherapy seems to be beneficial in patients with antibodies to LGI1 or Caspr2, stressing the need for early diagnosis. Half of the VGKC-positive patients lack antibodies to both LGI1 and Caspr2. This is a heterogeneous group of patients with a wide variety of clinical syndromes, raising the question whether VGKC-positivity is truly a marker of disease in these patients. Data regarding this issue are limited, but a recent study did not show any clinical relevance of VGKC-positivity in the absence of antibodies to LGI1 and Caspr2. The three VGKC-positive subgroups are essentially different, therefore, the lumping term 'VGKC-complex antibodies' should be abolished.

Non-paraneoplastic limbic encephalitis and central nervous HHV-6B reactivation: Causality or coincidence?

Autoantibody-related encephalopathies represent an important differential diagnosis in adult onset epilepsy. Here, we report the case of a 25-year-old patient with new-onset epilepsy and psychotic syndrome, who underwent biopsy resection for etiological classification. MRI analysis and neuropathological examination showed a T-lymphocytic dominated encephalitis with involvement of the limbic system. An indirect immunohistochemistry approach identified autoantibodies against glutamic acid decarboxylase (GAD) in cerebral spinal fluid and serum, which were confirmed by affinity purification / mass spectrometry analysis. Further examinations revealed evidence of chromosomally integrated human herpes virus type 6B (HHV-6B). However, astrocytic expression of HHV-6 lytic protein was detected by double immunofluorescence analysis. The cerebral expression of HHV-6 antigen, a clinical improvement under antiviral therapy as well as an initial finding of HHV-6 IgM antibodies strongly argue for an additional active HHV-6B infection. Review of the literature reveals singular reports of patients with GAD antibody-positive limbic encephalitis and central nervous system infections with HHV-6B. Since herpes simplex virus encephalitis has been recently reported as a trigger of N-methyl-D-aspartate receptor antibody encephalitis, it is tempting to speculate that HHV-6B infections may trigger a non-paraneoplastic form of limbic encephalitis in a parallel cascade.

Distinct white matter integrity in glutamic acid decarboxylase and voltage-gated potassium channel-complex antibody-associated limbic encephalitis.

OBJECTIVE: Autoantibodies against glutamic acid decarboxylase (GAD) and the voltage-gated potassium channel (VGKC) complex are associated with distinct subtypes of limbic encephalitis regarding clinical presentation, response to therapy, and outcome. The aim of this study was to investigate white matter changes in these two limbic encephalitis subtypes by means of diffusion tensor imaging (DTI). METHODS: Diffusion data were obtained in 14 patients with GAD antibodies and 16 patients with VGKC-complex antibodies and compared with age- and gender-matched control groups. Voxelwise statistical analysis was carried out using tract-based spatial statistics. The results were furthermore compared with those of 15 patients with unilateral histologically confirmed hippocampal sclerosis and correlated with verbal and figural memory performance. RESULTS: We found widespread changes of fractional anisotropy and all diffusivity parameters in GAD-associated limbic encephalitis, whereas no changes were found in VGKC-complex-associated limbic encephalitis. The changes observed in the GAD group were even more extensive when compared against those of the hippocampal sclerosis group, although the disease duration was markedly shorter in patients with GAD antibodies. Correlation analysis revealed areas with a trend toward a negative correlation of diffusivity parameters with figural memory performance located mainly in the right temporal lobe in the GAD group as well. SIGNIFICANCE: The present study provides further evidence that, depending on the associated antibody, limbic encephalitis features clearly distinct imaging characteristics by showing widespread white matter changes in GAD-associated limbic encephalitis and preserved white matter integrity in VGKC-complex-associated limbic encephalitis. Furthermore, our results contribute to a better understanding of the specific pathophysiologic properties in these two subforms of limbic encephalitis by revealing that patients with GAD antibodies show widespread affections of white matter across various regions of the brain. In contrast to this, the inflammatory process seems to be more localized in VGKC-complex-associated limbic encephalitis, primarily affecting mesiotemporal gray matter.

[LGI1 ENCEPHALITIS: THE FIRST HUNGARIAN PATIENT]. / AZ LGI1--ENCEPHALITIS HAZÁNKBAN ELSOKÉNT DIAGNOSZTIZÁLT ESETE.

In the recent years, it has been increasingly recognised that in a group of limbic encephalitis antibodies are directed against the scaffolding protein LGI1 (Leucine-rich glioma inactivated 1), which is part of the voltage gated potassium channel (VGKC) complex on neural synapses. Patients present with seizures and subacute history of neuropsychiatric symptoms, including psychosis and changes in memory, cognition, behaviour. Faciobrachial dystonic seizures can be observed, which are highly characteristic for LGI1 encephalitis. MRI shows medial temporal abnormalities in more than half of the cases. CSF evaluation is usually normal. Hyponatremia is frequently associated and may confuse the initial diagnosis. Early recognition and prompt initiation of immunotherapies are of great importance. The clinical improvements often correlate with the antibody levels. We present the case of a 64-year old man, who responded quickly to plasma exchange and major improvement was noted within few weeks.

Espectro clínico y valor diagnóstico de los anticuerpos contra el complejo proteico asociado a canales de potasio / Clinical spectrum and diagnostic value of antibodies against the potassium channel related protein complex

Introducción: Los anticuerpos contra un complejo proteico que incluye a los canales de potasio dependientes de voltaje (CKVD) se han descrito en pacientes con encefalitis límbica, hiperexcitabilidad del nervio periférico, síndrome de Morvan, así como en un creciente grupo de síndromes neurológicos. Desarrollo: En este artículo revisamos los síndromes asociados a anticuerpos contra proteínas relacionadas con los CKVD y los 2 antígenos principales de este complejo, las proteínas leucine rich glioma inactivated protein 1 (LGI1) y contactin-associated protein-like 2 (Caspr2). Así mismo describimos los problemas conceptuales y las implicaciones diagnósticas de la descripción de anticuerpos contra CKVD diferentes de LGI1 y Caspr2. Aunque inicialmente se consideró que existían anticuerpos dirigidos contra CKVD, recientemente se ha identificado que, en la mayor parte de los casos, los antígenos son una proteína neuronal secretada denominada LGI1, involucrada en el control de la excitabilidad sináptica, y la proteína Caspr2, localizada en la superficie neuronal de varias regiones cerebrales y en la región yuxtaparanodal de axones mielinizados. Mientras que los anticuerpos contra LGI1 se asocian preferentemente a un cuadro clásico de encefalitis límbica, los anticuerpos contra Caspr2 muestran un espectro clínico más amplio, incluyendo el síndrome de Morvan, la hiperexcitabilidad del nervio periférico o neuromiotonía, o una encefalitis límbica o difusa. Existen además casos descritos de pacientes con anticuerpos contra el complejo CKVD que no tienen anticuerpos contra LGI1 o Caspr2. En estos casos, la identidad y la localización de los antígenos es desconocida, la asociación sindrómica inespecífica y la respuesta al tratamiento, incierta. Conclusiones: El descubrimiento de los antígenos LG1 y Caspr2 ha permitido delimitar clínica y molecularmente el amplio grupo de síndromes previamente atribuidos a anticuerpos contra CKVD. Frente a la literatura que describe la presencia de anticuerpos contra CKVD diferentes a LGI1 y Caspr2, proponemos un algoritmo práctico para el diagnóstico y el tratamiento de estos pacientes

Introduction: Antibodies against a protein complex that includes voltage-gated potassium channels (VGKC) have been reported in patients with limbic encephalitis, peripheral nerve hyperexcitability, Morvan's syndrome, and a large variety of neurological syndromes. Review summary: In this article, a review is presented of the syndromes associated with antibodies against VGKC-related proteins and the main antigens of this protein complex, the proteins LGI1 (leucine rich glioma inactivated protein 1) and Caspr2 (contactin-associated protein-like 2). The conceptual problems and clinical implications of the description of antibodies against VGKC-related proteins other than LGI1 and Caspr2 are also discussed. Although initial studies indicated the occurrence of antibodies against VGKC, recent investigations have shown that the main antigens are a neuronal secreted protein known as LGI1 which modulates synaptic excitability, and a protein called Caspr2 located on the cell surface and processes of neurons of different brain regions, and at the juxtaparanodal region of myelinated axons. While antibodies against LGI1 preferentially associate with classical limbic encephalitis, antibodies against Caspr2 associate with a wider spectrum of symptoms, including Morvan's syndrome, peripheral nerve hyperexcitability or neuromyotonia, and limbic or more extensive encephalitis. In addition there are reports of patients with antibodies against VGKC-related proteins that are different from LGI1 or Caspr2. In these cases, the identity and location of the antigens are unknown, the syndrome association is not specific, and the response to treatment uncertain. Conclusions: The discovery of antigens such as LGI1 and Caspr2 has resulted in a clinical and molecular definition of the broad group of diseases previously attributed to antibodies against VGKC. Considering the literature that describes the presence of antibodies against VGKC other than LGI1 and Caspr2 proteins, we propose a practical algorithm for the diagnosis and treatment of these patients

Uncommon 18F-FDG-PET/CT findings in patients affected by limbic encephalitis: hyper-hypometabolic pattern with double antibody positivity and migrating foci of hypermetabolism.

Autoimmune limbic encephalitis (LE) is a rare disorder; its diagnosis can be challenging. We report two uncommon cases of LE evaluated by brain 2-deoxy-2-[18F]fluoro-d-glucose ((18)F-FDG) positron emission tomography/computed tomography describing the metabolic imaging patterns, which were different from those observed in previous studies: the first one presented an unprecedented (18)F-FDG brain mixed pattern, involving also the midbrain, despite negative magnetic resonance imaging exams; the second one showed migrating foci of hypermetabolism, one of which turned into hypometabolism at a later examination.