Review

Authors: Francesco Sanvito, Anna Pichiecchio, Matteo Paoletti...

Autoimmune encephalitis is a relatively novel nosological entity characterized by an immune-mediated damage of the central nervous system. While originally described as a paraneoplastic inflammatory phenomenon affecting limbic structures, numerous instances of non-paraneoplastic pathogenesis, as well as extra-limbic involvement, have been characterized. Given the wide spectrum of insidious clinical presentations ranging from cognitive impairment to psychiatric symptoms or seizures, it is crucial to raise awareness about this disease category. In fact, an early diagnosis can be dramatically beneficial for the prognosis both to achieve an early therapeutic intervention and to detect a potential underlying malignancy. In this scenario, the radiologist can be the first to pose the hypothesis of autoimmune encephalitis and refer the patient to a comprehensive diagnostic work-up - including clinical, serological, and neurophysiological assessments.In this article, we illustrate the main radiological characteristics of autoimmune encephalitis and its subtypes, including the typical limbic presentation, the features of extra-limbic involvement, and also peculiar imaging findings. In addition, we review the most relevant alternative diagnoses that should be considered, ranging from other encephalitides to neoplasms, vascular conditions, and post-seizure alterations. Finally, we discuss the most appropriate imaging diagnostic work-up, also proposing a suggested MRI protocol.

Topics: Humans; Encephalitis; Hashimoto Disease; Autoantibodies; Seizures; Radiologists; Autoimmune Diseases of the Nervous System; Limbic Encephalitis

PubMed: 38507081
DOI: 10.1007/s00234-024-03318-x

Review

Authors: Maëlle Dade, Giulia Berzero, Cristina Izquierdo...

Glutamic acid decarboxylase (GAD) is an intracellular enzyme whose physiologic function is the decarboxylation of glutamate to gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter within the central nervous system. GAD antibodies (Ab) have been associated with multiple neurological syndromes, including stiff-person syndrome, cerebellar ataxia, and limbic encephalitis, which are all considered to result from reduced GABAergic transmission. The pathogenic role of GAD Ab is still debated, and some evidence suggests that GAD autoimmunity might primarily be cell-mediated. Diagnosis relies on the detection of high titers of GAD Ab in serum and/or in the detection of GAD Ab in the cerebrospinal fluid. Due to the relative rarity of these syndromes, treatment schemes and predictors of response are poorly defined, highlighting the unmet need for multicentric prospective trials in this population. Here, we reviewed the main clinical characteristics of neurological syndromes associated with GAD Ab, focusing on pathophysiologic mechanisms.

Topics: Autoimmune Diseases of the Nervous System; Autoimmunity; Cerebellar Ataxia; Glutamate Decarboxylase; Humans; Limbic Encephalitis; Neurons; Stiff-Person Syndrome

PubMed: 32456344
DOI: 10.3390/ijms21103701

Review

Authors: Jiawei Yang, Xueyan Liu

Autoimmune encephalitis (AE) is an immune-mediated disease involving the central nervous system, usually caused by antigen-antibody reactions. With the advent of autoantibody-associated diseases, AE has become a hot research frontier in neuroimmunology. The first-line conventional treatments of autoimmune encephalitis consist of steroids, intravenous immunoglobulin (IVIG), plasma exchange (PLEX), and second-line therapy includes rituximab. Despite considerable research and expanding clinical experience, current treatments are still ineffective for a significant number of patients. Although there is no clear consensus, clinical trial evidence limited, and the level of evidence for some of the drugs based on single reports, third-line therapy is a viable alternative for refractory encephalitis patients. With the current rapid research progress, a breakthrough in the treatment of AE is critical. This article aims to review the third-line therapy for refractory AE.

Topics: Animals; Autoimmune Diseases; Clinical Trials as Topic; Disease Models, Animal; Drug Resistance; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Immunotherapy; Limbic Encephalitis; Plasma Exchange; Rituximab; Treatment Outcome

PubMed: 34975890
DOI: 10.3389/fimmu.2021.790962

Authors: Robin W Van Steenhoven, Juna M de Vries, Arlette L Bruijstens...

BACKGROUND AND OBJECTIVES

The clinical criteria for autoimmune encephalitis (AE) were proposed by Graus et al. in 2016. In this study, the AE criteria were validated in the real world, and common AE mimics were described. In addition, criteria for probable anti-LGI1 encephalitis were proposed and validated.

METHODS

In this retrospective cohort study, patients referred to our national referral center with suspicion of AE and specific neuroinflammatory disorders with similar clinical presentations were included from July 2016 to December 2019. Exclusion criteria were pure cerebellar or peripheral nerve system disorders. All patients were evaluated according to the AE criteria.

RESULTS

In total, 239 patients were included (56% female; median age 42 years, range 1-85). AE was diagnosed in 104 patients (44%) and AE mimics in 109 patients (46%). The most common AE mimics and misdiagnoses were neuroinflammatory CNS disorders (26%), psychiatric disorders (19%), epilepsy with a noninflammatory cause (13%), CNS infections (7%), neurodegenerative diseases (7%), and CNS neoplasms (6%). Common confounding factors were mesiotemporal lesions on brain MRI (17%) and false-positive antibodies in serum (12%). Additional mesiotemporal features (involvement extralimbic structures, enhancement, diffusion restriction) were observed more frequently in AE mimics compared with AE (61% vs 24%; = 0.005). AE criteria showed the following sensitivity and specificity: possible AE, 83% (95% CI 74-89) and 27% (95% CI 20-36); definite autoimmune limbic encephalitis (LE), 10% (95% CI 5-17) and 98% (95% CI 94-100); and probable anti-NMDAR encephalitis, 50% (95% CI 26-74) and 96% (95% CI 92-98), respectively. Specificity of the criteria for probable seronegative AE was 99% (95% CI 96-100). The newly proposed criteria for probable anti-LGI1 encephalitis showed a sensitivity of 66% (95% CI 47-81) and specificity of 96% (95% CI 93-98).

DISCUSSION

AE mimics occur frequently. Common pitfalls in AE misdiagnosis are mesiotemporal lesions (predominantly with atypical features) and false-positive serum antibodies. As expected, the specificity of the criteria for possible AE is low because these criteria represent the minimal requirements for entry in the diagnostic algorithm for AE. Criteria for probable AE (-LGI1, -NMDAR, seronegative) and definite autoimmune LE are applicable for decisions on immunotherapy in early disease stage, as specificity is high.

Topics: Adult; Retrospective Studies; Child, Preschool; Female; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Humans; Aged; Middle Aged; Male; Young Adult; Antibodies; Aged, 80 and over; Adolescent; Infant; Child; Hashimoto Disease; Encephalitis; Autoimmune Diseases; Limbic Encephalitis

PubMed: 37582614
DOI: 10.1212/NXI.0000000000200148

Authors: Andrew Rodriguez, C J Klein, Elia Sechi...

OBJECTIVE

To compare acute treatment responses and long-term outcome in leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis.

METHODS

Retrospective case series of 118 patients with LGI1 antibody encephalitis evaluated at Mayo Clinic across all US sites from 1 May 2008 to 31 March 2019. Patient clinical data were identified and analysed through the neuroimmunology laboratory and electronic medical record. LGI1 antibody detection was by cell-based indirect immunofluorescence assay of serum, cerebrospinal fluid or both. Clinical outcomes were faciobrachial dystonic seizure (FBDS) resolution, modified Rankin Scale (mRS) score, Kokmen Short Test of Mental Status (STMS) score (0-38 point scale) and neuropsychometric testing results.

RESULTS

Compared with intravenous immunoglobulin (IVIg) (n=21), patients treated with single-agent acute corticosteroids (intravenous, oral or both) (n=49) were more likely to experience resolution of FBDS (61% vs 7%, p=0.002) and improvements in mRS score (ΔmRS score 2 vs 0, p=0.008) and median Kokmen STMS scores (ΔKokmen STMS score 5 points vs 0 points, p=0.01). In 54 patients with long-term follow-up (≥2 years), the median mRS score was 1 (range 0-6) and the median Kokmen STMS score was 36 (range 24-38) after all combinations of immunotherapy. Neuropsychometric testing in 32 patients with long-term follow-up (≥2 years) demonstrated short-term memory impairments in 37%.

CONCLUSIONS

Corticosteroids appeared more effective acutely than IVIg in improving LGI1 antibody encephalitis in this retrospective comparison of immunotherapies. While improvement with immunotherapy is typical and long-term outcome is favourable, short-term memory deficits are noted in approximately a third of the patients.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Autoantibodies; Autoimmune Diseases; Female; Humans; Immunoglobulins, Intravenous; Intracellular Signaling Peptides and Proteins; Limbic Encephalitis; Male; Middle Aged; Retrospective Studies; Treatment Outcome; Young Adult

PubMed: 34824144
DOI: 10.1136/jnnp-2021-327302

Review

Authors: Jack B Ding, John Dongas, Kevin Hu...

Limbic encephalitis is an autoimmune cause of encephalitis. In addition to the usual symptoms of encephalitis such as altered consciousness, fever, and focal neurological deficits, limbic encephalitis can present with neuropsychiatric manifestations and seizures. Making a formal diagnosis involves a difficult and prolonged workup phase. The purpose of this review is to help readers delineate limbic encephalitis from other illnesses. This is done by presenting a spectrum of potential organic differential diagnoses and pertinent findings that distinguish them from limbic encephalitis. Instead of presenting a variety of psychiatric differential diagnoses, the authors present a review of psychiatric manifestations known to be associated with limbic encephalitis, as naturally, any psychiatric disorder could be a potential comorbid disease.

PubMed: 34603897
DOI: 10.7759/cureus.17529

Authors: Andreas Schulte-Mecklenbeck, Andre Dik, Christine Strippel...

Autoimmune limbic encephalitis (ALE) represents a heterogeneous disease associated with antibodies targeting extracellular (ALE) epitopes, intracellular (ALE) epitopes, anti-glutamic acid decarboxylase65 ALE (ALE), and ALE without detectable antibodies (ALE). Combining analysis of cellular parameters, investigated by flow cytometry, and soluble parameters in the blood and cerebrospinal fluid (CSF) from a large cohort of 148 ALE patients (33 ALE, 12 ALE, 28 ALE-GAD65, 37 ALE) in comparison to paradigmatic examples for neuro-inflammatory (51 relapsing remitting MS patients (RRMS)), and neuro-degenerative (34 Alzheimer's disease patients (AD)) diseases revealed discrete immune signatures in ALE subgroups. Identification of ALE-subtype specific markers facilitated classification of rare ALE-associated tumors, which may prompt further diagnostic efforts in clinical practice. While ALE exhibited features of neuro-inflammation, ALE displayed features of neuro-inflammation as well as neuro-degeneration. Moreover, ALE and ALE lacked hallmarks of inflammation. This may explain the low efficacy of anti-inflammatory treatment regimens in ALE and presumably also ALE.

Topics: Limbic Encephalitis; Humans; Female; Male; Middle Aged; Glutamate Decarboxylase; Adult; Autoantibodies; Aged; Autoimmune Diseases; Biomarkers; Alzheimer Disease; Cohort Studies; Multiple Sclerosis, Relapsing-Remitting; Young Adult

PubMed: 39401553
DOI: 10.1016/j.bbi.2024.10.018

Observational Study

Authors: Saraswathy Sabanathan, Omar Abdel-Mannan, Kshitij Mankad...

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.

Topics: Adolescent; Autoantibodies; Autoimmune Diseases; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Immunologic Factors; Intensive Care Units, Pediatric; Limbic Encephalitis; Male; Outcome Assessment, Health Care; Plasma Exchange; Retrospective Studies; Rituximab; Seizures

PubMed: 35015932
DOI: 10.1002/acn3.51494

Review

Authors: Adrian Budhram, Andrew Leung, Michael W Nicolle...

Topics: Autoantibodies; Autoimmune Diseases; Cerebrospinal Fluid; Electroencephalography; Guidelines as Topic; Humans; Limbic Encephalitis; Magnetic Resonance Imaging; Neuroimaging

PubMed: 31085562
DOI: 10.1503/cmaj.181548

Authors: F Graus, D Escudero, L Oleaga...

BACKGROUND AND PURPOSE

The aim was to report the clinical characteristics of 12 patients with limbic encephalitis (LE) who were antibody-negative after a comprehensive immunological study.

METHODS

The clinical records of 163 patients with LE were reviewed. Immunohistochemistry on rat brain, cultured neurons and cell-based assays were used to identify neuronal autoantibodies. Patients were included if (i) there was adequate clinical, cerebrospinal fluid (CSF) and magnetic resonance imaging information to classify the syndrome as LE, (ii) magnetic resonance images were accessible for central review and (iii) serum and CSF were available and were confirmed negative for neuronal antibodies.

RESULTS

Twelve (7%) of 163 LE patients [median age 62 years; range 40-79; 9 (75%) male] without neuronal autoantibodies were identified. The most frequent initial complaints were deficits in short-term memory leading to hospital admission in a few weeks (median time 2 weeks; range 0.5-12). In four patients the short-term memory dysfunction remained as an isolated symptom during the entire course of the disease. Seizures, drowsiness and psychiatric problems were unusual. Four patients had solid tumors (one lung, one esophagus, two metastatic cervical adenopathies of unknown primary tumor) and one chronic lymphocytic leukemia. CSF showed pleocytosis in seven (58%) with a median of 13 white blood cells/mm (range 9-25). Immunotherapy included corticosteroids, intravenous immunoglobulins and combinations of both drugs or with rituximab. Clinical improvement occurred in six (54%) of 11 assessable patients.

CONCLUSIONS

Despite the discovery of new antibodies, 7% of LE patients remain seronegative. Antibody-negative LE is more frequent in older males and usually develops with predominant or isolated short-term memory loss. Despite the absence of antibodies, patients may have an underlying cancer and respond to immunotherapy.

Topics: Adult; Aged; Animals; Autoantibodies; Autoantigens; Cells, Cultured; Female; Humans; Immunohistochemistry; Immunotherapy; Leukocytes; Leukocytosis; Limbic Encephalitis; Magnetic Resonance Imaging; Male; Memory Disorders; Memory, Short-Term; Middle Aged; Neoplasms; Neurons; Rats; Treatment Outcome

PubMed: 29667271
DOI: 10.1111/ene.13661