Stiff Person Syndrome and GAD Antibody-Spectrum Disorders.

OBJECTIVE: Antibodies against glutamic acid decarboxylase (GAD), originally associated with stiff person syndrome (SPS), define the GAD antibody-spectrum disorders that also include cerebellar ataxia, autoimmune epilepsy, limbic encephalitis, progressive encephalomyelitis with rigidity and myoclonus (PERM), and eye movement disorders, all of which are characterized by autoimmune neuronal excitability. This article elaborates on the diagnostic criteria for SPS and SPS spectrum disorders, highlights disease mimics and misdiagnoses, describes the electrophysiologic mechanisms and underlying autoimmunity of stiffness and spasms, and provides a step-by-step therapeutic scheme. LATEST DEVELOPMENTS: Very-high serum GAD antibody titers are diagnostic for GAD antibody-spectrum disorders and also predict the presence of GAD antibodies in the CSF, increased intrathecal synthesis, and reduced CSF γ-aminobutyric acid (GABA) levels. Low serum GAD antibody titers or the absence of antibodies generates diagnostic challenges that require careful distinction in patients with a variety of painful spasms and stiffness, including functional neurologic disorders. Antibodies against glycine receptors, first found in patients with PERM, are seen in 13% to 15% of patients with SPS, whereas amphiphysin and gephyrin antibodies, seen in 5% of patients with SPS spectrum disorders, predict a paraneoplastic association. GAD-IgG from different SPS spectrum disorders recognizes the same dominant GAD intracellular epitope and, although the pathogenicity is unclear, is an excellent diagnostic marker. The biological basis of muscle stiffness and spasms is related to autoimmune neuronal hyperexcitability caused by impaired reciprocal γ-aminobutyric acid-mediated (GABA-ergic) inhibition, which explains the therapeutic response to GABA-enhancing agents and immunotherapies. ESSENTIAL POINTS: It is essential to distinguish SPS spectrum disorders from disease mimics to avoid both overdiagnoses and misdiagnoses, considering that SPS is treatable if managed correctly from the outset to prevent disease progression. A step-by-step, combination therapy of GABA-enhancing medications along with immunotherapies ensures prolonged clinical benefits.

Clinical features, investigations, and outcomes of pediatric limbic encephalitis: A multicenter study.

OBJECTIVES: To describe the clinical presentation, investigations, management, and disease course in pediatric autoimmune limbic encephalitis (LE). METHODS: In this retrospective observational study, from the UK Childhood Neuroinflammatory Disease network, we identified children from six tertiary centers with LE <18 years old between 2008 and 2021. Clinical and paraclinical data were retrieved from medical records. RESULTS: Twenty-five children fulfilling LE criteria were identified, with median age of 11 years (IQR 8, 14) and median follow-up of 24 months (IQR 18, 48). All children presented with seizures; 15/25 (60%) were admitted to intensive care. Neuroimaging demonstrated asymmetric mesial temporal changes in 8/25 (32%), and extra-limbic changes with claustrum involvement in 9/25 (38%). None were positive for LGI1/CASPR2 antibodies (Abs), 2/25 were positive for serum anti-NMDAR Abs, and 2/15 positive for anti-Hu Abs; one died from relapsing neuroblastoma. Two children had serum and CSF anti-GAD antibodies. Initial immune therapy included steroids in 23/25 (92%), intravenous immunoglobulin (IVIg) in 14/25 (56%), and plasma exchange in 7/25 (28%). The commonest second-line treatment was rituximab in 15/25 (60%). Median duration of hospital admission was 21 days (IQR 11, 30). At last follow-up, 13/25 (52%) had refractory seizures and 16/25 (64%) had memory impairment. Six children (24%) had modified Rankin Scale (mRS) scores ≥3. There was no significant difference in mRS, or long-term cognitive and epilepsy outcomes in those who received rituximab versus those who did not. INTERPRETATION: A diagnosis of autoimmune LE was associated with significant morbidity and adverse outcomes in this pediatric cohort.

A case of bilateral limbic and recurrent unilateral cortical encephalitis with anti-myelin oligodendrocyte glycoprotein antibody positivity.

BACKGROUND: Anti-myelin oligodendrocyte glycoprotein (MOG) antibody can be detected not only in acute disseminated encephalomyelitis or optic neuritis but also in limbic or cortical encephalitis. However, no previous reports have demonstrated a relapsing case of these two types of encephalitis. CASE REPORT: An 11-year-old girl presented with fever, headache, abnormal behavior, focal impaired awareness seizures (FIAS) on the left side, and MRI hyperintensities in the bilateral amygdala, hippocampus, and right posterior temporal cortex. The symptoms were alleviated with two courses of intravenous methylprednisolone (IVMP) and one course of immunoglobulin. At 16 years of age, the patient returned with left-sided headache and MRI hyperintensities in the left temporal, parietal, and insular cortices, which improved after 3 courses of IVMP. Oral prednisolone (PSL) was tapered over 6 months, when FIAS reappeared on the right side of the body. MRI showed recurrence in the same regions as in the second episode. She received 3 courses of IVMP, followed by gradually tapered PSL without relapse for 1.5 year. Anti-MOG antibodies were positive in both serum and the cerebrospinal fluid prior to treatment in all three episodes. CONCLUSION: Our results revealed that anti-MOG antibody-related bilateral limbic and unilateral cortical encephalitis can manifest with a variety of phenotypes over time in the same patient.

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.

Limbic encephalitis in a child with ovarian teratoma and influenza B. Case report and critical review of the history of autoimmune anti-N-methyl-d-aspartate receptor encephalitis.

We report the appearance of clinical symptoms and signs of N-methyl-d-Aspartate (NMDA) receptor encephalitis in a patient presenting just days after contraction of influenza B. The offending mature ovarian teratoma was identified and removed on the 10th day after the appearance of symptoms, with subsequent nearly complete resolution of symptoms over the subsequent 6 months. We provide a focused literature review of the clinical and pathophysiologic literature of anti-NMDA receptor encephalitis pertaining to influenza B virus and the pediatric population. Taken together, this study contributes to the pathophysiological understanding of anti-NMDA receptor encephalitis and aids clinicians in its early recognition and management.

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.

Takotsubo syndrome associated with autoimmune limbic encephalitis: a case report.

BACKGROUND: Central nervous system diseases are common triggers of Takotsubo syndrome. We herein report a rare case of Takotsubo syndrome associated with autoimmune limbic encephalitis. CASE PRESENTATION: A 68-year-old Japanese woman presented to our emergency room with disturbed consciousness. At admission, she showed hypoxemia. Left ventriculography showed akinesia in the middle part of the left ventricle and hyperkinesia in the apical and basal parts of the left ventricle, and the diagnosis of midventricular Takotsubo syndrome was established. However, after an improvement in disturbed consciousness and Takotsubo syndrome symptoms, her brother noticed something wrong with her behavior during his visit to the hospital. Subsequently, we consulted the neurology department 1 week after admission. Her brother revealed a history of abnormal behavior by the patient (such as mistaken entry in the wrong apartment in her building or in another person's car) a few days prior to the onset of disturbed consciousness, suggesting disorientation of place. Brain magnetic resonance imaging showed an increased signal in the medial aspect of the temporal lobes, which was most clearly observed on the fluid-attenuated inversion recovery sequence; additionally, a cerebrospinal fluid analysis revealed mild lymphocytic pleocytosis. Finally, we established a diagnosis of midventricular Takotsubo syndrome associated with autoimmune limbic encephalitis. CONCLUSIONS: It is presumed that the dysfunction of limbic system due to autonomic limbic encephalopathy is associated with exaggerated sympathetic stimulation. This likely resulted in Takotsubo syndrome in our patient.

[Ictal electroencephalography (EEG) activity and cerebral blood flow dynamics as potential pathological indicators: a case of anti-leucine-rich glioma-inactivated 1 protein (LGI1) encephalitis].

A 29 year-old, right-handed woman was admitted to our hospital due to her headache with fever elevation lasting for two months followed by a prolonged loss of awareness with an involuntary movement in her left hand and mouth. This movement appeared very frequently, and the duration was very short, so called "faciobrachial dystonic seizures (FBDS)". Some of FBDS were followed by prolonged loss of awareness. Brain MRI fluid attenuated inversion recovery (FLAIR) image revealed high intensity lesion in the left mesial temporal lobe. Arterial spin labeling (ASL) image indicated hyper perfusion in this lesion and also the lateral temporal region. No ictal electroencephalography (EEG) change was observed before the onset of FBDS. FBDS was often followed by focal impaired awareness seizure (FIAS) in which ictal EEG showed rhythmic alpha activity arising from left mid-temporal region. This EEG seizure pattern was clearly visible in the time-frequency analysis. Given these clinical findings, along with an evidence of serum anti-leucine-rich glioma-inactivated 1 (LGI1) antibody positive, she was diagnosed with anti-LGI1 encephalitis. Immunotherapy (methylpredonisolone and intravenous immunoglobulin) with a multiple anti-epileptic drugs therapy (lacosamide, perampanel, and lamotrigine) was highly responsible to her symptoms. Although the high intensity lesion in FLAIR image still remained after the treatment, findings of ASL and EEG showed clear correlation to her cognitive function and seizures, respectively. Temporal change in ASL imaging suggested that the hyper perfusion in ASL during the acute stage could be provided by inflammation of the encephalitis its self and also the seizures activities (FBDS and FIAS). The pathophysiological indication of anti-LGI1 encephalitis was limited in terms of the therapeutic strategy, however, our findings collectively suggested that the combination analysis of EEG activity and cerebral blood flow dynamics (ASL) could be the potential candidate.

Anti-CASPR2 clinical phenotypes correlate with HLA and immunological features.

OBJECTIVE: Antibodies 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. METHODS: A 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. RESULTS: Cluster 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%). INTERPRETATION: Symptoms' 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.

Neurobehavioral Disorders: The Corticolimbic System in Health and Disease.

The corticolimbic system (prefrontal cortices, amygdala, and hippocampus) integrates emotion with cognition and produces a behavioral output that is flexible based on the environmental circumstances. It also modulates pain, being implicated in pathophysiology of maladaptive pain. Because of the anatomic and function overlap between corticolimbic circuitry for pain and emotion, the pathophysiology for maladaptive pain conditions is extremely complex. Addressing environmental needs and underlying triggers is more important than pharmacotherapy when dealing with feline orofacial pain syndrome or feline hyperesthesia syndrome. By contrast, autoimmune limbic encephalitis requires prompt diagnosis and management with immunosuppression and seizure control.

Fixel-based analysis links white matter characteristics, serostatus and clinical features in limbic encephalitis.

Limbic encephalitis (LE) is an autoimmune syndrome often associated with temporal lobe epilepsy. Recent research suggests that particular structural changes in LE depend on the type of the associated antibody and occur in both mesiotemporal gray matter and white matter regions. However, it remains questionable to what degree conventional diffusion tensor imaging (DTI)-methods reflect alterations in white matter microstructure, since these methods do not account for crossing fibers. To address this methodological shortcoming, we applied fixel-based analysis as a novel technique modeling distinct fiber populations. For our study, 19 patients with LE associated with autoantibodies against glutamic acid decarboxylase 65 (GAD-LE, mean age = 35.9 years, 11 females), 4 patients with LE associated with autoantibodies against leucine-rich glioma-inactivated 1 (LGI1-LE, mean age = 63.3 years, 2 females), 5 patients with LE associated with contactin-associated protein-like 2 (CASPR2, mean age = 57.4, 0 females), 20 age- and gender-matched control patients with hippocampal sclerosis (19 GAD-LE control patients: mean age = 35.1 years, 11 females; 4 LGI1-LE control patients: mean age = 52.6 years, 2 females; 5 CASPR2-LE control patients: mean age = 42.7 years, 0 females; 10 patients are included in more than one group) and 33 age- and gender-matched healthy control subjects (19 GAD-LE healthy controls: mean age = 34.6 years, 11 females; 8 LGI1-LE healthy controls: mean age = 57.0 years, 4 females, 10 CASPR2-LE healthy controls: mean age = 57.2 years, 0 females; 4 subjects are included in more than one group) underwent structural imaging and DTI at 3 T and neuropsychological testing. Patient images were oriented according to lateralization in EEG resulting in an affected and unaffected hemisphere. Fixel-based metrics fiber density (FD), fiber cross-section (FC), and fiber density and cross-section (FDC = FD · FC) were calculated to retrieve information about white matter integrity both on the micro- and the macroscale. As compared to healthy controls, patients with GAD-LE showed significantly (family-wise error-corrected, p < 0.05) lower FDC in the superior longitudinal fascicle bilaterally and in the isthmus of the corpus callosum. In CASPR2-LE, lower FDC in the superior longitudinal fascicle was only present in the affected hemisphere. In LGI1-LE, we did not find any white matter alteration of the superior longitudinal fascicle. In an explorative tract-based correlation analysis within the GAD-LE group, only a correlation between the left/right ratio of FC values of the superior longitudinal fascicle and verbal memory performance (R = 0.64, Holm-Bonferroni corrected p < 0.048) remained significant after correcting for multiple comparisons. Our results underscore the concept of LE as a disease comprising a broad and heterogeneous group of entities and contribute novel aspects to the pathomechanistic understanding of this disease that may strengthen the role of MRI in the diagnosis of LE.

CD19+ B-cells in autoantibody-negative limbic encephalitis.

PURPOSE: Flow cytometry helps to elucidate the cellular immune repertoire's mechanisms in patients with temporal lobe epilepsy (TLE) due to limbic encephalitis (LE) subcategories and carries potential significance for subtype-specific treatment. METHODS: We enrolled 62 patients with TLE due to LE associated with no autoantibodies (n = 40), neural autoantibodies (n = 22), as well as autoantibodies against intracellular antigens (n = 15/22). All patients underwent neuropsychological testing, brain magnetic resonance imaging (MRI), electroencephalography (EEG) recordings, and peripheral blood (PB) and cerebrospinal fluid (CSF) investigations including flow cytometry. RESULTS: CD19+ B-cells were increased in the PB and CSF of patients with antibody-negative LE compared with those associated with antibodies against intracellular antigens (Kruskal-Wallis one way analysis of variance (ANOVA) on ranks with Dunn's test, p < 0.05). There were no differences in CD138+ B-cells, CD4+ T-cells, human leukocyte antigen - DR isotype (HLA-DR+) CD4+ T-cells, CD8+ T-cells, and HLA-DR+ CD8+ T-cells in the CSF between groups with LE. The blood-brain barrier is more often impaired in patients with antibody-negative LE than in LE with antibodies against intracellular antigens (chi-square test, p < 0.05). In addition, we detected no correlations between immune cell subsets and clinical or paraclinical parameters in patients with antibody-negative and intracellular antibody-positive LE. CONCLUSIONS: The increase of CD19+ B-cells in the CSF and frequent signs of dysfunctional blood-brain barrier in patients with antibody-negative rather than intracellular antibody-positive LE suggest that CD19+ B-cells play a role in antibody-negative encephalitis although their pathogenic role in the central nervous system (CNS) immunity because of missing correlations between immune cells and clinical and paraclinical parameters remains unknown. Further studies are required to evaluate the usefulness of these B-cells as a biomarker for the stratification of treatment strategies.

Neurologic syndromes related to anti-GAD65: Clinical and serologic response to treatment.

OBJECTIVE: Antibodies against glutamic acid decarboxylase 65 (anti-GAD65) are associated with a number of neurologic syndromes. However, their pathogenic role is controversial. Our objective was to describe clinical and paraclinical characteristics of anti-GAD65 patients and analyze their response to immunotherapy. METHODS: Retrospectively, we studied patients (n = 56) with positive anti-GAD65 and any neurologic symptom. We tested serum and CSF with ELISA, immunohistochemistry, and cell-based assay. Accordingly, we set a cutoff value of 10,000 IU/mL in serum by ELISA to group patients into high-concentration (n = 36) and low-concentration (n = 20) groups. We compared clinical and immunologic features and analyzed response to immunotherapy. RESULTS: Classical anti-GAD65-associated syndromes were seen in 34/36 patients with high concentration (94%): stiff-person syndrome (7), cerebellar ataxia (3), chronic epilepsy (9), limbic encephalitis (9), or an overlap of 2 or more of the former (6). Patients with low concentrations had a broad, heterogeneous symptom spectrum. Immunotherapy was effective in 19/27 treated patients (70%), although none of them completely recovered. Antibody concentration reduction occurred in 15/17 patients with available pre- and post-treatment samples (median reduction 69%; range 27%-99%), of which 14 improved clinically. The 2 patients with unchanged concentrations showed no clinical improvement. No differences in treatment responses were observed between specific syndromes. CONCLUSION: Most patients with high anti-GAD65 concentrations (>10,000 IU/mL) showed some improvement after immunotherapy, unfortunately without complete recovery. Serum antibody concentrations' course might be useful to monitor response. In patients with low anti-GAD65 concentrations, especially in those without typical clinical phenotypes, diagnostic alternatives are more likely.

18F-FDG-PET/MRI in the diagnostic work-up of limbic encephalitis.

INTRODUCTION: Limbic encephalitis (LE) is an immune-related, sometimes paraneoplastic process of the central nervous system. Initial diagnosis and treatment are based on the clinical presentation as well as antibody profiles and MRI. This study investigated the diagnostic value of integrated 18F-FDG-PET/MRI in the diagnostic work-up of patients with LE for a cerebral and whole-body imaging concept. MATERIAL AND METHODS: Twenty patients with suspected LE were enrolled in this prospective study. All patients underwent a dedicated PET/MRI protocol of the brain as well as the whole-body. Two neuroradiologists, one body radiologist and one nuclear medicine physician performed blinded consensus readings of each corresponding MRI and PET/MRI dataset of the brain and whole-body. Diagnostic confidence was evaluated on a Likert scale. RESULTS: Based on integrated PET/MRI 19 / 20 patients were found to show morphologic and / or metabolic changes indicative of LE, whereas sole MRI enabled correct identification in 16 / 20 patients. Three patients with negative MRI showed metabolic changes of the limbic system or extra-limbic regions, shifting the diagnosis from (negative) MRI to positive for LE in PET/MRI. Whole-body staging revealed suspected lesions in 2/20 patients, identified by MRI and PET, one confirmed as malignant and one false positive. Diagnostic confidence for cerebral and whole-body imaging reached higher scores for PET/MRI (cerebral: 2.7 and whole body: 4.8) compared to MRI alone (cerebral: 2.4 and whole body: 4.5). CONCLUSION: LE diagnosis remains challenging for imaging as it shows only subtle imaging findings in most patients. Nevertheless, based on the simultaneous and combined analysis of morphologic and metabolic data, integrated PET/MRI may enable a dual platform for improved diagnostic confidence and overall detection of LE as well as whole-body imaging for exclusion of paraneoplastic LE.

Human hippocampal CA3 damage disrupts both recent and remote episodic memories.

Neocortical-hippocampal interactions support new episodic (event) memories, but there is conflicting evidence about the dependence of remote episodic memories on the hippocampus. In line with systems consolidation and computational theories of episodic memory, evidence from model organisms suggests that the cornu ammonis 3 (CA3) hippocampal subfield supports recent, but not remote, episodic retrieval. In this study, we demonstrated that recent and remote memories were susceptible to a loss of episodic detail in human participants with focal bilateral damage to CA3. Graph theoretic analyses of 7.0-Tesla resting-state fMRI data revealed that CA3 damage disrupted functional integration across the medial temporal lobe (MTL) subsystem of the default network. The loss of functional integration in MTL subsystem regions was predictive of autobiographical episodic retrieval performance. We conclude that human CA3 is necessary for the retrieval of episodic memories long after their initial acquisition and functional integration of the default network is important for autobiographical episodic memory performance.

Anti-glutamic acid decarboxylase antibody paraneoplastic limbic encephalitis associated with Acute Myeloid Leukemia.

A 75-year-old woman developed a frontal lobe disorder a few days after the diagnostic of an Acute Myeloid Leukemia secondary to a myelodysplastic syndrome. The patterns on the cerebral Magnetic Resonance Imaging and positron emission tomography and the find of antiglutamic acid decarboxylase antibody on cerebral spinal fluid were in favor of a paraneoplastic limbic encephalitis. In cerebral spinal fluid, there were no micro-organisms nor leukemic cells. We found no sign of cancer on full body computerized tomography-scan, on full-body PET and on rectosigmoidoscopy. The patient was treated by corticosteroid and intravenous immunoglobulins with success, but she died before receiving chemotherapy. It's known that anti- glutamic acid decarboxylase antibody is involved in paraneoplastic syndromes. Paraneoplastic limbic encephalitis is frequently associated with carcinoma or Hodgkin's lymphoma, but it was only reported associated with Acute Myeloid Leukemia in one case report. Even if Acute Myeloid Leukemia is not frequently associated with paraneoplastic limbic encephalitis, the clinicians must consider paraneoplastic limbic encephalitis as an etiology of unexplained neurological disorders.

Immune checkpoint inhibitor induced anti-glutamic acid decarboxylase 65 (Anti-GAD 65) limbic encephalitis responsive to intravenous immunoglobulin and plasma exchange.

Immune checkpoint inhibitors have made significant advances in available cancer treatment options towards progression-free and overall survival in cancer patients by potentiating own anti-tumor immune response. Anti-programmed death (PD-1) and anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) have been increasingly associated with neurologic complications. LE is a rare complication and like many complications secondary to immunotherapy, there is no standard for evaluation and treatment. Anti-GAD65-associated LE has been associated with thymic carcinoma. We describe a patient who presented with progressive memory loss 2 weeks after her third cycle of Ipilimumab and Nivolumab with associated elevated Anti-GAD65 levels. Treatment with IVIG and PLEX led to complete resolution of her symptoms and improvement in her brain imaging and CSF findings.

Low CSF CD4/CD8+ T-cell proportions are associated with blood-CSF barrier dysfunction in limbic encephalitis.

PURPOSE: Investigating immune cells in autoimmune limbic encephalitis (LE) will contribute to our understanding of its pathophysiology and may help to develop appropriate therapies. The aim of the present study was to analyze immune cells to reveal underlying immune signatures in patients with temporal lobe epilepsy (TLE) with LE. METHODS: We investigated 68 patients with TLE with LE compared with 7 control patients with TLE with no signs of LE screened from 154 patients with suspected LE. From the patients with TLE-LE, we differentiated early seizure onset (<20 years, n = 9) and late seizure onset group (≥20 years, n = 59) of patients. Patients underwent neuropsychological assessment, electroencephalography (EEG), brain magnetic resonance imaging (MRI), and peripheral blood (PB) and cerebrospinal fluid (CSF) analysis including flow cytometry. RESULTS: We identified a higher CD4/8+ T-cell ratio in the PB in all patients with TLE-LE and in patients with late-onset TLE-LE each compared with controls (Kruskal-Wallis one-way ANOVA (analysis of variance) with Dunn's test, p < 0.05). Moreover, a lower CD4/CD8+ T-cell ratio is detected in all patients with TLE-LE with blood-CSF barrier dysfunction, unlike in those with none (Kruskal-Wallis one-way ANOVA with Dunn's test, p < 0.05). CONCLUSIONS: These findings suggest that the proportion of CD4+ and CD8+ T-cells in the CSF of patients with LE associated with blood-CSF barrier dysfunction plays a potential role in CNS (central nervous system) inflammation in these patients. Thus, flow cytometry as a methodology reveals novel insights into LE's genesis and symptomatology. The CD4/8+ T-cell ratio in PB as a biomarker for LE requires further investigation.