Limbic Encephalitis Research Articles

Parallel roles of neuroinflammation in feline and human epilepsies

Autoimmune encephalitis refers to a group of disorders characterised by a non-infectious encephalitis, often with prominent seizures and surface neuronal autoantibodies. AE is an important cause of new-onset refractory status epilepticus in humans and is frequently responsive to immunotherapies including corticosteroids, plasma exchange, intravenous immunoglobulin G and rituximab. Recent research suggests that parallel autoantibodies can be detected in non-human mammalian species. The best documented example is leucine-rich glioma-inactivated 1 (LGI1)-antibodies in domestic cats with limbic encephalitis (LE). In this review, we discuss the role of neuroinflammation and autoantibodies in human and feline epilepsy and LE.

Neurological disorders associated with glutamic acid decarboxylase 65 antibodies: Clinical spectrum and prognosis of a cohort from China.

ObjectiveTo describe clinical phenotypes and prognosis of neurological autoimmunity related to glutamic acid decarboxylase 65 (GAD65) antibodies in China.MethodIn this retrospective observational study from Peking Union Medical College Hospital, we identified patients with neurological disorders related to GAD65 antibodies (cell-based assay) from May 2015 to September 2021. Clinical manifestations, immunotherapy responsiveness, and outcomes were collected after obtaining informed consent from all patients.ResultsFifty-five patients were included: 40 (72.73%) were women and initial neurological symptoms developed at 42(34-55) years of age. The median time to the nadir of the disease was 5 months (range from 1 day to 48 months). The clinical syndromes included limbic encephalitis (LE) or epilepsy (Ep) (n = 34, 61.82%), stiff-person syndromes (SPS) (n = 18, 32.73%), autoimmune cerebellar ataxia (ACA) (n = 11, 20%), and overlap syndrome in eight (14.55%) patients. Thirty-two (58.2%) patients had comorbidities of other autoimmune diseases, including Hashimoto thyroiditis (n = 17, 53.13%), T1DM (n = 11, 34.78%), vitiligo (n = 6, 18.75%), and others (n=5, 15.63%). Two (3.64%) patients had tumors, including thymoma and small cell lung cancer. Fifty-one (92.7%) patients received first-line immunotherapy (glucocorticoids and/or IV immunoglobulin), and 4 (7.3%) received second-line immunotherapy (rituximab). Long-term immunotherapy (mycophenolate mofetil) was administered to 23 (41.8%) patients. At the median time of 15 months (IQR 6–33.75 month, range 3–96 month) of follow-up, the patients' median modified Rankin Score (mRS) had declined from 2 to 1. Thirty-eight (70.4%) patients experienced clinical improvement (mRS declined ≥1), 47 (87%) had favorable clinical outcomes (mRS ≤2), and nine were symptom-free (16.7%). The sustained response to immunotherapy ranged from 7/15 (63.63%) in ACA patients and 22/34 (64.7%) in LE/Ep patients to 14/17 (82.35%) in SPS patients.ConclusionsLE/Ep was the most common neurological phenotype of GAD65 antibody neurological autoimmunity in our cohort. Most patients had comorbidities of other autoimmune diseases, but underlying tumors were rare. Most patients responded to immunotherapy. However, the long-term prognosis varied among different clinical phenotypes.

Primary Adrenal Small Cell Carcinoma Associated with Anti-Hu Positive Limbic Encephalitis: A Case Report

Primary Adrenal Small Cell Carcinoma Associated with Anti-Hu Positive Limbic Encephalitis: A Case Report

Panhypopituitarism as the first sign of paraneoplastic limbic encephalitis in a patient with cured testicular cancer: a case report

BackgroundParaneoplastic limbic encephalitis is a rare neurologic syndrome that affects patients with cancer and commonly presents with symptoms of personality changes, visual disturbances, seizures, vertigo, and memory loss. It has an immune-mediated pathophysiology and is associated with antibodies directed against both the tumor and limbic structures in the nervous system. Here, we report a case of paraneoplastic limbic encephalitis with an unusual presentation with initial symptoms of panhypopituitarism.Case presentationA 28-year-old Caucasian man with history of testicular cancer in remission for almost 2 years was admitted to our hospital for altered mental status, syncope, vertical gaze palsy, ataxia, and tremor. Three months prior to admission, he began to have initial symptoms of fatigue, weight gain, and hypogonadism. A few weeks before admission, he also developed worsening neurological symptoms that led him to present to the hospital. While hospitalized, he had an episode of syncope. Evaluation of his syncope revealed that he was hypovolemic due to polyuria, concerning for diabetes insipidus. While the patient did not meet criteria for diabetes insipidus, further endocrine laboratory testing to evaluate his central hormonal axes revealed panhypopituitarism. He also underwent a neurologic work-up with brain magnetic resonance imaging and lumbar puncture, with results consistent with encephalitis. He received high-dose steroids, plasmapheresis, and intravenous immunoglobulin, which did not significantly improve his physical examination or mental status. Extensive testing did not show any recurrence of his testicular cancer. Paraneoplastic antibodies were also ordered, with anti-Ma2 antibodies eventually returning positive, consistent with anti-Ma2 paraneoplastic limbic encephalitis.ConclusionParaneoplastic limbic encephalitis is often a difficult diagnosis due to its variable presentation and timeline of presentation, leading to delays in both diagnosis and treatment. While paraneoplastic limbic encephalitis usually presents with neurological symptoms, it may also present with panhypopituitarism. A high index of suspicion is warranted for paraneoplastic syndromes in patients with history of malignancy, even if the malignancy is in remission.

18F-FDG PET for the diagnosis and assessment of treatment response of autoimmune limbic encephalitis

18F-FDG PET for the diagnosis and assessment of treatment response of autoimmune limbic encephalitis

MRI Features of Anti-Ma1/Ma2 Paraneoplastic Neurologic Syndrome.

Anti-Ma1/Ma2 paraneoplastic neurologic syndrome (PNS) is rare and often associated with testicular malignancies.1 Diencephalitis is a characteristic feature of anti-Ma1/Ma2 PNS.1 In contrast to classical limbic encephalitis,2 the clinical and radiologic manifestations of diencephalitis may be initially subtle and under-recognized as PNS.

18 F-Fluorodeoxy Glucose and 11 C-Methionine Accumulation in Demyelinating Lesions.

Background Few studies have evaluated the accumulation of 18 F-fluorodeoxyglucose (FDG), 11 C-methionine (MET), and other positron emission tomography (PET) tracers in patients with demyelinating disease. Purpose This study aimed to investigate the accumulation of FDG-PET/computed tomography (CT) and MET-PET/CT in demyelinating lesions. Material and Methods A retrospective search of the patient database in our hospital identified five patients with demyelinating disease in whom PET studies performed in the past 10 years revealed accumulation of FDG or MET. The clinical diagnoses were multiple sclerosis ( n =1), myelitis ( n =1), limbic encephalitis ( n =1), chronic inflammatory demyelinating polyneuropathy (CIDP; n =1), and acute demyelinating encephalomyelitis (ADEM; n =1). Two patients received FDG-PET/CT alone and three patients received both FDG-PET/CT and MET-PET/CT on the same day. Images were visually and conjointly reviewed by two radiologists. In semiquantitative evaluation, the maximum standardized uptake value (SUV max ) of the lesion was measured. The lesion-to-normal brain uptake ratio (L/N ratio) was calculated. Results FDG and/or MET accumulated to a part of the lesions seen on MRI. SUV max on FDG-PET/CT ranged from 3.8 to 10.3, and L/N ratio on MET-PET/CT ranged from 16.6 to 2.4. Conclusion It has been established that neoplastic and demyelinating lesions can be differentiated on the basis of FDG or MET uptake. However, as accumulation of FDG and MET can also occur in demyelinating lesions; knowledge of this possibility is of clinical importance.

Autoimmune neuromyotonia.

Autoimmune neuromyotonia encompasses a group of rare immune-mediated neurological disorders frequently associated with anti-contactin-associated protein-like 2 (CASPR2) antibodies and featuring clinical and electrical signs of peripheral nerve hyperexcitability (PNH). We aim to summarize the current knowledge on immune-mediated neuromyotonia, focusing on clinical presentations, pathophysiology, and management. Neuromyotonia is a major feature of several autoimmune neurological syndromes characterized by PNH with or without central neurological system involvement. Experimental and clinical evidence suggest that anti-CASPR2 antibodies are directly pathogenic in autoimmune neuromyotonia patients. Neuromyotonia, a form of PNH, is a major feature in several syndromes associated with anti-CASPR2 antibodies, including cramp-fasciculation syndrome, Isaacs syndrome, Morvan syndrome, and autoimmune limbic encephalitis. Diagnosis relies on the identification of motor, sensory, and autonomic signs of PNH along with other neurological symptoms, anti-CASPR2 antibody-positivity, and of characteristic electroneuromyographic abnormalities. Paraneoplastic associations with thymoma are possible, especially in Morvan syndrome. Patients usually respond to immune-active treatments, including steroids, intravenous immunoglobulins, plasma exchanges, and rituximab.

Dysregulation of the hippocampal neuronal network by LGI1 auto-antibodies.

LGI1 is a neuronal secreted protein highly expressed in the hippocampus. Epileptic seizures and LGI1 hypo-functions have been found in both ADLTE, a genetic epileptogenic syndrome and LGI1 limbic encephalitis (LE), an autoimmune disease. Studies, based mainly on transgenic mouse models, investigated the function of LGI1 in the CNS and strangely showed that LGI1 loss of function, led to a decreased AMPA-receptors (AMPA-R) expression. Our project intends at better understanding how an altered function of LGI1 leads to epileptic seizures. To reach our goal, we infused mice with LGI1 IgG purified from the serum of patients diagnozed with LGI1 LE. Super resolution imaging revealed that LGI1 IgG reduced AMPA-R expression at the surface of inhibitory and excitatory neurons only in the dentate gyrus of the hippocampus. Complementary electrophysiological approaches indicated that despite reduced AMPA-R expression, LGI1 IgG increased the global hyperexcitability in the hippocampal neuronal network. Decreased AMPA-R expression at inhibitory neurons and the lack of LGI1 IgG effect in presence of GABA antagonist on excitability, led us to conclude that LGI1 function might be essential for the proper functioning of the overall network and orchestrate the imbalance between inhibition and excitation. Our work suggests that LGI1 IgG reduced the inhibitory network activity more significantly than the excitatory network shedding lights on the essential role of the inhibitory network to trigger epileptic seizures in patients with LGI1 LE.

Anti-Hu Encephalitis Associated With Small Cell Lung Cancer,A Case Report

Paraneoplastic limbic encephalitis (PLE) is a rare neurologic that can be a manifestation of lung cancer. These manifestations are frequently seen in patients diagnosed with small cell lung cancer (SCLC), as in our case. This is a case report of a 66-years-old woman, with SCLC that has been diagnosed due to paraneoplastic encephalitis staining positive for anti-Hu antibodies. Sometimes differential diagnosis involves endocrinopathies and other neurological conditions, so many specialists must co-operate in each patient

A Case Report of Wernicke’s Encephalopathy Disguised As Limbic Encephalitis: A Clinical Puzzle

Wernicke's encephalopathy (WE) is the presence of neurological symptoms in the central nervous system caused by thiamine (Vitamin B1) deficiency. It is an acute clinical condition characterized by confusion, ataxia, and ophthalmoplegia triad. WE is most commonly observed in chronic alcohol users, while it can also present in non-alcoholics. We present a 33-year-old man with alcohol-induced WE who presented with altered mental status and fever. His initial diagnosis was skewed towards bacterial meningitis and limbic encephalitis, but MRI findings were consistent with WE. The patient responded promptly to intravenous (IV) thiamine infusion, and his mental status changed significantly. Repeat EEG in 15 days shows complete recovery with normal brain wave activity. Untreated WE is a significant cause of permanent neurological morbidity and mortality, easily preventable. High suspicion of WE should always be entertained, especially when patients have a known history of alcohol use. Early initiation of IV thiamine could prevent the consequences. Hence, it is essential to raise awareness of WE to take measures without delay and reduce mortality and morbidity with an improved prognosis.

Differential diagnosis of amnestic dementia patients based on an FDG-PET signature of autopsy-confirmed LATE-NC.

Limbic age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is common in advanced age and can underlie a clinical presentation mimicking Alzheimer's disease (AD). We studied whether an autopsy-derived fluorodeoxyglucose positron emission tomography (FDG-PET) signature of LATE-NC provides clinical utility for differential diagnosis of amnestic dementia patients. Ante mortem FDG-PET patterns from autopsy-confirmed LATE-NC (N = 7) and AD (N = 23) patients were used to stratify an independent cohort of clinically diagnosed AD dementia patients (N = 242) based on individual FDG-PET profiles. Autopsy-confirmed LATE-NC and AD groups showed markedly distinct temporo-limbic and temporo-parietal FDG-PET patterns, respectively. Clinically diagnosed AD dementia patients showing a LATE-NC-like FDG-PET pattern (N = 25, 10%) were significantly older, showed less abnormal AD biomarker levels, lower APOE ε4, and higher TMEM106B risk allele load. Clinically, they exhibited a more memory-predominant profile and a generally slower disease course. An autopsy-derived temporo-limbic FDG-PET signature identifies older amnestic patients whose clinical, genetic, and molecular biomarker features are consistent with underlying LATE-NC.

A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode

The leucine-rich glioma-inactivated (LGI) family consists of four highly conserved paralogous genes, LGI1-4, that are highly expressed in mammalian central and/or peripheral nervous systems. LGI1 antibodies are detected in subjects with autoimmune limbic encephalitis and peripheral nerve hyperexcitability syndromes (PNHSs) such as Isaacs and Morvan syndromes. Pathogenic variations of LGI1 and LGI4 are associated with neurological disorders as disease traits including familial temporal lobe epilepsy and neurogenic arthrogryposis multiplex congenita 1 with myelin defects, respectively. No human disease has been reported associated with either LGI2 or LGI3. We implemented exome sequencing and family-based genomics to identify individuals with deleterious variants in LGI3 and utilized GeneMatcher to connect practitioners and researchers worldwide to investigate the clinical and electrophysiological phenotype in affected subjects. We also generated Lgi3-null mice and performed peripheral nerve dissection and immunohistochemistry to examine the juxtaparanode LGI3 microarchitecture. As a result, we identified 16 individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. Deep phenotypic characterization showed LGI3 LoF causes a potentially clinically recognizable PNHS trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons. Our data demonstrate bi-allelic LoF variants in LGI3 cause a clinically distinguishable disease trait of PNHS, most likely caused by disturbed Kv1 channel distribution in the absence of LGI3.

Anti-Ma2-associated limbic encephalitis presenting with transient epileptic amnesia

Anti-Ma2-associated limbic encephalitis presenting with transient epileptic amnesia

Persistent hiccup as one of the initial symptoms of leucine-rich glioma-inactivated-1 encephalitis: a case report

BackgroundAnti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis, an autoimmune disorder, is characterized by faciobrachial dystonic seizures, epilepsy, memory deficits and altered mental status while hiccup is not commonly found in patients.Case presentationA 62-year-old male was presented with slurred speech, abnormal gait, faciobrachial dystonic seizures and impaired cognition. Besides, the hiccup was one of the initial symptoms. His brain magnetic resonance images (MRI) revealed multiple lesions with left caudate nucleus, putamen, insula and left hippocampus involvement. Because a diagnosis of antibody-related limbic encephalitis was suspected, studies including an autoimmune profile were done by cell-based assays. After anti-LGI1 antibodies were detected in both cerebrospinal fluid and serology, pulse methylprednisolone and intravenous immunoglobulin were started and hence hiccups disappeared along with other symptoms.ConclusionsClinicians should be aware that persistent hiccups might be one of the initial manifestations of LGI1 subtype of voltage-gated potassium channel complex antibody associated autoimmune encephalitis.

A Rare Presentation of Anti-Gad Associated Neurological Disorder in A Fifteen-YearOld Girl

Anti-GAD antibodies have been associated with numerous neurological conditions that have a wide variety of presentations. These conditions include limbic encephalitis, stiff person syndrome, opsoclonus-myoclonus-ataxia syndrome, cerebellar ataxia, and status epilepticus. In this paper, we aimed to present a female patient admitted with complaints of acute weakness and right peripheral facial palsy, pancytopenia, hepatosplenomegaly, and anti-glutamate decarboxylase antibody and report the diversity and clinical features of neurological diseases associated with anti-glutamate decarboxylase antibodies. Conclusion Besides the common primary syndromes, other new clinical and neurological manifestations have been associated with anti- anti-glutamate decarboxylase antibodies.

TDP-43 Pathology Exacerbates Cognitive Decline in Primary Age-Related Tauopathy.

Primary age-related tauopathy (PART) refers to tau neurofibrillary tangles restricted largely to the medial temporal lobe in the absence of significant beta-amyloid plaques. PART has been associated with cognitive impairment, but contributions from concomitant limbic age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) are underappreciated. We compare prevalence of LATE-NC and vascular copathologies in age- and Braak-matched patients with PART (n=45, Braak stage I-IV, Thal phase 0-2) or early stage Alzheimer disease neuropathologic change (ADNC; n=51, Braak I-IV, Thal 3-5), and examine their influence on clinical and cognitive decline. Concomitant LATE-NC and vascular pathology were equally common, and cognition was equally impaired, in PART (Mini-Mental State Examination [MMSE]=24.8± 6.9) and ADNC (MMSE=24.2± 6.0). Patients with LATE-NC were more impaired than those without LATE-NC on the MMSE (by 5.8 points, 95% confidence interval [CI] = 3.0-8.6), Mattis Dementia Rating Scale (DRS; 17.5 points, 95% CI=7.1-27.9), Clinical Dementia Rating, sum of boxes scale (CDR-sob; 5.2 points, 95% CI=2.1-8.2), memory composite (0.8 standard deviations [SD], 95% CI=0.1-1.6), and language composite (1.1 SD, 95% CI=0.2-2.0), and more likely to receive a dementia diagnosis (odds ratio=4.8, 95% CI=1.5-18.0). Those with vascular pathology performed worse than those without on the DRS (by 10.2 points, 95% CI=0.1-20.3) and executive composite (1.3 SD, 95% CI=0.3-2.3). Cognition declined similarly in PART and ADNC over the 5 years preceding death; however, LATE-NC was associated with more rapid decline on the MMSE (β=1.9, 95% CI=0.9-3.0), DRS (β=7.8, 95% CI=3.4-12.7), CDR-sob (β=1.9, 95% CI=0.4-3.7), language composite (β=0.5 SD, 95% CI=0.1-0.8), and vascular pathology with more rapid decline on the DRS (β=5.2, 95% CI=0.6-10.2). LATE-NC, and to a lesser extent vascular copathology, exacerbate cognitive impairment and decline in PART and early stage ADNC. ANN NEUROL 2022;92:425-438.

Case report of anti-NMDA receptor encephalitis in a 24-year-old female: an uncommon presentation

BackgroundAnti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a form of autoimmune encephalitis. Due to the variability of the initial symptoms, anti-NMDAR encephalitis is not only underdiagnosed but also can be misdiagnosed as viral encephalitis or other pathologies. The origin of this disease is often paraneoplastic. Anti-NMDAR encephalitis preferentially affects children and young adults, and it has a male/female ratio of 1/4. In case of clinical suspicion, electroencephalogram and brain magnetic resonance imaging are useful, but lumbar puncture for cerebrospinal fluid analysis is used to confirm the diagnosis. Treatment for this disease includes immunosuppression and tumour resection when indicated.Case presentationWe report the case of a 24-year-old female admitted to the emergency room following the onset of acute confusion. Due to the rapid deterioration of consciousness, swallowing disorders, respiratory failure and severe bradycardia the patient was intubated. On day 23 after presentation, brain magnetic resonance suggested autoimmune limbic encephalitis. Cerebrospinal fluid results were positive for anti-NMDA antibodies. After IV methylprednisolone and plasmapheresis and a second line therapy with corticosteroid and mycophenolic acid, the patient’s clinical condition gradually improved.ConclusionsAnti-NMDAR encephalitis typically occurs in young patients with no history of acute psychiatric symptoms. The possibility of this pathology should be taken into account before diagnosing a patient with a psychiatric illness.

Evaluation of LGI1-antibody Encephalitis, a Rare Cause of Limbic Encephalitis, from Diagnosis to Treatment

Evaluation of LGI1-antibody Encephalitis, a Rare Cause of Limbic Encephalitis, from Diagnosis to Treatment

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

BackgroundSystemic 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 presentationHere, 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.ConclusionsNPE 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.