Temporal lobe epilepsy with GAD antibodies: neurons killed by T cells not by complement membrane attack complex.

Temporal lobe epilepsy (TLE) is one of the syndromes linked to antibodies against glutamic acid decarboxylase (GAD). It has been questioned whether 'limbic encephalitis with GAD antibodies' is a meaningful diagnostic entity. The immunopathogenesis of GAD-TLE has remained enigmatic. Improvement of immunological treatability is an urgent clinical concern. We retrospectively assessed the clinical, MRI and CSF course as well as brain tissue of 15 adult patients with GAD-TLE who underwent temporal lobe surgery. Brain tissue was studied by means of immunohistochemistry, multiplex fluorescent microscopy and transcriptomic analysis for inflammatory mediators and neuronal degeneration. In 10 patients, there was a period of mediotemporal swelling and T2 signal increase; in nine cases this occurred within the first 6 years after symptom onset. This resulted in unilateral or bilateral hippocampal sclerosis; three cases developed hippocampal sclerosis within the first 2 years. All CSF studies done within the first year (n = 6) revealed intrathecal synthesis of immunoglobulin G. Temporal lobe surgeries were done after a median disease duration of 9 years (range 3 weeks to 60 years). Only two patients became seizure-free. Brain parenchyma collected during surgery in the first 6 years revealed high numbers of plasma cells but no signs of antibody-mediated tissue damage. Even more dense was the infiltration by CD8+ cytotoxic T lymphocytes (CTLs) that were seen to locally proliferate. Further, a portion of these cells revealed an antigen-specific resident memory T cell phenotype. Finally, CTLs with cytotoxic granzyme B+ granules were also seen in microglial nodules and attached to neurons, suggesting a CTL-mediated destruction of these cells. With longer disease duration, the density of all lymphocytes decreased. Whole transcriptome analysis in early/active cases (but not in late/inactive stages) revealed 'T cell immunity' and 'Regulation of immune processes' as the largest overrepresented clusters. To a lesser extent, pathways associated with B cells and neuronal degeneration also showed increased representation. Surgically treated patients with GAD-TLE go through an early active inflammatory, 'encephalitic' stage (≤6 years) with CTL-mediated, antigen-driven neuronal loss and antibody-producing plasma cells but without signs of complement-mediated cell death. Subsequently, patients enter an apparently immunologically inactive or low-active stage with ongoing seizures, probably caused by the structural damage to the temporal lobe. 'Limbic encephalitis' with GAD antibodies should be subsumed under GAD-TLE. The early tissue damage explains why immunotherapy does not usually lead to freedom from seizures.

Distinctive sleep complaints and polysomnographic findings in antibody subgroups of autoimmune limbic encephalitis.

INTRODUCTION: Sleep disturbances are being increasingly recognized in association with autoimmune encephalitis (AIE). We investigated the prevalence of sleep-related symptoms and polysomnographic features of patients with AIE and the long-term outcomes in these patients in a multi-center, prospective study from Turkey. METHODS: We prospectively evaluated patients with definite AIE in a common database including demographics, AIE-related and sleep-related symptomatology. Maximum and latest modified Rankin scores (mRS) and Liverpool Outcome Score (LOS) were noted. RESULTS: Of 142 patients, 87 patients (61.3%) fulfilled the criteria for definite AIE (mean age, 46.8+18.8 years; 51.7% women; mean disease duration, 21.0+38.4 months). 78.9% of patients had at least one or more new onset or worsened sleep-related symptomatology: insomnia (55.3%), excessive daytime sleepiness (EDS, 28.0%), sleep apnea (18.7%), REM sleep behavior disorder (RBD, 17.3%), restless legs syndrome (10.7%) and oneiric stupor (9.3%). Sleep efficiency, N3 and REM sleep were decreased and N1 sleep was increased in patients with Ab[+] AIE. LOS points were highest in those with insomnia and sleep apnea, and lowest in those with EDS, RBD and oneiric stupor. RBD and sleep apnea were more common in anti-LG1 Ab[+] group than anti-NMDAR Ab[+] group. Index of periodic leg movements was highest in anti-LG1 Ab[+] group. Patients with EDS and oneiric stupor had more common memory problems. Maximum and latest mRS scores were positively correlated with EDS and oneiric stupor. EDS, RBD and oneiric stupor were negatively correlated with LOS points. CONCLUSION: Our study emphasizes the presence and importance of early diagnosis of sleep disturbances in AIE in regard to their deteriorative influences on disease prognosis.

Immune-mediated diseases involving central and peripheral nervous systems.

BACKGROUND AND PURPOSE: In addition to combined central and peripheral demyelination, other immune diseases could involve both the central nervous system (CNS) and peripheral nervous system (PNS). METHODS: To identify immune-mediated diseases responsible for symptomatic combined central/peripheral nervous system involvement (ICCPs), we conducted a multicentric retrospective study and assessed clinical, electrophysiological, and radiological features of patients fulfilling our ICCP criteria. RESULTS: Thirty patients (20 males) were included and followed during a median of 79.5 months (interquartile range [IQR] = 43-145). The median age at onset was 51.5 years (IQR = 39-58). Patients were assigned to one of four groups: (i) monophasic disease with concomitant CNS/PNS involvement including anti-GQ1b syndrome (acute polyradiculoneuropathy + rhombencephalitis, n = 2), checkpoint inhibitor-related toxicities (acute polyradiculoneuropathy + encephalitis, n = 3), and anti-glial fibrillary acidic protein astrocytopathy (subacute polyradiculoneuropathy and meningoencephalomyelitis with linear gadolinium enhancements, n = 2); (ii) chronic course with concomitant CNS/PNS involvement including paraneoplastic syndromes (ganglionopathy/peripheral hyperexcitability + limbic encephalitis, n = 4); (iii) chronic course with sequential CNS/PNS involvement including POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome (polyradiculoneuropathy + strokes, n = 2), histiocytosis (polyradiculoneuropathy + lepto-/pachymeningitis, n = 1), and systemic vasculitis (multineuropathy + CNS vasculitis/pachymeningitis, n = 2); and (iv) chronic course with concomitant or sequential CNS/PNS involvement including combined central and peripheral demyelination (polyradiculoneuropathy + CNS demyelinating lesions, n = 10) and connective tissue diseases (ganglionopathy/radiculopathy/multineuropathy + limbic encephalitis/transverse myelitis/stroke, n = 4). CONCLUSIONS: We diagnosed nine ICCPs. The timing of central and peripheral manifestations and the disease course help determine the underlying immune disease. When antibody against neuroglial antigen is identified, CNS and PNS involvement is systematically concomitant, suggesting a common CNS/PNS antigen and a simultaneous disruption of blood-nerve and blood-brain barriers.

CD8+ T-Lymphocyte-Driven Limbic Encephalitis Results in Temporal Lobe Epilepsy.

OBJECTIVE: Limbic encephalitis (LE) comprises a spectrum of inflammatory changes in affected brain structures including the presence of autoantibodies and lymphoid cells. However, the potential of distinct lymphocyte subsets alone to elicit key clinicopathological sequelae of LE potentially inducing temporal lobe epilepsy (TLE) with chronic spontaneous seizures and hippocampal sclerosis (HS) is unresolved. METHODS: Here, we scrutinized pathogenic consequences emerging from CD8+ T cells targeting hippocampal neurons by recombinant adeno-associated virus-mediated expression of the model-autoantigen ovalbumin (OVA) in CA1 neurons of OT-I/RAG1-/- mice (termed "OVA-CD8+ LE model"). RESULTS: Viral-mediated antigen transfer caused dense CD8+ T cell infiltrates confined to the hippocampal formation starting on day 5 after virus transduction. Flow cytometry indicated priming of CD8+ T cells in brain-draining lymph nodes preceding hippocampal invasion. At the acute model stage, the inflammatory process was accompanied by frequent seizure activity and impairment of hippocampal memory skills. Magnetic resonance imaging scans at day 7 of the OVA-CD8+ LE model revealed hippocampal edema and blood-brain barrier disruption that converted into atrophy until day 40. CD8+ T cells specifically targeted OVA-expressing, SIINFEKL-H-2Kb -positive CA1 neurons and caused segmental apoptotic neurodegeneration, astrogliosis, and microglial activation. At the chronic model stage, mice exhibited spontaneous recurrent seizures and persisting memory deficits, and the sclerotic hippocampus was populated with CD8+ T cells escorted by NK cells. INTERPRETATION: These data indicate that a CD8+ T-cell-initiated attack of distinct hippocampal neurons is sufficient to induce LE converting into TLE-HS. Intriguingly, the role of CD8+ T cells exceeds neurotoxic effects and points to their major pathogenic role in TLE following LE. ANN NEUROL 2021;89:666-685.

Agrypnia excitata as the main feature in anti-leucine-rich glioma-inactivated 1 encephalitis: a detailed clinical and polysomnographic semiological analysis.

BACKGROUND AND PURPOSE: The core manifestations of leucine-rich glioma-inactivated 1 (LGI1) autoantibody-mediated encephalitis are limbic encephalitis and faciobrachial dystonic seizures. Agrypnia excitata (AE) is a rare syndrome characterized by sleep-wake cycle disruption, autonomic hyperactivation and episodes of oneiric stupor. Only a few diseases are known to present with AE. An autoimmune etiology must be considered when accompanied by neuromyotonia. A case of anti-LGI1 encephalitis presenting with AE is reported. METHODS: Detailed clinical, video-polysomnographic, laboratory, radiological and long-term follow-up assessments were performed. RESULTS: A previously healthy 58-year-old man was referred for a rapidly progressive change in mental status, characterized by persistent drowsiness and confusion, accompanied by frequent episodes of unconscious gestures ranging from simple stereotyped movements to more complex actions mimicking various daily activities. Other symptoms included tachycardia, hyperhidrosis, mild hyponatremia, rare faciobrachial dystonic seizures, and a single generalized tonic-clonic seizure, but no neuromyotonia. Prolonged video-polysomnography excluded epileptic activity and showed continuous monomorphic slowing of background activity not consistent with a regular wakefulness or sleep state. A brain magnetic resonance imaging scan was unremarkable. Brain fluorodeoxyglucose positron emission tomography revealed hypermetabolism of the hippocampi, amygdala and basal ganglia. Anti-LGI1 antibodies were detected in the cerebrospinal fluid. The sleep disorder resolved progressively after starting immunotherapy. CONCLUSIONS: Agrypnia excitata can be a dominant, treatable manifestation of anti-LGI1 encephalitis. Oneiric stupor episodes are a useful clinical feature for establishing diagnostic suspicion and could provide a window to understanding the mechanisms behind some movement disorders in autoimmune encephalitis.

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.

Neuropsychiatric lupus erythematosus with neurogenic pulmonary edema and anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor limbic encephalitis: a case report.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune inflammatory disease predominantly found in women of child-bearing age. Neurogenic pulmonary edema (NPE) is a recalcitrant complication that occurs after injury to the central nervous system and has an acute onset and rapid progression. Limbic encephalitis is an inflammatory encephalopathy caused by viruses, immune responses, or other factors involving the limbic system. NPE caused by SLE is rare. CASE PRESENTATION: Here, we report a case of a 21-year-old woman with SLE who experienced five episodes of generalized tonic-clonic seizure after headache and dyspnea. Anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) 2 antibody was tested positive in the serum and cerebrospinal fluid. Electrocardiography (EEG) indicated paroxysmal or sporadic medium amplitude theta activity. In addition, chest computed tomography (CT) showed multiple diffuse consolidations and ground-glass opacities. We finally considered a diagnosis of NPE and AMPAR limbic encephalitis. The patient's symptoms improved obviously after methylprednisolone pulse therapy and antiepileptic treatment. CONCLUSIONS: NPE can be a complication of neuropsychiatric lupus erythematosus (NPSLE). AMPAR2 antibodies may be produced in NPSLE patients, especially in those with high polyclonal IgG antibody titers. More basic and clinical studies are required to confirm these observations and elucidate the pathogenicity of encephalitis-related autoantibodies in SLE patients.

A case of new cognitive changes in a patient with seronegative paraneoplastic limbic encephalitis: encephalitis relapse or Wernicke's encephalopathy?

Wernicke's encephalopathy (WE) and paraneoplastic limbic encephalitis (PLE) can both present with acute-to-subacute memory impairment and cognitive dysfunction. Both can lead to significant morbidity and mortality without rapid identification and treatment. Often patients with WE may not have the typical clinical triad of ophthalmoplegia, gait ataxia, and altered mental status. Furthermore, both WE and PLE may share similar MRI findings. Here, we present a case of a patient with a history of seronegative PLE presenting with acute-to-subacute cognitive changes and gait imbalance. Initially, it was felt to be a relapse of PLE but upon further history and testing may potentially have represented WE in the setting of a recent dietary change.

Stiff Person Syndrome and Encephalitis with GAD Antibodies with Severe Anterograde Amnesia in an Adolescent: A Case Study and Literature Review.

Antiglutamic acid decarboxylase (GAD65) encephalitis is rare and few pediatric cases have been reported, with variable clinical presentations. A 14-year-old female adolescent was managed in our department. She had been treated for several months for drug-resistant temporal lobe epilepsy and gradually presented major anterograde amnesia with confusion. Upon her arrival at the University Hospital Centre, she showed a classical form of stiff person syndrome. The brain magnetic resonance imaging showed bitemporal hyperintensities and hypertrophy of the amygdala. The blood and cerebrospinal fluid were positive for GAD65 antibodies. At 2 years of immunosuppressive treatment and rehabilitation, the course showed partial improvement of the memory and neuropsychiatric impairment, and epilepsy that continued to be active. GAD65 antibodies are associated with various neurological syndromes, and this presentation combining limbic encephalitis and stiff person syndrome is the first pediatric form published to date; there are also few cases described in adults.

Nonparaneoplastic Anti-GAD Limbic Encephalitis: Seizure Outcome and Long-term Neuropsychological Follow-up After Immunotherapy.

Antibodies against glutamate decarboxylase (GAD-Abs), especially GAD65 antibodies, are associated with limbic encephalitis (LE) manifested by temporal lobe epilepsy and neuropsychological deficits. We present the case of a 42-year-old Greek woman with nonparaneoplastic anti-GAD LE, discussing the therapeutic management and highlighting the role of neuropsychological assessment. The patient underwent functional and structural brain studies and was investigated longitudinally over a 6-year period with a battery of neuropsychological tests that were designed to document her intellectual function and verbal and visual memory. The patient suffered from refractory temporal-impaired awareness seizures and memory impairment that was mediated by autoimmune nonparaneoplastic LE and comorbid autoimmune disorders (ie, Hashimoto thyroiditis and vitiligo). Neuroimaging studies demonstrated hyperintensities in the medial temporal lobes bilaterally on T2WI MRI sequences. Serial EEGs showed bitemporal intermittent delta activity as well as epileptiform discharges. Tumor blood markers and onconeural antibodies were negative. Immunological screening revealed extremely high GAD-Abs titers in both serum and CSF, as well as the presence of CSF oligoclonal bands. Neuropsychological testing revealed anterograde amnesia with relative preservation of more remote, premorbid memories. The patient underwent first-line immunotherapy followed by immunosuppressive maintenance treatment that led to a reduction of seizures, EEG improvement, and a significant decline in GAD-Abs titers. Neuropsychological evaluations at 5 months, 1 year, and 6 years posttreatment demonstrated improvement, particularly in recent memory and everyday functionality. In this case of anti-GAD LE, the long-term seizure reduction and the improvement of neuropsychological deficits were most likely related to the immunotherapy.

What Is Different about Teratoma-Associated Anti-LGI1 Encephalitis? A Long-Term Clinical and Neuroimaging Case Series.

INTRODUCTION: Anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis is clinically heterogeneous, especially at presentation, and though it is sometimes found in association with tumor, this is by no means the rule. METHODS: Clinical data for 10 patients with anti-LGI1 encephalitis were collected including one case with teratoma and nine cases without and compared for clinical characteristics. Microscopic pathological examination and immunohistochemical assay of the LGI1 antibody were performed on teratoma tissue obtained by laparoscopic oophorocystectomy. RESULTS: In our teratoma-associated anti-LGI1 encephalitis case, teratoma pathology was characterized by mostly thyroid tissue and immunohistochemical assay confirmed positive nuclear staining of LGI1 in some tumor cells. The anti-LGl1 patient with teratoma was similar to the non-teratoma cases in many ways: age at onset (average 47.3 in non-teratoma cases); percent presenting with rapidly progressive dementia (67% of non-teratoma cases) and psychiatric symptoms (33%); hyponatremia (78%); normal cerebrospinal fluid results except for positive LGI1 antibody (78%); bilateral hippocampal hyperintensity on magnetic resonance imaging (44%); diffuse slow waves on electroencephalography (33%); good response to immunotherapy (67%); and mild residual cognitive deficit (22%). Her chronic anxiety and presentation with status epilepticus were the biggest differences compared with the non-teratoma cases. CONCLUSION: In our series, anti-LGI1 encephalitis included common clinical features in our series: rapidly progressive dementia, faciobrachial dystonic seizures, behavioral disorders, hyponatremia, hippocampal hyperintensity on magnetic resonance imaging, and residual cognitive deficit. We observed some differences (chronic anxiety and status epilepticus) in our case with teratoma, but a larger accumulation of cases is needed to improve our knowledge base.

Sexual behaviour change in seronegative limbic encephalitis due to the involvement of the left amygdala.

Limbic encephalitis (LE), a rare cause of encephalitis, generally presents with neuropsychiatric manifestations, memory deficits, seizures, and movement disorders. The case of a 41-year-old female patient with LE involving the left amygdala is presented. The patient was admitted to the emergency department with complaints of unconsciousness and seizures. Paraneoplastic and limbic markers were negative. This case was diagnosed as seronegative LE. Three to four months after the diagnosis, it was observed that her sexual preference changed to the female sex. No report has been published so far, concerning any case of LE associated with changes in sexual behaviour. The patient was treated with intravenous methylprednisolone (IVP) and triple antiepileptic therapy. After treatment, changes in sexual behaviour returned to the previous state.

Determinants of cognition in autoimmune limbic encephalitis-A retrospective cohort study.

Autoimmune limbic encephalitis (ALE) is the most common type of autoimmune encephalitis (AIE). Subacute memory disturbance, temporal lobe seizures, and psychiatric symptoms are clinical hallmarks of the disease. However, little is known on the factors contributing to cognitive functioning in ALE. Hence, we here investigate major determinants of cognitive functioning in ALE. In a retrospective analysis of 102 patients with ALE, we first compared verbal learning capacity, nonverbal learning capacity, and attentional and executive functioning by absence or presence of different types of neural autoantibodies (AABs). Subsequently we established three linear regression models including 63, 38, and 61 patients, respectively to investigate how cognitive functioning in these domains may depend on common markers of ALE such as intrathecal inflammation, blood-cerebrospinal fluid (CSF)-barrier function, mesiotemporal epileptiform discharges and slowing, determined by electroencephalography (EEG) and structural mesiotemporal changes, measured with magnetic resonance imaging (MRI). We also accounted for possible effects of cancer- and immunotherapy and other centrally effective medication. There was no effect of AAB status on cognitive functioning. Although the regression models could not predict verbal and nonverbal learning capacity, structural mesiotemporal neural network alterations on T2-/fluid attenuated inversion recovery (FLAIR)-signal-weighted MRI and mesiotemporal epileptiform discharges or slowing on EEG exerted a significant impact on memory functions. In contrast, the regression model significantly predicted attentional and executive functioning with CSF white blood cell count and centrally effective medication being significant determinants. In this cohort, cognitive functioning in ALE does not depend on the AAB status. Common markers of ALE cannot predict memory functioning that only partially depends on structural and functional alterations of mesiotemporal neural networks. Common markers of ALE significantly predict attentional and executive functioning that is significantly related to centrally effective medication and CSF white blood cell count, which may point toward inflammation affecting brain regions beyond the limbic system.

Neuropsychiatric symptoms in limbic-predominant age-related TDP-43 encephalopathy and Alzheimer's disease.

There is clinical overlap between presentations of dementia due to limbic-predominant age-related TDP-43 encephalopathy (LATE) and Alzheimer's disease. It has been suggested that the combination of Alzheimer's disease neuropathological change (ADNC) and LATE neuropathological changes (LATE-NC) is associated with greater neuropsychiatric symptom burden, compared to either pathology alone. Longitudinal Neuropsychiatric Inventory and psychotropic medication prescription data from neuropathologically diagnosed pure ADNC (n = 78), pure LATE-NC (n = 14) and mixed ADNC/LATE-NC (n = 39) brain bank donors were analysed using analysis of variance and linear mixed effects regression models to examine the relationship between diagnostic group and neuropsychiatric symptom burden. Nearly all donors had dementia; three (two pure LATE-NC and one pure ADNC) donors had mild cognitive impairment and another two donors with LATE-NC did not have dementia. The mixed ADNC/LATE-NC group was older than the pure ADNC group, had a higher proportion of females compared to the pure ADNC and LATE-NC groups, and had more severe dementia versus the pure LATE-NC group. After adjustment for length of follow-up, cognitive and demographic factors, mixed ADNC/LATE-NC was associated with lower total Neuropsychiatric Inventory and agitation factor scores than pure ADNC, and lower frontal factor scores than pure LATE-NC. Our findings indicate that concomitant LATE pathology in Alzheimer's disease is not associated with greater neuropsychiatric symptom burden. Future longitudinal studies are needed to further investigate whether mixed ADNC/LATE-NC may be protective against agitation and frontal symptoms in dementia caused by Alzheimer's disease or LATE pathology.

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.

Development of the clinical assessment scale in autoimmune encephalitis.

OBJECTIVE: There is no scale for rating the severity of autoimmune encephalitis (AE). In this study, we aimed to develop a novel scale for rating severity in patients with diverse AE syndromes and to verify the reliability and validity of the developed scale. METHODS: The key items were generated by a panel of experts and selected according to content validity ratios. The developed scale was initially applied to 50 patients with AE (development cohort) to evaluate its acceptability, reproducibility, internal consistency, and construct validity. Then, the scale was applied to another independent cohort (validation cohort, n = 38). RESULTS: A new scale consisting of 9 items (seizure, memory dysfunction, psychiatric symptoms, consciousness, language problems, dyskinesia/dystonia, gait instability and ataxia, brainstem dysfunction, and weakness) was developed. Each item was assigned a value of up to 3 points. The total score could therefore range from 0 to 27. We named the scale the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). The new scale showed excellent interobserver (intraclass correlation coefficient [ICC] = 0.97) and intraobserver (ICC = 0.96) reliability for total scores, was highly correlated with modified Rankin scale (r = 0.86, p < 0.001), and had acceptable internal consistency (Cronbach α = 0.88). Additionally, in the validation cohort, the scale showed high interobserver reliability (ICC = 0.99) and internal consistency (Cronbach α = 0.92). INTERPRETATION: CASE is a novel clinical scale for AE with a high level of clinimetric properties. It would be suitable for application in clinical practice and might help overcome the limitations of current outcome scales for AE. ANN NEUROL 2019;85:352-358.

Diagnosis and treatment of limbic encephalitis in the cancer patient.

Limbic encephalitis is an inflammatory process involving the limbic structures of the brain, manifested with short-term memory deficits, confusion, depression and seizures. It is usually a paraneoplastic condition but it may also appear as a nonparaneoplastic syndrome. Patients with this condition may exhibit a variety of antibodies in their serum or/and cerebrospinal fluid targeting basement membrane components that bind to a variety of neurotransmitter receptors such as α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and GABA B and proteins associated to the ion channels such as LGI1, Caspr2 or intracellular components. Flurodeoxyglucose PET/computed tomography usually demonstrates increased uptake in the limbic structures, and it may reveal the site of the primary tumor. Treatment consists of tumor removal if possible. Symptomatic treatment includes steroids, gamma immune globulin, plasma exchange, immunosuppressive therapies and anti-epileptic drugs. Prognosis is better when it is associated with antibodies against basement membrane rather than intracellular antibodies.

Synergistic effect of rituximab with anti-epileptic drugs in treating sero-negative limbic encephalitis: a case report.

Background: Limbic encephalitis can be associated with antibodies directed against intracellular antigens or cell surface antigens, or can be sero-negative. It is still unclear if rituximab can benefit sero-negative limbic encephalitis.Case presentation: Here, we report that a sero-negative limbic encephalitis patient with refractory seizures was treated successfully with rituximab combined with anti-epileptic drugs. Pulsed intravenous methylprednisolone (IVMP) combined with intravenous immunoglobulin (IVIg) in this patient resulted in limited effect.Conclusion: We conclude that rituximab may be tried in sero-negative limbic encephalitis if IVMP combined with IVIg failed, and delayed use of rituximab could also be effective.

Neuropsychiatric Disorders Due to Limbic Encephalitis: Immunologic Aspect.

Limbic encephalitis (LE) is a rare cause of encephalitis presenting as an acute and subacute onset of neuropsychiatric manifestations, particularly with memory deficits and confusion as core features, along with seizure occurrence, movement disorders, or autonomic dysfunctions. LE is caused by neuronal antibodies targeting the cellular surface, synaptic, and intracellular antigens, which alter the synaptic transmission, especially in the limbic area. Immunologic mechanisms involve antibodies, complements, or T-cell-mediated immune responses in different degree according to different autoantibodies. Sensitive cerebrospinal fluid markers of LE are unavailable, and radiographic findings may not reveal a typical mesiotemporal involvement at neurologic presentations; therefore, a high clinical index of suspicions is pivotal, and a neuronal antibody testing is necessary to make early diagnosis. Some patients have concomitant tumors, causing paraneoplastic LE; therefore, tumor survey and treatment are required in addition to immunotherapy. In this study, a review on the molecular and immunologic aspects of LE was conducted to gain awareness of its peculiarity, which we found quite different from our knowledge on traditional psychiatric illness.

Characterizing memory loss in patients with autoimmune limbic encephalitis hippocampal lesions.

Since the publication of Scoville and Milner's (1957) seminal paper, the precise functional role played by the hippocampus in support of human memory has been fiercely debated. For instance, the single question of whether the hippocampus plays a time-limited or an indelible role in the recollection of personal memories led to a deep and tenacious schism within the field. Similar polarizations arose between those who debated the precise nature of the role played by the hippocampus in support of semantic relative to episodic memories and in recall/recollection relative to familiarity-based recognition. At the epicenter of these divisions lies conflicting neuropsychological findings. These differences likely arise due to the consistent use of heterogeneous patient populations to adjudicate between these positions. Here we utilized traditional neuropsychological measures in a homogenous patient population with a highly discrete hippocampal lesion (i.e., VGKCC-Ab related autoimmune limbic encephalitis patients). We observed consistent impairment of recent episodic memories, a present but less striking impairment of remote episodic memories, preservation of personal semantic memory, and recall but not recognition memory deficits. We conclude that this increasingly well-characterized patient group may represent an important homogeneous population in which the functional role played by the hippocampus may be more precisely delineated.