Management of Autoimmune Encephalitis in a 7-Year-Old Child With CTLA-4 Haploinsufficiency and AMPA Receptor Antibodies: A Case Report.

OBJECTIVES: We report on the therapeutic management of early-onset severe neurologic symptoms in cytotoxic T lymphocyte antigen-4 haploinsufficiency (CTLA-4h) and the presence of antibodies to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) as an important finding. METHODS: This is a case report from a Dutch academic hospital. Repeated clinical examinations, repeated brain MRI and extended diagnostics on serum and CSF were performed. We used the CARE checklist. RESULTS: A 7-year-old boy was diagnosed with CTLA-4h based on family screening. On diagnosis, he had mild chronic diarrhea and autism spectrum disorder, but no abnormalities in extensive laboratory screening. Six months later, he presented with sudden-onset autoimmune encephalitis. Repeated brain MRI revealed no abnormalities, but immunohistochemistry analysis on serum and CSF showed the presence of AMPAR antibodies. Treatment was initially focused on immunomodulation and targeted CTLA-4 replacement therapy. Because of the persistent fluctuating cerebellar and neuropsychiatric symptoms and the potential clinical significance of the AMPAR antibodies, treatment was intensified with repetition of first-line immunomodulation and rituximab. This combined therapy resulted in sustained clinical improvement and served as a bridge to curative hematopoietic stem cell transplantation. DISCUSSION: This case illustrates the rare early onset of autoimmune encephalitis and presence of AMPAR antibodies in CTLA-4h. Targeted CTLA-4 replacement therapy resulted in a partial response. However, awaiting its optimal therapeutic effect, refractory CNS symptoms required intensification of immunomodulation. The identification of AMPAR antibodies guided our treatment decisions. CLASSIFICATION OF EVIDENCE: This provides Class IV evidence. It is a single observational study without controls.

Autoimmunity, New Potential Biomarkers and the Thyroid Gland-The Perspective of Hashimoto's Thyroiditis and Its Treatment.

Autoimmune thyroid disease (AITD) is the most common organic specific illness of the thyroid gland. It may manifest as the overproduction or the decline of thyroxine and triiodothyronine. Hyperthyroidism develops due to the overproduction of hormones as an answer to the presence of stimulatory antibodies against the TSH receptor. Hashimoto's thyroiditis (HT) is generally characterized by the presence of thyroid peroxidase and thyroglobulin antibodies, with a concomitant infiltration of lymphocytes in the thyroid. Due to the progressive destruction of cells, AITD can lead to subclinical or overt hypothyroidism. Pathophysiology of AITD is extremely complicated and still not fully understood, with genetic, environmental and epigenetic factors involved in its development. Due to increasing incidence and social awareness of this pathology, there is an urgent need to expand the background concerning AITD. A growing body of evidence suggests possible ways of treatment apart from traditional approaches. Simultaneously, the role of potential new biomarkers in the diagnosis and monitoring of AITD has been highlighted recently, too. Therefore, we decided to review therapeutic trends in the course of AITD based on its pathophysiological mechanisms, mainly focusing on HT. Another aim was to summarize the state of knowledge regarding the role of new biomarkers in this condition.

Mimickers of autoimmune encephalitis: a literature review.

Autoimmune encephalitis (AIE) is a rapid, progressive neurological disorder characterized by nervous system inflammation. While the Graus criteria are the best known criteria for AIE diagnosis, other differential diagnoses meeting the Graus criteria must be considered before management. This narrative review discusses the most common etiologies that resemble AIE. We suggest routine exclusion of mimickers meeting the Graus criteria before confirming an AIE diagnosis. We reviewed 28 studies including 356 patients. The main initial diagnosis was AIE, then paraneoplastic limbic encephalitis and anti-N-methyl-D-aspartate receptor encephalitis. Only 194 patients met the possible Graus criteria. The most frequent conditions among the total population were dementia, other neurodegenerative diseases, and psychiatric and functional neurological disorders. AIE is often misdiagnosed, leading to unnecessary treatment. Despite publication of the Graus criteria, medical cases mimicking this condition are being published. Many neurological diseases entering the differential diagnosis of AIE could be excluded through a detailed history, neurological examination, laboratory analysis, and other investigations, including cerebrospinal fluid and brain magnetic resonance imaging. However, some differential diagnoses complied with the possible Graus criteria, with some having concurrent antineuronal antibodies, which were considered true mimickers. AIE diagnosis suspicion is primarily clinical, but a definitive diagnosis requires various diagnostic tools.

Difficulties in investigating and treating fibrosing thyroid disorder (overlap of fibrosing variant of Hashimoto's thyroiditis and Riedel's thyroiditis).

A gentleman in his 90s presented with a slowly enlarging goitre over 18 months, causing manifestations of superior vena cava obstruction, dysphagia and hoarseness of voice. Investigations were suggestive of a fibrosing thyroid pathology. Surgical management was avoided due to high surgical risk. Treatment included prednisolone and tamoxifen with palliative management in the event of further medical deterioration. This article illustrates the difficulties in diagnosing and managing fibrosing thyroid diseases.

Autoimmune encephalitis in glial fibrillary acidic protein astrocytopathy.

Autoimmune encephalitis due to glial fibrillar acidic protein (GFAP) astrocytopathy is a rare cause of subacute neuropsychiatric changes. In this case, a young patient presented with a viral prodrome and meningismus, followed by progressive encephalopathy and movement disorders over the span of 2 weeks. Due to his clinical trajectory, inflammatory cerebrospinal fluid (CSF) analysis, initial normal brain imaging and negative serum autoimmune encephalopathy panel, his initial diagnosis was presumed viral meningoencephalitis. The recurrence and progression of neuropsychiatric symptoms and myoclonus despite antiviral treatment prompted further investigation, inclusive of testing for CSF autoimmune encephalopathy autoantibodies, yielding a clinically meaningful, positive GFAP autoantibody. This case highlights the importance of appropriately testing both serum and CSF autoantibodies when an autoimmune encephalitic process is considered. Through this case, we review the clinical and radiographic manifestations of GFAP astrocytopathy, alongside notable pearls pertaining to this autoantibody syndrome and its management.

Study on clinical features and factors related to long-term outcomes of antibody-negative autoimmune encephalitis.

OBJECTIVE: To delineate the clinical characteristics of antibody-negative autoimmune encephalitis (AE) and to investigate factors associated with long-term outcomes among antibody-negative AE. METHODS: Patients diagnosed with antibody-negative AE were recruited from January 2016 to December 2022 at the Second Xiangya Hospital of Central South University. The study assessed the long-term outcomes of antibody-negative AE using the modified Rankin scale (mRS) and the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). Predictors influencing long-term outcomes were subsequently analyzed. External validation of RAPID scores (refractory status epilepticus [RSE], age of onset ≥60 years, ANPRA [antibody-negative probable autoimmune encephalitis], infratentorial involvement, and delay of immunotherapy ≥1 month) was performed. RESULTS: In total, 100 (47 females and 53 males) antibody-negative AE patients were enrolled in this study, with approximately 49 (49%) experiencing unfavorable long-term outcomes (mRS scores ≥3). Antibody-negative AE was subcategorized into ANPRA, autoimmune limbic encephalitis (LE), and acute disseminated encephalomyelitis (ADEM). Psychiatric symptoms were prevalent in LE and ANPRA subtypes, while weakness and gait instability/dystonia were predominant in the ADEM subtype. Higher peak CASE scores (odds ratio [OR] 1.846, 95% confidence interval [CI]: 1.163-2.930, p = 0.009) and initiating immunotherapy within 30 days (OR 0.210, 95% CI: 0.046-0.948, p = 0.042) were correlated with long-term outcomes. Receiver operating characteristic (ROC) analysis returned that the RAPID scores cutoff of 1.5 best discriminated the group with poor long-term outcomes (sensitivity 85.7%, specificity 56.9%). INTERPRETATION: The ANPRA subtype exhibited poorer long-term outcomes compared to LE and ADEM subtypes, and early immunotherapy was crucial for improving long-term outcomes in antibody-negative AE. The use of RAPID scoring could aid in guiding clinical decision making.

Cardiopulmonary Coupling Spectrogram as an Ambulatory Method for Assessing Sleep Disorders in Patients With Autoimmune Encephalitis.

BACKGROUND AND OBJECTIVES: Sleep disorders are a common and important clinical feature in patients with autoimmune encephalitis (AE); however, they are poorly understood. We aimed to evaluate whether cardiopulmonary coupling (CPC), an electrocardiogram-based portable sleep monitoring technology, can be used to assess sleep disorders in patients with AE. METHODS: Patients fulfilling the diagnostic criteria of AE were age- and sex-matched with recruited healthy control subjects. All patients and subjects received CPC testing between August 2020 and December 2022. Demographic data, clinical information, and Pittsburgh Sleep Quality Index (PSQI) scores were collected from the medical records. Data analysis was performed using R language programming software. RESULTS: There were 60 patients with AE (age 26.0 [19.8-37.5] years, male 55%) and 66 healthy control subjects (age 30.0 [25.8-32.0] years, male 53%) included in this study. Compared with healthy subjects, patients with AE had higher PSQI scores (7.00 [6.00-8.00] vs 3.00 [2.00-4.00], p < 0.001), lower sleep efficiency (SE 80% [71%-87%] vs 92% [84%-95%], p < 0.001), lower percentage of high-frequency coupling (25% [14%-43%] vs 45% [38%-53%], p < 0.001), higher percentage of REM sleep (19% ± 9% vs 15% ± 7%, p < 0.001), higher percentage of wakefulness (W% 16% [11%-25%] vs 8% [5%-16%], p = 0.074), higher low-frequency to high-frequency ratio (LF/HF 1.29 [0.82-2.40] vs 0.91 [0.67-1.29], p = 0.001), and a higher CPC-derived respiratory disturbance index (9.78 [0.50-22.2] vs 2.95 [0.40-6.53], p < 0.001). Follow-up evaluation of 14 patients showed a decrease in the PSQI score (8.00 [6.00-9.00] vs 6.00 [5.00-7.00], p = 0.008), an increased SE (79% [69%-86%] vs 89% [76%-91%], p = 0.030), and a decreased W% (20% [11%-30%] vs 11% [8%-24], p = 0.035). Multiple linear regression indicated that SE (-7.49 [-9.77 to -5.21], p < 0.001) and LF/HF ratio (0.37 [0.13-0.6], p = 0.004) were independent factors affecting PSQI scores in patients with AE. DISCUSSION: Sleep disorders with autonomic dysfunction are common in patients with AE. Improvements in the PSQI score and SE precede the restoration of sleep microstructural disruption in the remission stage. CPC parameters may be useful in predicting sleep disorders in patients with AE.

[The diagnostic challenge of autoimmune encephalitis]. / Le défi diagnostique des encéphalites auto-immunes.

Autoimmune encephalitis encompasses a spectrum of neurological disorders characterized by an autoimmune response directed against neurons and glia. Around two-thirds of cases exhibit autoantibodies targeting neuronal or glial antigens in the cerebrospinal fluid and/or serum. The diagnosis is based on specific criteria combining a subacute clinical presentation and complementary test results. However, approximately one-quarter of patients do not present any paraclinical abnormalities, making the diagnosis complex. Testing for anti-antibodies is pivotal for diagnosis, and their interpretation should be contextual. Best practices for anti-neural antibody detection involve appropriate sample collection and confirmation of positive results in relation to the clinical picture.

L'encéphalite auto-immune comprend un spectre de troubles neurologiques caractérisés par une réponse auto-immunitaire dirigée contre les neurones et les cellules gliales. Environ deux tiers des cas présentent des autoanticorps dirigés contre des antigènes neuronaux et gliaux dans le liquide céphalorachidien et/ou le sérum. Le diagnostic repose sur des critères spécifiques combinant une présentation clinique subaiguë et des résultats d'examens complémentaires. Environ un quart des patients ne présente pas d'anomalie paraclinique, rendant le diagnostic complexe. La recherche des autoanticorps est cruciale pour le diagnostic de certitude et son interprétation doit être contextuelle. Les bonnes pratiques pour leur dosage impliquent le prélèvement d'échantillons appropriés et la confirmation des résultats positifs par rapport au tableau clinique.

Primary Thyroid Lymphoma: A Retrospective-Observational Study in a Single Institutional Center.

Background and Objectives: primary thyroid lymphoma (PTL) is a rare neoplasm, displaying a variety of histological features. It is often a challenge for pathologists to diagnose this tumor. Materials and Methods: this study is a retrospective analysis of clinical and pathological characteristics of a group of eleven patients (eight women and three men, mean age 68 years, range 50-80 years) diagnosed with PTL. Results: nine patients (81.81%) presented a tumor with progressive growth in the anterior cervical region, usually painless and accompanied by local compressive signs. Histologically, we identified six cases (55%) of diffuse large B-cell lymphoma, three cases (27%) of extranodal marginal zone lymphoma, one case (9%) of follicular lymphoma, and one case (9%) of mixed follicular-diffuse lymphoma. PTL was associated with microscopic Hashimoto autoimmune thyroiditis in ten cases (90.9%). Ten patients (90.9%) presented with localized disease (stage I-IIE). A percentage of 60% of patients survived over 5 years. We observed an overall longer survival in patients under 70 years of age. Conclusions: PTL represents a diagnosis that needs to be taken into account, especially in women with a history of Hashimoto autoimmune thyroiditis, presenting a cervical tumor with progressive growth. PTL is a lymphoid neoplasia with favorable outcome, with relatively long survival if it is diagnosed at younger ages.

[Clinical characteristics of seizure-predominant autoimmune encephalitis and utility of anti-neuronal antibody scores for early treatment].

We analyzed 20 patients diagnosed with autoimmune neurological diseases with seizure predominance. In these patients, we examined the usefulness of Antibody Prevalence in Epilepsy and Encephalopathy (APE2) score and Antibodies Contributing to Focal Epilepsy Signs and Symptoms (ACES) score in autoimmune encephalitis (AE) for facilitating early treatment. APE2 score was positive in 19 of 20 patients. ACES score was positive in 15 of 20 patients, and 4 of 5 of the patients with negative ACES score did not have AE. Comprehensive assessment including the use of the above scores is desirable in the early stage of AE.

Interest of rare autoantibodies in autoimmune encephalitis and paraneoplastic neurological syndromes: the utility (or futility) of rare antibody discovery.

PURPOSE OF REVIEW: The increasing recognition and diagnosis of autoimmune encephalitis (AE) and paraneoplastic neurological syndromes (PNS) is partly due to neural autoantibody testing and discovery. The past two decades witnessed an exponential growth in the number of identified neural antibodies. This review aims to summarize recent rare antibody discoveries in the context of central nervous system (CNS) autoimmunity and evaluate the ongoing debate about their utility. RECENT FINDINGS: In the last 5 years alone 15 novel neural autoantibody specificities were identified. These include rare neural antibody biomarkers of autoimmune encephalitis, cerebellar ataxia or other movement disorders, including multifocal presentations. SUMMARY: Although the clinical applications of these rare antibody discoveries may be limited by the low number of positive cases, they still provide important diagnostic, prognostic, and therapeutic insights.

Optimizing the diagnostic performance of neural antibody testing for paraneoplastic and autoimmune encephalitis in clinical practice.

The detection of neural antibodies in patients with paraneoplastic and autoimmune encephalitis has majorly advanced the diagnosis and management of neural antibody-associated diseases. Although testing for these antibodies has historically been restricted to specialized centers, assay commercialization has made this testing available to clinical chemistry laboratories worldwide. This improved test accessibility has led to reduced turnaround time and expedited diagnosis, which are beneficial to patient care. However, as the utilization of these assays has increased, so too has the need to evaluate how they perform in the clinical setting. In this chapter, we discuss assays for neural antibody detection that are in routine use, draw attention to their limitations and provide strategies to help clinicians and laboratorians overcome them, all with the aim of optimizing neural antibody testing for paraneoplastic and autoimmune encephalitis in clinical practice.

[Autoimmune encephalitis: psychiatric aspects]. / Autoimmunnye entsefality: psikhiatricheskie aspekty.

Autoimmune encephalitis is a group of diseases researched by both neurologists and psychiatrists. Despite a large number of studies and practical recommendations, the differential diagnosis and early diagnostics still remains an important issue. The most difficult to diagnose are cases that debut as mental disorders and/or occur without neurological symptoms. The literature review presents the current state of the problem with an emphasis on the practice of a psychiatrist.

Lessons in clinical reasoning - pitfalls, myths, and pearls: a woman brought to a halt.

OBJECTIVES: Limitations in human cognition commonly result in clinical reasoning failures that can lead to diagnostic errors. A metacognitive structured reflection on what clinical findings fit and/or do not fit with a diagnosis, as well as how discordance of data can help advance the reasoning process, may reduce such errors. CASE PRESENTATION: A 60-year-old woman with Hashimoto thyroiditis, diabetes, and generalized anxiety disorder presented with diffuse arthralgias and myalgias. She had been evaluated by physicians of various specialties and undergone multiple modalities of imaging, as well as a electromyography/nerve conduction study (EMG/NCS), leading to diagnoses of fibromyalgia, osteoarthritis, and lumbosacral plexopathy. Despite treatment for these conditions, she experienced persistent functional decline. The only definitive alleviation of her symptoms identified was in the few days following intra-articular steroid injections for osteoarthritis. On presentation to our institution, she appeared fit with a normal BMI. She was a long-time athlete and had been training consistently until her symptoms began. Prediabetes had been diagnosed the year prior and her A1c progressed despite lifestyle modifications and 10 pounds of intentional weight loss. She reported fatigue, intermittent nausea without emesis, and reduced appetite. Examination revealed intact strength and range of motion in both the shoulders and hips, though testing elicited pain. She had symmetric hyperreflexia as well as a slowed, rigid gait. Autoantibody testing revealed strongly positive serum GAD-65 antibodies which were confirmed in the CSF. A diagnosis of stiff-person syndrome was made. She had an incomplete response to first-line therapy with high-dose benzodiazepines. IVIg was initiated with excellent response and symptom resolution. CONCLUSIONS: Through integrated commentary on the diagnostic reasoning process from clinical reasoning experts, this case underscores the importance of frequent assessment of fit along with explicit explanation of dissonant features in order to avoid misdiagnosis and halt diagnostic inertia. A fishbone diagram is provided to visually demonstrate the major factors that contributed to the diagnostic error. The case discussant demonstrates the power of iterative reasoning, case progression without commitment to a single diagnosis, and the dangers of both explicit and implicit bias. Finally, this case provides clinical teaching points in addition to a pitfall, myth, and pearl specific to overcoming diagnostic inertia.

Intestinal microbiota regulates the gut-thyroid axis: the new dawn of improving Hashimoto thyroiditis.

Intestinal microbiota plays an indispensable role in the host's innate immune system, which may be related to the occurrence of many autoimmune diseases. Hashimoto thyroiditis (HT) is one of the most common autoimmune diseases, and there is plenty of evidence indicating that HT may be related to genetics and environmental triggers, but the specific mechanism has not been proven clearly. Significantly, the composition and abundance of intestinal microbiota in patients with HT have an obvious difference. This phenomenon led us to think about whether intestinal microbiota can affect the progress of HT through some mechanisms. By summarizing the potential mechanism of intestinal microflora in regulating Hashimoto thyroiditis, this article explores the possibility of improving HT by regulating intestinal microbiota and summarizes relevant biomarkers as therapeutic targets, which provide new ideas for the clinical diagnosis and treatment of Hashimoto thyroiditis.

Characterization of neurological morbidity associated with thyroid antibodies: Hashimoto's encephalopathy and beyond.

BACKGROUND: Hashimoto's Encephalopathy (HE) manifests with various neurologic symptoms associated with elevated thyroglobulin (TG) and/or thyroperoxidase (TPO) antibodies. Some patients with thyroid antibodies exhibit neurological presentations not consistent with HE. This study aims to characterize the spectrum of neurological morbidity in patients with thyroid antibodies. METHODS: We reviewed all patients tested for TG or TPO antibodies from 2010 to 2019. Patients tested for thyroid antibodies as part of a neurological workup for new symptoms were classified into the following categories: patients meeting full criteria for HE, patients with other neuroimmunological disorders, patients with unexplained neurological symptoms not fully meeting HE criteria, and patients with incidental non neuroimmunological disorders. RESULTS: There were 2717 patients with positive thyroid antibodies in the dataset including 227 patients (78% female, age 54 ± 19 years) who met inclusion criteria. Twelve patients (5%) met HE criteria, 30 (13%) had other neuroimmunological disorders, 32 (14%) had unexplained neurological symptoms, and 153 (67.4%) had incidental disorders. In addition to cognitive dysfunction, seizures, movement disorders, motor weakness, and psychosis, HE patients were also more likely to have cerebellar dysfunction, language impairment, and sensory deficits. They were more likely to carry a Hashimoto's thyroiditis diagnosis and had higher titers of thyroid antibodies. They all had a robust response to steroids. CONCLUSION: The neurological spectrum of HE may be wider than previously reported, including frequent cerebellar, sensory, and language dysfunction. A subgroup of thyroid antibody positive patients with unexplained neurological symptoms may represent further expansion of thyroid antibody-related neurological disorders.

Autoimmune encephalitis in a resource-limited public health setting: a case series analysis.

BACKGROUND: Autoimmune encephalitis (AE) consists of a group of acquired diseases that affect the central nervous system. A myriad of phenotypes may be present at the onset. Due to the heterogeneity of clinical presentations, it is difficult to achieve uniformity for the diagnostic and therapeutic processes and follow-up strategies. OBJECTIVE: To describe a series of patients diagnosed with AE in a resource-limited public hospital in southern Brazil and to analyze therapeutics and outcomes. METHODS: We retrospectively reviewed the electronic medical records of patients diagnosed with AE at the Hospital de Clínicas de Porto Alegre from 2014 to 2022. Data collected included clinical presentation, neuroimaging, cerebrospinal fluid testings, electroencephalogram, autoantibodies, treatments, outcomes, follow-up time, degree of neurological impairment, and mortality. RESULTS: Data from 17 patients were retrieved. Eleven cases were classified as definite AE and 6 as possible AE. Autoantibodies were identified in 9 patients. Timing for diagnosis was impacted by the high costs associated with autoantibody testing. Most patients became functionally dependent (82.4%) and most survivors remained with autoimmune-associated epilepsy (75%). Five patients died during hospitalization, and one after a 26-month of follow-up. CONCLUSION: In this resource-limited hospital, patients with AE had a worse clinical outcome than that previously described in the literature. Development of epilepsy during follow-up and mortality were greater, whilst functional outcome was inferior. Autoantibody testing was initially denied in most patients, which impacted the definitive diagnosis and the use of second-line therapies.

ANTECEDENTES: A encefalite autoimune (EA) consiste em um grupo de doenças adquiridas que afetam o sistema nervoso central. OBJETIVO: Descrever uma série de pacientes diagnosticados com EA em um contexto de atenção terciária à saúde com recursos limitados e analisar a terapêutica e os resultados. MéTODOS: Revisamos retrospectivamente os prontuários eletrônicos de pacientes diagnosticados com EA no Hospital de Clínicas de Porto Alegre de 2014 a 2022. Os dados coletados incluíram apresentação clínica, neuroimagem, exames de líquido cefalorraquidiano, eletroencefalograma, autoanticorpos, tratamentos, resultados, tempo de acompanhamento, grau de comprometimento neurológico e mortalidade. RESULTADOS: Dados de 17 pacientes foram coletados. Onze casos foram classificados como EA definitivo e seis como EA possível. Autoanticorpos foram identificados em nove pacientes. O tempo para o diagnóstico foi afetado pelos altos custos associados ao teste de autoanticorpos. A maioria dos pacientes tornou-se funcionalmente dependente (82,4%), e a maioria dos sobreviventes permaneceu com epilepsia autoimune associada (75%). Cinco pacientes faleceram durante a internação, e um após 26 meses de seguimento. CONCLUSãO: No hospital em questão, os pacientes com EA tiveram um desfecho clínico pior do que o previamente descrito na literatura. O desenvolvimento de epilepsia durante o acompanhamento e a mortalidade foram maiores, enquanto o desfecho funcional foi inferior. Os testes de autoanticorpos foram inicialmente negados para a maioria dos pacientes, o que impactou o diagnóstico definitivo e o uso de terapias de segunda linha.